Evidence-Based Reviews

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

Coping by movement. Victims might attempt to cope with stalking through sev­eral means,² including:
   • moving away—trying to avoid contact with the stalker
   • moving with—negotiating a more acceptable form of relationship with the stalker
   • moving against—attempting to harm, constrain, or punish the stalker
   • moving inward—seeking self-control or self-actualization
   • moving outward—seeking the assis­tance of others.

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

 

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

Keeping victims at the center
Several authors have written about the need to return to a victim-centered model of care. This approach (1) puts the vic­tim’s understanding of her (his) situation at the center of victim assistance work and (2) views service providers as consultants in the decision-making process.^20,21 The victim-centered approach to treatment, in which the client has a greater voice and degree of control over interventions, is associated with positive outcomes.^22,23

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

Coping by movement. Victims might attempt to cope with stalking through sev­eral means,² including:
   • moving away—trying to avoid contact with the stalker
   • moving with—negotiating a more acceptable form of relationship with the stalker
   • moving against—attempting to harm, constrain, or punish the stalker
   • moving inward—seeking self-control or self-actualization
   • moving outward—seeking the assis­tance of others.

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

 

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

Keeping victims at the center
Several authors have written about the need to return to a victim-centered model of care. This approach (1) puts the vic­tim’s understanding of her (his) situation at the center of victim assistance work and (2) views service providers as consultants in the decision-making process.^20,21 The victim-centered approach to treatment, in which the client has a greater voice and degree of control over interventions, is associated with positive outcomes.^22,23

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

Coping by movement. Victims might attempt to cope with stalking through sev­eral means,² including:
   • moving away—trying to avoid contact with the stalker
   • moving with—negotiating a more acceptable form of relationship with the stalker
   • moving against—attempting to harm, constrain, or punish the stalker
   • moving inward—seeking self-control or self-actualization
   • moving outward—seeking the assis­tance of others.

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

 

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

Keeping victims at the center
Several authors have written about the need to return to a victim-centered model of care. This approach (1) puts the vic­tim’s understanding of her (his) situation at the center of victim assistance work and (2) views service providers as consultants in the decision-making process.^20,21 The victim-centered approach to treatment, in which the client has a greater voice and degree of control over interventions, is associated with positive outcomes.^22,23

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

 

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

 

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

 

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

 

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

 

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

 

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

The rationale for these recommendations is based on efficacy data, tolerability dif­ferences, FDA-approved indications, and recent FDA approvals with sparse post-marketing data. Of note, there are a lack of robust data for newer antipsychotics (eg, aripiprazole, paliperidone, iloperidone, asenapine, and lurasidone) in effectively and safely treating FEP; however, given the results of other antipsychotics studies, it is likely the efficacy and tolerability of these drugs can be extrapolated from experience with multi-episode patients.

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

 

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

 

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

 

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

 

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

 

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

The rationale for these recommendations is based on efficacy data, tolerability dif­ferences, FDA-approved indications, and recent FDA approvals with sparse post-marketing data. Of note, there are a lack of robust data for newer antipsychotics (eg, aripiprazole, paliperidone, iloperidone, asenapine, and lurasidone) in effectively and safely treating FEP; however, given the results of other antipsychotics studies, it is likely the efficacy and tolerability of these drugs can be extrapolated from experience with multi-episode patients.

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

 

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

 

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

 

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

 

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

 

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery.¹ However, relapse prevention is a major clinical challenge because >80% of patients will relapse within 5 years, and, on average, 40% to 50% of patients with a first-episode schizophrenia will relapse within 2 years depending on the definition used and patient characteristics.² Although there are several explanations and contributing factors to relapses, non­adherence—partial or complete discontinuation of antipsychotics—is a primary risk factor, contributing to a 5-fold increase in relapse risk.³

As such, optimal antipsychotic selection, dosing, and monitoring play an important role in managing this illness. Patients with first-episode psychosis (FEP) are unusual in some ways, compared with patients with multiple episodes of psychosis and represent a different stage of schizophrenia.

In this 2-part series, we will discuss pharmacotherapy for FEP. This article focuses on antipsychotic selection, dosage, and duration of treat­ment among these patients. The second article, in the July 2015 issue, reviews the rationale and evidence for non-standard, first-line thera­pies, including long-acting injectable antipsychotics and clozapine.

Defining FEP
FEP refers to a patient who has presented, been evaluated, and received treatment for the first psychotic episode associated with a schizophre­nia spectrum diagnosis.⁴ FEP is part of a trajectory marked by tran­ sitional periods. The patient transitions from being “healthy” to a prodromal state characterized by: (1) nonpsychotic behav­ioral disturbances such as depression or obsessive-compulsive disorder, (2) attenu­ated psychotic symptoms not requiring treatment, then converting to (3) psychotic symptoms prompting initial presentation for antipsychotic pharmacotherapy, lead­ing to (4) a formal diagnosis of schizo­phreniform disorder and, subsequently, schizophrenia, requiring treatment to sta­bilize symptoms.

There are 2 critical periods along this continuum: prodromal stage and the dura­tion of untreated psychosis (DUP). The prodromal period is a retrospectively iden­tified time where the patient shows initial nonpsychotic disturbances (eg, cognitive and behavioral symptoms) before exhibit­ing clinical diagnostic criteria for a schizo­phrenia spectrum disorder. Approximately one-third of patients exhibiting these symptoms convert to psychosis within 1 year, and early treatment engagement at this stage has been shown to improve out­comes.⁵ The DUP is the time from when a patient has noticeable psychotic symptoms to initiation of drug treatment. The DUP is a consistent predictor of clinical out­come in schizophrenia, including negative symptoms, quality of life, and functional capacity.¹

Antipsychotic selection
Treatment goals for FEP patients include:
   • minimizing the DUP
   • rapidly stabilizing psychosis
   • achieving full symptomatic remission
   • preventing relapse.

Several treatment guidelines for manag­ing schizophrenia offer variable recommen­dations for initial antipsychotic treatment in patients with first-episode schizophre­nia (Table 1).^6-15 Most recom­mend second-generation antipsychotics (SGAs) over first-generation antipsy­chotics (FGAs)^6,8,9,13,15 with specific recom­mendations on minimizing neurologic and metabolic adverse effects—to which FEP patients are susceptible—by avoid­ing high-potency and neurotoxic FGAs (eg, haloperidol and fluphenazine),⁷ clo­zapine,^11,14 olanzapine,¹¹ or ziprasidone.¹⁴ Two guidelines—the National Institute for Health and Care Excellence and the Scottish Intercollegiate Guidelines Network—do not state a preference for antipsychotic selection.^10,12

The rationale for these recommendations is based on efficacy data, tolerability dif­ferences, FDA-approved indications, and recent FDA approvals with sparse post-marketing data. Of note, there are a lack of robust data for newer antipsychotics (eg, aripiprazole, paliperidone, iloperidone, asenapine, and lurasidone) in effectively and safely treating FEP; however, given the results of other antipsychotics studies, it is likely the efficacy and tolerability of these drugs can be extrapolated from experience with multi-episode patients.

Study design and demographics. Research studies of FEP share some simi­larities in study design; however, there is enough variability to make it difficult to compare studies and generalize find­ings (Table 2).¹⁶ The variability of DUP is a limitation when comparing studies because it is a significant predic­tor of clinical outcome. Patients who abuse substances—and often are more challeng­ing to treat¹⁷—typically are excluded from these trials, which could explain the high response rate documented in studies of first-episode schizophrenia.

 

In addition, some FEP patients included in clinical trials might not be truly antipsy­chotic naïve; an estimated 25% to 75% of patients in these studies are antipsychotic naïve. This is an important consideration when comparing data on adverse effects that occur early in treatment. Additionally, acknowledging the advantages and disad­vantages of how to handle missing data is critical because of the high dropout rate observed in these studies.¹⁸

Efficacy. There is a high response rate to antipsychotic therapy—ranging from 46% to 96%, depending on the study—in patients with first-episode schizophrenia.³ The response mainly is seen in reduction of positive symptoms because typically negative and cognitive symptoms do not respond to antipsychotics. One study reported only 29% of patients achieved both positive and negative symptom remis­sion.¹⁹ It is likely that secondary negative symptoms caused by social withdrawal, reduced speech, and avoidance improve when positive symptoms subside, but pri­mary negative symptoms endure.In general, there is a lack of evidence suggesting that 1 antipsychotic class or agent is more effective than another. Studies mainly assess effectiveness using the primary outcome measure of all-cause discontinuation, such as the Clinical Antipsychotic Trials of Intervention Effectiveness study.²⁰ This outcome mea­sure is a mixture of patient preference, tol­erability, and efficacy that provides a more generalizable gauge on how well the treat­ment works in the clinic rather than tightly regulated settings such as clinical trials. A recent meta-analysis supports no differ­ences in efficacy among antipsychotics in early-episode psychosis.²¹

 

Tolerability. Because there are no significant differences among antipsychotic classes or agents in terms of efficacy in first-episode schizophrenia, drug selection is guided mainly by (1) the adverse effect profile and (2) what should be avoided depending on patient-specific variables. Evidence sug­gests first-episode patients are more sen­sitive to adverse effects of antipsychotics, particularly neurologic side effects (see this article at CurrentPsychiatry.com for a table comparing adverse effects of antipsychot­ics in first-episode psychosis).^18,22-29 Overall adverse effect profiles remain similar across FEP or multi-episode patients, but tend to be more exaggerated in drug-naïve patients with FEP.

Regarding FGA side effects, McEvoy et al¹⁸ demonstrated the neuroleptic threshold occurs at 50% lower haloperi­dol dosages in patients with first-episode schizophrenia (2.1 mg/d) compared with multi-episode schizophrenia (4.3 mg/d). Other trials suggest SGAs are associated with a lower risk of extrapyramidal side effects (EPS) or use of adjunctive therapies such as anticholinergic drugs or benzo­diazepines.^23-27 An exception to this state­ment is that higher risperidone dosages (≥4 to 6 mg/d) have been found to have higher rates of EPS and use of adjunctive medica­tions to treat these symptoms in FEP.²⁶ This is important because studies report higher discontinuation rates with more severe adverse effects of antipsychotics.

Cardiometabolic effects are of particular concern in first-episode patients because most weight gain happens in the first 3 to 4 months of treatment and remains throughout the first year.^18,24,29,30 Studies have shown that olanzapine, quetiap­ine, and risperidone are associated with more clinically significant weight gain compared with haloperidol and ziprasi­done.^23-25 Olanzapine-associated weight gain has been reported to be twice that of quetiapine and risperidone.¹⁸ Regardless, the EUFEST trial did not find a difference in clinically significant weight gain after 12 months among the antipsychotics studied, including haloperidol and ziprasidone.²⁵

Weight gain associated with these anti­psychotics is accompanied by changes in fasting triglycerides, glucose, total choles­terol,²³ and high-density lipoprotein cho­lesterol as well as an increase in body mass index (BMI) categorization²⁹ (eg, shift from normal to overweight).^18,25 Patients with lower baseline BMI and in racial minor­ity groups might experience more rapid weight gain regardless of antipsychotic selection.^29,30

Hyperprolactinemia could be under-recognized and could contribute to early treatment discontinuation.³¹ Evidence in patients with first-episode schizophrenia suggests similar outcomes as those seen in multi-episode patients, in whom ris­peridone is associated with higher pro­lactin elevations and clinically significant hyperprolactinemia (eg, galactorrhea and gynecomastia) compared with olanzapine, quetiapine, and low-dose haloperidol.^18,23,24 However, there is a lack of studies that assess whether long-term therapy with strong D2 receptor antagonists increases the risk of bone demineralization or path­ological fractures when started before patients’ bones reach maximum density in their mid-20s.³¹

Antipsychotic dosing
Given the high rate of treatment response in FEP and patients’ higher sensitivity to antipsychotic adverse effects, particularly EPS, guidelines recommend antipsychotic dosages lower than those used for multi-episode schizophrenia,¹¹ especially FGAs. Based on trial data, commonly used dos­ages include:
   • haloperidol, ≤5 mg/d^23-25,29
   • olanzapine, 10 mg/d^18,23,25,29
   • risperidone, ≤4 to 6 mg/d.^18,24,29,32

In general, haloperidol and risperidone, 2 to 3 mg/d, were well tolerated and effec­tive in trials. Higher quetiapine dosages of 500 to 600 mg/d could be required.^11,18,25

According to a survey on prescribing practices of antipsychotic selection and dosing in first-episode schizophrenia,4 clinical prescribing practices tend to use unnecessarily high initial antipsychotic dosing compared with trial data. There also is variability in the usual target anti­psychotic dosage ranging from 50% lower dosages to normal dosages in chronic schizophrenia to above FDA-approved maximum dosages for olanzapine (which may be necessary to counteract tobacco-induced cytochrome P450 1A2 enzyme induction).

In addition, these clinicians reported prescribing aripiprazole, an antipsychotic with weaker evidence (eg, case reports, case series, open-label studies) support­ing its efficacy and tolerability in FEP. These prescribing practices could reflect attempts to reduce the DUP and achieve symptom remission, so long as tolerability is not a concern.

Essentially, prescribed dosages should be based on symptom improvement and tolerability. This ideal dosage will vary as illustrated by Kapur et al,³³ who reported that FEP patients (N = 20) given haloper­idol, 1 mg or 2.5 mg/d, had D2 receptor occupancy rates of 38% to 87%, which was significantly dose-related (1 mg/d mean = 59%, 2.5 mg/d mean = 75%). Clinical response and EPS significantly increased as D2 receptor occupancy exceeded 65% and 78%, respectively.

Antipsychotic response
When should you expect to see symp­tom improvement in patients with first-episode schizophrenia?
Emsley et al³⁴ reported a 77.6% response rate among first-episode patients (N = 522) treated with low dosages of risperidone (mean modal dosage [MMD] = 3.3 mg/d) and haloperidol (MMD = 2.9 mg/d). They found variable response times that were evenly dispersed over a 10-week period. Nearly one-quarter (22.5%) did not respond until after week 4 and 11.2% did not respond until after week 8. In a study of FEP patients (N = 112) treated with olanzapine (MMD = 11.8 mg/d) or risperi­done (MMD = 3.9 mg/d), Gallego et al³⁵ reported a cumulative response of 39.6% at week 8 and 65.1% at week 16.

 

Although there is evidence that, among multi-episode patients, early nonresponse to antipsychotic therapy could predict subsequent nonresponse,³⁶ the evidence is mixed for first-episode schizophrenia. Studies by Emsley et al³⁴ and Gallego et al³⁵ did not find that early nonresponse at weeks 1 or 2 predicted subsequent nonre­sponse at week 4 or later. However, other studies support the idea that early nonre­sponse predicts subsequent nonresponse and early antipsychotic response predicts future response in first-episode patients, with good specificity and sensitivity.^37,38

Overall, treatment response in first-episode schizophrenia is variable. An adequate antipsychotic trial may be lon­ger, 8 to 16 weeks, compared with 4 to 8 weeks in multi-episode patients. Because research suggests that failure to respond to treatment may lead to medication non­adherence,³⁹ it is reasonable to consider switching antipsychotics when a patient experiences minimal or no response to antipsychotic therapy at week 2; however, this should be a patient-specific decision.

How long should you continue therapy after symptom remission?
There is a lack of consensus on the dura­tion of therapy for a patient treated for first-episode schizophrenia because a small percentage (10% to 20%) do not relapse after the first psychotic episode.³ In general, treatment guidelines and expert consensus statements recommend at least 1 to 2 years of treatment before considering a discon­tinuation trial.^7,10-11 Discuss the benefits and risks of maintenance treatment with your patient and obtain informed consent. With patients with minimal insight, obtaining proper consent is not possible and the phy­sician must exercise judgment unilaterally, if necessary, after educating the family.

After at least 12 months of treatment, antipsychotic therapy could continue indefinitely, depending on patient-specific factors. There are no predictors for identi­fying patients who do not require mainte­nance therapy beyond the first psychotic episode. The absence of negative and cog­nitive deficits could provide clues that a patient might be a candidate for antipsy­chotic tapering.

Predicting the treatment course
Research investigating clinical predic­tors or biomarkers that forecast whether a patient will respond to treatment is pre­liminary. Many characteristics have been identified (Table 3^{1,3,4,23,25,40}) and include shorter DUP,¹ poorer premorbid function,³ antipsychotic discontinuation,³ a trusting patient-doctor relationship,⁴¹ and antipsychotic-related adverse effects,^23,25 which are predictive of response, nonre­sponse, relapse, adherence, and nonadher­ence, respectively.
 

Bottom Line
The goals of pharmacological treatment of first-episode schizophrenia are to minimize the duration of untreated psychosis and target full remission of positive symptoms using the lowest possible antipsychotic dosages. Pharmacotherapy should continued for 1 to 2 years, with longer duration considered if it is discussed with the patient and with vigilant monitoring for adverse effects and suboptimal medication nonadherence to prevent relapse.
 

Editor’s note: The second article in this series in the July 2015 issue reviews the rationale and evidence for non-standard, first-line therapies, including long-acting injectable antipsychotics and clozapine.

 

Related Resources
• Recovery After an Initial Schizophrenia Episode (RAISE) Project Early Treatment Program. National Institute of Mental Health. http://raiseetp.org.
• Martens L, Baker S. Promoting recovery from first epi­sode psychosis: a guide for families. Centre for Addiction and Mental Health. http://www.camh.ca/en/hospital/ Documents/www.camh.net/AboutCAMH/Guideto CAMH/MentalHealthPrograms/SchizophreniaProgram/ 3936PromotingRecoveryFirstEpisodePsychosisfinal.pdf.

Drug Brand Names
Aripiprazole • Abilify                Lurasidone • Latuda
Asenapine • Saphris                Olanzapine • Zyprexa
Clozapine • Clozaril                 Paliperidone • Invega
Fluphenazine • Prolixin            Quetiapine • Seroquel
Iloperidone • Fanapt               Risperidone • Risperdal
Haloperidol • Haldol                Ziprasidone • Geodon

 

Disclosures
Dr. Gardner reports no financial relationships with any companies whose products are mentioned in this article or with manufacturers of competing products.
Dr. Nasrallah is a consultant to Acadia, Alkermes, Lundbeck, Janssen, Merck, Otsuka, and Sunovion, and is a speaker for Alkermes, Lundbeck, Janssen, Otsuka, and Sunovion.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

 

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

 

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

 

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

 

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Recent studies suggest that most older adults main­tain sexual interest well into late life; many, however, experience sexual dysfunction. This article provides psychiatric practitioners with current information regard­ing sexuality and aging, as well as psychiatric and systemic medical comorbidities and sexual side effects of medi­cations. Practice guidelines for assessing and managing sexual dysfunction have been developed for use in many medical specialties, and such guidance would be welcome in psychiatric practice.

This article addresses the myth of “geriatric asexuality” and its potential impact on clinical practice, the effects of age-related physiological changes on sexual activity, the importance of sexuality in the lives of older adults, and sensitive questions clinicians can pose about geriatric sexu­ality. We also will discuss:  
   • the importance of including a sexual assessment in the comprehensive psychiatric evaluation  
   • recognizing sexual dysfunction  
   • providing appropriate management within a multi-disciplinary, collaborative approach.

Sexuality after 65
Regardless of age, sexual activity can provide a sense of com­fort and elicit a positive emotional and physical response.¹ Hillman² defined human sexuality as any combination of sex­ual behavior, emotional intimacy, and sense of sexual identity.

Sexuality in the aging population gen­erally is an understudied area, obscured by the myth of “geriatric asexuality” and subject to numerous psychosocial vari­ables.¹ Previous research, focused on a bio­logical perspective of sexuality, has largely overlooked psychological and social influ­ences.³ It has been assumed that, with age, physical and hormonal changes or chronic illness ordinarily reduce or eliminate sex­ual desire and sexual behavior.³ However, the majority of older adults (defined as age ≥65) report a moderate-to-high level of sexual interest well into late life.^1,3

Sexual function remains a subject often neglected in psychiatry. Sexual dysfunc­tions, as described in the DSM-5,⁴ do not include age-related changes in sexual func­tion. In addition to physiological changes, sexual difficulties can result from relation­ship strain, systemic medical or psychi­atric disorders, and sexual side effects of medications.

CASE REPORT
Mr. C, age 71 and married, is being treated for a major depressive episode that followed a course of shingles and persistent posther­petic neuralgia. Medications are: escitalo­pram, 20 mg/d; pregabalin, 150 mg/d; and ramipril, 5 mg/d. Mr. C is physically active and involved in social activities; he has no substance use history. He attends clinic visits with his wife.

Mr. C reports that despite significant improvement of his depressive and pain symptoms, he now experiences sexual dif­ficulties, which he seems hesitant to discuss in detail. According to his wife, Mr. C appears to lack sexual desire and has difficulty initi­ating and maintaining an erection. She asks Mr. C’s psychiatrist whether she should stop her estrogen treatment, intended to enhance her sexual function, given that the couple is no longer engaging in sexual intercourse.

Mr. C admits to missing physical inti­macy; however, he states, “If I have to make a choice between having sex with my wife and getting this depression out of my head, I’m going to pick getting rid of the depres­sion.” Mrs. C says she is becoming dissatisfied with their marriage and the limited time she and her husband now spend together. Mr. C’s psychiatrist suggests that Mr. C and his wife undergo couples counseling.

Physiological changes with aging
In both women and men, the reproductive system undergoes age-related physiologi­cal changes.

Women. In women, the phase of decline in ovarian function and resulting decline in sex steroid production (estradiol and pro­gesterone) is referred to as the climacteric, with menopause being determined retro­spectively by the cessation of a menstrual period for 1 year.⁵

Menopausal symptoms typically occur between age 40 and 58; the average age of menopause is 51.^6,7 Both estradiol and pro­gesterone levels decline with menopause, and anovulation and ovarian failure ensue. A more gradual decline of female testoster­one levels also occurs with aging, starting in the fourth decade of life.⁸

Clinical manifestations of menopause include vasomotor symptoms (ie, “hot flushes”), sleep disturbances, anxiety and depressive symptoms, decreased bone min­eral density, and increased risk of cardio­vascular disease.^6,7 Loss of estrogen as well as continued loss of testosterone can result in dyspareunia because of atrophy and decreased vulvar and vaginal lubrication, with sexual excitement achieved less quickly, and a decreased intensity of orgasm.⁷

Men. Research has shown that testosterone levels are highest in men in the second and third decades, with a subsequent gradual decline.⁹ Older men with a low testosterone level are described as experiencing “late-onset hypogonadism,” also known by the popularized term “andropause.”¹⁰ This is attributed to decreased activity at the tes­ticular and hypothalamic levels.¹⁰

Nonetheless, only a small fraction of older men with confirmed androgen defi­ciency are clinically symptomatic.^11,12 Low testosterone is associated with decreased libido; it can hinder morning erections, contribute to erectile dysfunction, and result in erections that require physical stimulation.¹³

 

Notably, erectile dysfunction involves several other etiologic factors: psychiatric (eg, relationship difficulties, depression), neurogenic (eg, spinal cord injury), endo­crine (eg, hyperprolactinemia), arteriogenic (eg, hypertension, type 2 diabetes mellitus), and drug-induced (eg, antidepressants, antihypertensives).¹⁴ A low testosterone level also has been associated with potential cognitive changes, decreased bone mineral density, metabolic syndrome (eg, increased risk of type 2 diabetes mellitus), and cardio­vascular mortality.¹⁰

Effects on sexual activity. How much age-related physiological changes impact sexual practices in the geriatric popula­tion is uncertain. A study following 3,302 women through menopause over 6 years found some decline in sexual activity; how­ever, this decline was not associated with increased sexual pain, decreased desire, or lack of arousal.¹⁵ Men continue to find ways to remain sexually active despite physiolog­ical changes (eg, erectile difficulties), but the etiology of sexual dysfunction in later life remains multi-modal, involving physical, psychological, and relational factors.^16,17

Sexual practices in older adults
Researchers for the National Social Life, Health, and Aging Project (NSHAP) have examined sexual activities, behaviors, and problems in >3,000 older community-dwelling men and women across the United States, using information collected from in-home interviews.18 This study found that sexual activity, defined as any mutually voluntary sexual contact with another person, declines with age; how­ever, even in the oldest age group (age 75 to 85), 39% of men and 17% of women reported being sexually active in the last 12 months. Among these persons, 54% reported sexual activity at least 2 times per month; 23% reported having sex at least once a week; and 32% reported engaging in oral sex. Partner availability predicted sexual activity.

Respondents with self-reported poor physical health were more likely to experi­ence sexual problems (eg, difficulty with erection or lubrication, dyspareunia, and lack of pleasure). The most commonly reported reason for sexual inactivity in those with a spouse or other intimate partner was the male partner’s poor physical health.¹⁸

A longitudinal study, part of the Women’s Healthy Ageing Project, examined changes in sexual function at late menopause com­pared with early menopause. Although the researchers also found an age-related decrease in sexual activity, 50% of their late-menopause respondents (mean age, 70; range, 64 to 77) still reported sexual activity in the previous month, with 35% of this subgroup reporting sexual activity at least once a week; 83% reported sexual thoughts or fantasies.¹⁹ Availability of a partner, absence of a history of depression, moder­ate (compared with no) alcohol consump­tion, and better cognitive function were significantly associated with a higher level of sexual activity.¹⁹

In the Successful Aging Evaluation study, conducted in San Diego County, California, community-dwelling older partnered adults age 50 to 99 (mean age, 75) were surveyed about their sexual health after a cogni­tive screen by telephone²⁰; rating scales for depression, anxiety, and physical function also were included. Results included 41% of men and 35% of women reporting sexual activity at least once a week, and only 21% of men and 24% of women reporting no sex­ual activity in the previous year. Depressive symptoms were most highly correlated with lack of sexual activity.²⁰

Overall, these studies reveal that posi­tive physical and mental health, access to a healthy partner, and a positive attitude toward sex are correlated with sexual activ­ity in later life, whereas barriers to sexual activity include lack of a healthy sexual partner, depression, and chronic systemic medical illnesses, such as coronary artery disease or type 2 diabetes mellitus.^13,17,21-24 Sexual activity and satisfaction have been positively associated with perceived general well-being and self-esteem.^25,26 Conversely, sexual difficulties secondary to disease can be a source of distress for couples.²⁷

Possibly overlooked? It is important to note that sexuality itself is a subjective area. Psychological intimacy is a universal phe­nomenon, and its physical expression may evolve as couples accommodate to age-related bodily changes. Means of achieving physical closeness, other than intercourse (eg, intimate touching, hand holding, kiss­ing, or even acts of caretaking), may not be adequately captured in studies that look specifically at sexual activity.

Taking a sexual history in a geriatric patient
Because sexuality can be an uncomfort­able topic for geriatric patients to discuss, sexual problems in this population often go unrecognized. It has been suggested that psychiatrists are more likely to inquire about sexual activity in middle-aged patients than geriatric patients with the same psychiatric presentation—perhaps illustrating a bias against taking a sexual history from a geriatric patient.²⁸ However, because many older patients can experi­ence depression or anxiety disorders in relation to normal sexual changes or sex­ual dysfunction within the context of their intimate relationships, it is essential to bring these issues to light.

Although a sexual history may not be the focus of a first clinical encounter, consider making such an assessment at a relatively early stage of patient care. The importance of such dialogue is 2-fold:
   • It demonstrates to the patient that talking about sexuality in a respectful and empathic manner is appropriate and can encourage patients to communicate more effectively about sexuality with clinicians and with sexual partners.
   • It helps elicit medical information needed to make an accurate diagnosis and provide adequate management.

 

How to begin. As a starting point to taking a sexual history, an open-ended invitation for the geriatric patient to share informa­tion may be best, such as “What would you like to tell me about your sexual life?” See further suggestions (Table 1) and examples of more detailed questions to ask once a dialogue has been initiated (Table 2). Additional factors that may contribute to sexual dysfunction are presented in Table 3.^1,27,29,30

CASE CONTINUED
In Mr. C’s case, an assessment of his sexual history, including risk factors for sexual dysfunction, is completed. Results from laboratory investigations, including a total testosterone level, are within normal limits.

Mr. C asks about using medications with fewer sexual side effects (he has been taking 3 medications that can contribute to sexual dysfunction). A gradual cross-taper of esci­talopram, 20 mg/d, to mirtazapine, 45 mg/d, is implemented, along with tapering prega­balin to 50 mg/d.

Mr. C’s psychiatric and pain symptom improvement is maintained. He notices a boost in his sexual desire but has minimal improvement in erectile dysfunction. He is encouraged to speak with his primary care physician about an antihypertensive agent with less impact on sexual function, as well as therapeutic agents for erectile dysfunc­tion; these, he declines.

At a subsequent visit, Mr. C reports feeling less apprehension about sexual performance. He is now willing to consider further medica­tion options with his primary care physician, and agrees to a recommendation for couples psychotherapy.

As illustrated in Mr. C’s case, the recom­mended sexual assessment and manage­ment strategies to consider at a minimum in psychiatric practice are listed in Table 4.

STI risk in geriatric patients
The risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), often is overlooked in sexually active older adults. Although STIs are more common among younger adults, there is recent evidence of increased incidence in the geriatric population31 (with the high­est risk of incident HIV and some STIs in older men who have sex with men³²). These increased rates can be explained, at least in part, by:
   • older men being less likely to use a condom during sexual activity
   • promotion of viral entry in older women through a drier, thinner vaginal wall
   • increased longevity of HIV-positive persons.³¹

Routine STI screening is not warranted in all older adults, but education and prevention strategies in sexually active seniors who are at greater risk of STIs are recommended. Particularly, clinicians should seek opportunities to discuss risk factors and safe sex practices (eg, using condoms, limiting number of sexual part­ners, practicing good hygiene, engaging in preventive care), and provide behavioral counseling where appropriate.^31,33

Additional considerations in geriatric sexuality
Because psychiatric and systemic medical conditions can hinder sexual function, it is essential to identify and manage these conditions. Several neuropsychiatric dis­orders, including mood and neurocogni­tive disorders, can not only cause sexual dysfunction, but also can raise ethical dilemmas for clinicians, such as reduced decisional capacity in cognitively impaired patients to consent to sexual activity.^1,34

In some patients, psychological, envi­ronmental, and pharmacological treatment options may help. A phosphodiesterase type 5 inhibitor for erectile dysfunction can be prescribed by the primary care phy­sician, a psychiatrist, or another specialist, depending on the physician’s expertise and comfort level.

Sequencing of sexual dysfunction. Notably, there is a common paradox in mood disorders. Decreased sexual interest or performance may represent an aspect of anhedonia associated with depres­sion, whereas sexual dysfunction could also result from medication use (particularly that of serotonergic antidepressants, such as selective serotonin reuptake inhibitors and serotonin-norepinephrine inhibitors), even as other depressive symptoms improve. Therefore, it is critical to analyze sequencing of sexual dysfunction—as part of the pre­senting mood symptoms or dysfunction induced by antidepressant treatment.

Geriatric sexuality in the digital age. Because older adults represent a rapidly growing segment of digital device users,³⁵ Internet use is likely to play a role in the future of sexuality and “digital intimacy,” in that older adults can engage in online sexual activities. The Internet also can be a tool to access medical education.

Related Resources
• Burghardt KJ, Gardner KN. Sildenafil for SSRI-induced sexual dysfunction. Current Psychiatry. 2013;12(4):29-32,A.
• Maciel M, Laganà L. Older women’s sexual desire prob­lems: biopsychosocial factors impacting them and barriers to their clinical assessment [published online January 5, 2014]. Biomed Res Int. 2014;2014:107217. doi: 10.1155/2014/107217.

Drug Brand Names
Bupropion • Wellbutrin, Zyban                   Mirtazapine • Remeron
Carbamazepine • Tegretol                         Oxcarbazepine • Trileptal
Clonidine • Catapres                                 Phenobarbital • Luminal
Donepezil • Aricept                                   Phenytoin • Dilantin
Escitalopram • Lexapro                             Pregabalin • Lyrica
Gabapentin • Neurontin                            Ramipril • Altace
Lamotrigine • Lamictal                              Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                       Trazodone • Desyrel
Memantine • Namenda                             Valproic acid • Depakote

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Lack of insight or “unawareness of illness” occurs within a set of self-assessment problems commonly seen in schizophrenia.¹ In the clinical domain, people who do not realize they are ill typically are unwilling to accept treatment, including medication, with potential for worsened illness. They also may have difficulty self-assess­ing everyday function and functional potential, cognition, social cognition, and attitude, often to a variable degree across these domains (Table 1).^1-3

Self-assessment of performance can be clinically help­ful whether performance is objectively good or bad. Those with poor performance could be helped to attempt to match their aspirations to accomplishments and improve over time. Good performers could have their functioning bolstered by recognizing their competence. Thus, even a population whose performance often is poor could ben­efit from accurate self-assessment or experience additional challenges from inaccurate self-evaluation.

This article discusses patient characteristics associated with impairments in self-assessment and the most accu­rate sources of information for clinicians about patient functioning. Our research shows that an experienced psy­chiatrist is well positioned to make accurate judgments of functional potential and cognitive abilities for people with schizophrenia.

Patterns in patients with impaired self-assessment
Healthy individuals routinely overestimate their abilities and their attractiveness to others.⁴ Feedback that deflates these exag­gerated estimates increases the accuracy of their self-assessments. Mildly depressed individuals typically are the most accurate judges of their true functioning; those with more severe levels of depression tend to underestimate their competence. Thus, sim­ply being an inaccurate self-assessor is not “abnormal.” These response biases are con­sistent and predictable in healthy people.

People with severe mental illness pose a different challenge. As in the following cases, their reports manifest minimal cor­relation with other sources of information, including objective information about performance.

CASE 1
JR, age 28, is referred for occupational therapy because he has never worked since graduat­ing from high school. He tells the therapist his cognitive abilities are average and intact, although his scores on a comprehensive cog­nitive assessment suggest performance at the first percentile of normal distribution or less. His self-reported Beck Depression Inventory (BDI) score is 4. He says he would like to work as a certified public accountant, because he believes he has an aptitude for math. He admits he has no idea what the job entails, but he is quite motivated to set up an interview as soon as possible.

CASE 2
LM, age 48, says his “best job” was managing an auto parts store for 18 months after he earned an associate’s degree and until his second psychotic episode. His most recent work was approximately 12 years ago at an oil-change facility. He agrees to discuss employment but feels his vocational skills are too deteriorated for him to succeed and requests an assessment for Alzheimer’s disease. His cognitive perfor­mance averages in the 10th percentile of the overall population, and his BDI score is 18. Tests of his ability to perform vocational skills sug­gest he is qualified for multiple jobs, including his previous technician position.

Individuals with schizophrenia who report no depression and no work history routinely overestimate their functional potential, whereas those with a history of unsuccessful vocational attempts often underestimate their functional potential. Inaccurate self-assessment can contrib­ute to reduced functioning—in JR’s case because of unrealistic assessment of the match between skills and vocational poten­tial, and in LM’s case because of overly  pessimistic self-evaluation. For people with schizophrenia, inability to self-evaluate can have a bidirectional adverse impact on func­tioning: overestimation may lead to trying tasks that are too challenging, and under­estimation may lead to reduced effort and motivation to take on functional tasks.

Metacognition and introspective accuracy
“Metacognition” refers to self-assessment of the quality and accuracy of performance on cognitive tests.^5-7 Problem-solving tests— such as the Wisconsin Card Sorting test (WCST), in which the person being assessed needs to solve the test through performance feedback—are metacognition tests. When errors are made, the strategy in use needs to be discarded; when responses are correct, the strategy is retained. People with schizo­phrenia have disproportionate difficulties with the WCST, and deficits are especially salient when the test is modified to measure self-assessment of performance and ability to use feedback to change strategies.

“Introspective accuracy” is used to describe the wide-ranging self-assessment impairments in severe mental illness. Theories of metacognition implicate a broad spectrum, of which self-assessment is 1 component, whereas introspective accuracy more specifically indicates judg­ments of accuracy. Because self-assessment is focused on the self, and hence is intro­spective, this conceptualization can be applied to self-evaluations of:
   • achievement in everyday functioning (“Did I complete that task well?”)
   • potential for achievement in everyday functioning (“I could do that job”)
   • cognitive performance (“Yes, I remembered all of those words”)
   • social cognition (“He really is angry”).

 

Domains of impaired introspective accuracy
Everyday functioning. The 3 global domains of everyday functioning are social outcomes, productive/vocational out­comes, and everyday activities, including residential independence/support for peo­ple with severe mental illness. Two areas of inquiry are used in self-assessing everyday functioning: (1) what are you doing now and (2) what could you do in the future? For people with schizophrenia, a related question is how perceived impairments in everyday functioning are associated with subjective illness burden.

People with schizophrenia report illness burden consistent with their self-reported disability, suggesting their reports in these domains are not random.⁸ Studies have consistently found, however, that these patients report:
   • less impairment on average in their everyday functioning than observed by clinicians
   • less subjective illness burden com­pared with individuals with much less severe illnesses.

Their reports also fail to correlate with cli­nicians’ observations.9 Patients with schizo­phrenia who have never been employed may report greater vocational potential than those employed full-time. Interestingly, patients who were previously—but not currently—employed reported the least vocational potential.¹⁰ These data suggest that experience may be a factor: individuals who have never worked have no context for their self-assessments, whereas people who are persistently unemployed may have a perspective on the challenges associated with employment.

In our research,⁹ high-contact clinicians (ie, case manager, psychiatrist, therapist, or residential facility manager) were bet­ter able than family or friends to generate ratings from an assessment questionnaire that correlated with performance-based measures of patients’ ability to perform everyday functional skills. The ratings were generated across multiple functional status scales, suggesting that the rater was more important than the specific scale. We concluded that high-contact clinicians can generate ratings of everyday functioning that are convergent with patients’ abilities, even when they have no information about actual performance scores.

Cognitive performance. When self-reported cognitive abilities are correlated with the results of performance on neuro­psychological assessments, the results are quite consistent. Patients provide reports that do not correlate with their objective performance.¹¹ Interestingly, when clini­cians were asked to use the same strategies as patients to generate ratings of cognitive impairment, clinician ratings had consider­ably greater evidence of validity. In several studies, patients’ ratings of their cognitive performance did not correlate with their neuropsychological test performance, even though they had just been tested on the assessment battery. Ratings by clinicians or other high-contact informants (who were unaware of patients’ test performance) were much more strongly related to patients’ objective test performance, compared with patient self-reports.¹²

The convergence of clinician ratings of cognitive performance with objective test data has been impressive. Correlation coef­ficients of at least r = 0.5, reflecting a moder­ate to large relationships between clinician ratings and objective performance, have been detected. Individual cognitive test domains, such as working memory and processing speed, often do not correlate with each other or with aspects of everyday functioning to that extent.¹³ These data sug­gest that a clinician assessment of cognitive performance, when focused on the correct aspects of cognitive functioning, can be a highly useful proxy for extensive neuropsy­chological testing.

Social cognitive performance. Introspective accuracy for social cognitive judg­ments can be assessed similarly to the strategies used to assess the domains of everyday functioning and cognitive perfor­mance. Patients are asked to complete a typi­cal social cognitive task, such as determining emotions from facial stimuli or examin­ing the eye region of the face, to determine the mental state of the depicted person. Immediately after responding to each stimu­lus, participants rate their confidence in the correctness of that response.

Consistent with the pattern of introspec­tive accuracy for everyday functioning, patients with schizophrenia tend to make more high-confidence errors than healthy individuals on social cognitive tasks. That is, the patients are less likely to realize when they are wrong in their judgments of social stimuli. A similar pattern has been found for mental state attribution,¹⁴ rec­ognition of facial emotion from the self,¹⁵ and recognition of facial emotion from others.¹⁶ These high-confidence errors also are more likely to occur for more difficult stimuli, such as faces that display only mildly emotional expressions. These dif­ficulties appear to be specific to judgments in an immediate evaluation situation. When asked to determine if the behavior of another individual is socially appropri­ate, individuals with schizophrenia are as able as healthy individuals to recognize social mistakes.¹⁷ This work suggests that, at least within the domain of social cogni­tion, introspective accuracy impairment is not caused by generalized poor judgment, just as self-assessments of disability and illness burden are generated at random.

Choosing a reliable informant
If a clinician has not had adequate time or exposure to a patient to make a cogni­tive or functional judgment, what should the strategy be? If asking the patient is uninformative, who should be asked? Our group has gathered information that may help clinicians identify informants who can provide ratings of cognitive perfor­mance and everyday functioning that are convergent with objective evidence.

In a systematic study of validity of reports of various informants, we com­pared correlations between reports of competence of everyday functioning with objective measures of cognitive test per­formance and ability to perform everyday functional skills. Our findings:
   • Patient reports of everyday function­ing were not correlated with performance-based measures for any of 6 rating scales.⁹
   • Clinician reports of everyday func­tioning were correlated with objective per­formance across 4 of 6 rating scales.
   • Correlations between ratings gener­ated by friend or relative informants and other information were almost shocking in their lack of validity (Table 2).⁹

 

We concluded that ratings generated by a generic informant—someone who simply knows the patient and is willing to provide ratings—are highly likely to be uninformative. If a friend or relative provides information of limited useful­ness, the report could easily lead to clinical decisions with high potential for bad out­comes. For example, attempts could fail to transition someone with impaired every­day living skills to independent living, or a patient whose potential is underesti­mated might not be offered opportunities to achieve attainable functional goals.

We found that the closer the rater was to a full caregiver role, the better and more accurate the information obtained. Caregivers who had regular contact with patients had much more valid rat­ings when performance on functionally relevant objective measures was consid­ered. Patients with caregivers had greater impairments in everyday outcomes, how­ever, suggesting that this subset was more impaired than the overall sample. For patients without caregivers, other sources of information—including careful obser­vation by high-contact clinicians—seem to be required to generate a valid assessment of functioning.

Direct functional implications of impaired introspective accuracy
Clinical effects of reduced awareness of ill­ness include reduced adherence to medi­cation, followed by relapse, disturbed behavior, leading to emergency room treat­ments or acute admissions, and—more rarely—disturbed behavior associated with violence or self-harm. Relapses such as these can adversely affect brain structure and function, with declines in cognitive functioning early in the illness.

Our recent study¹⁸ quantifies the direct impact of impairments in introspective accuracy on everyday functioning. We asked 214 individuals with schizophrenia to self-evaluate their cognitive ability with a systematic rating scale and to self-report their everyday functioning in social, voca­tional, and everyday activities domains. We used performance-based measures to assess their cognitive abilities and everyday functional skills. Concurrently, high-contact clinicians rated these same abilities with the same rating scales. We then predicted everyday functioning, as rated by the cli­nicians, with the discrepancies between self-assessed and clinician-assessed func­tioning, and patients’ scores on the perfor­mance-based measures.

Impaired introspective accuracy, as indexed by difference scores between cli­nician ratings and self-reports, was a more potent predictor of everyday functional deficits in social, vocational, and every­day activities domains than scores on performance-based measures of cognitive abilities and functional skills. Even when we analyzed only deficits in introspective accuracy for cognition as the predictor of everyday outcomes in these 3 real-world functional domains, the results were the same. Impaired introspective accuracy was the single best predictor of everyday func­tioning in all 3 domains, with actual abili­ties considerably less important.

Patient characteristics that predict introspective accuracy
Patient characteristics associated with impairments in introspective accuracy (Table 3)^19,20 are easy to identify and assess. Subjective reports of depression have a bell-shaped relationship with introspec­tive accuracy. A self-reported score of 0 by a disabled schizophrenia patient suggests some unawareness of an unfortunate life situation; mild to moderate scores are asso­ciated with more accurate self-assessment; and more severe scores, as seen in other conditions, often predict overestimation of disability.¹⁹

Psychosis and negative symptoms are associated with reduced introspective accu­racy and global over-reporting of functional competence.²⁰ Patients who have never worked have no way to comprehend the specific challenges associated with obtain­ing and sustaining employment. Patients who had a job and have not been able to return work may perceive barriers as more substantial than they are.

Tips to manage impairments in introspective accuracy
Ensure that assessment information is valid. If a patient has limited ability to self-assess, seek other sources of data. If a patient has psychotic symptoms, denies being depressed, or has limited life experi­ence, the clinician should adjust her (his) interpretation of the self-report accord­ingly, because these factors are known to adversely affect the accuracy of self-assessment. Consider informants’ level and quality of contact with the patient, as well as any motivation or bias that might influence the accuracy of their reports. Other professionals, such as occupational therapists, can provide useful information as reference points for treatment planning.

Consider treatments aimed at increasing introspective accuracy, such as structured training and exposure to self-assessment situations,⁶ and interventions aimed at increasing organization and skills perfor­mance. Cognitive remediation therapies, although not widely available, have poten­tial to improve functioning, with excellent persistence over time.²¹

Related Resources
• Harvey PD, ed. Cognitive impairment in schizophrenia: characteristics, assessment and treatment. Cambridge, United Kingdom: Cambridge University Press; 2013.
• Gould F, McGuire LS, Durand D, et al. Self-assessment in schizophrenia: accuracy of assessment of cognition and everyday functioning [published online February 2, 2015]. Neuropsychology.
• Dunning D. Self-insight: detours and roadblocks on the path to knowing thyself. New York, NY: Psychology Press; 2012.

 

Acknowledgment
This paper was supported by Grants MH078775 to Dr. Harvey and MH093432 to Drs. Harvey and Pinkham from the National Institute of Mental Health.

Disclosures
Dr. Harvey has received consulting fees from AbbVie, Boehringer Ingelheim, Forum Pharmaceuticals, Genentech, Otsuka America Pharmaceuticals, Roche, Sanofi, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals. Dr. Pinkham has served as a consultant for Otsuka America Pharmaceuticals.

Lack of insight or “unawareness of illness” occurs within a set of self-assessment problems commonly seen in schizophrenia.¹ In the clinical domain, people who do not realize they are ill typically are unwilling to accept treatment, including medication, with potential for worsened illness. They also may have difficulty self-assess­ing everyday function and functional potential, cognition, social cognition, and attitude, often to a variable degree across these domains (Table 1).^1-3

Self-assessment of performance can be clinically help­ful whether performance is objectively good or bad. Those with poor performance could be helped to attempt to match their aspirations to accomplishments and improve over time. Good performers could have their functioning bolstered by recognizing their competence. Thus, even a population whose performance often is poor could ben­efit from accurate self-assessment or experience additional challenges from inaccurate self-evaluation.

This article discusses patient characteristics associated with impairments in self-assessment and the most accu­rate sources of information for clinicians about patient functioning. Our research shows that an experienced psy­chiatrist is well positioned to make accurate judgments of functional potential and cognitive abilities for people with schizophrenia.

Patterns in patients with impaired self-assessment
Healthy individuals routinely overestimate their abilities and their attractiveness to others.⁴ Feedback that deflates these exag­gerated estimates increases the accuracy of their self-assessments. Mildly depressed individuals typically are the most accurate judges of their true functioning; those with more severe levels of depression tend to underestimate their competence. Thus, sim­ply being an inaccurate self-assessor is not “abnormal.” These response biases are con­sistent and predictable in healthy people.

People with severe mental illness pose a different challenge. As in the following cases, their reports manifest minimal cor­relation with other sources of information, including objective information about performance.

CASE 1
JR, age 28, is referred for occupational therapy because he has never worked since graduat­ing from high school. He tells the therapist his cognitive abilities are average and intact, although his scores on a comprehensive cog­nitive assessment suggest performance at the first percentile of normal distribution or less. His self-reported Beck Depression Inventory (BDI) score is 4. He says he would like to work as a certified public accountant, because he believes he has an aptitude for math. He admits he has no idea what the job entails, but he is quite motivated to set up an interview as soon as possible.

CASE 2
LM, age 48, says his “best job” was managing an auto parts store for 18 months after he earned an associate’s degree and until his second psychotic episode. His most recent work was approximately 12 years ago at an oil-change facility. He agrees to discuss employment but feels his vocational skills are too deteriorated for him to succeed and requests an assessment for Alzheimer’s disease. His cognitive perfor­mance averages in the 10th percentile of the overall population, and his BDI score is 18. Tests of his ability to perform vocational skills sug­gest he is qualified for multiple jobs, including his previous technician position.

Individuals with schizophrenia who report no depression and no work history routinely overestimate their functional potential, whereas those with a history of unsuccessful vocational attempts often underestimate their functional potential. Inaccurate self-assessment can contrib­ute to reduced functioning—in JR’s case because of unrealistic assessment of the match between skills and vocational poten­tial, and in LM’s case because of overly  pessimistic self-evaluation. For people with schizophrenia, inability to self-evaluate can have a bidirectional adverse impact on func­tioning: overestimation may lead to trying tasks that are too challenging, and under­estimation may lead to reduced effort and motivation to take on functional tasks.

Metacognition and introspective accuracy
“Metacognition” refers to self-assessment of the quality and accuracy of performance on cognitive tests.^5-7 Problem-solving tests— such as the Wisconsin Card Sorting test (WCST), in which the person being assessed needs to solve the test through performance feedback—are metacognition tests. When errors are made, the strategy in use needs to be discarded; when responses are correct, the strategy is retained. People with schizo­phrenia have disproportionate difficulties with the WCST, and deficits are especially salient when the test is modified to measure self-assessment of performance and ability to use feedback to change strategies.

“Introspective accuracy” is used to describe the wide-ranging self-assessment impairments in severe mental illness. Theories of metacognition implicate a broad spectrum, of which self-assessment is 1 component, whereas introspective accuracy more specifically indicates judg­ments of accuracy. Because self-assessment is focused on the self, and hence is intro­spective, this conceptualization can be applied to self-evaluations of:
   • achievement in everyday functioning (“Did I complete that task well?”)
   • potential for achievement in everyday functioning (“I could do that job”)
   • cognitive performance (“Yes, I remembered all of those words”)
   • social cognition (“He really is angry”).

 

Domains of impaired introspective accuracy
Everyday functioning. The 3 global domains of everyday functioning are social outcomes, productive/vocational out­comes, and everyday activities, including residential independence/support for peo­ple with severe mental illness. Two areas of inquiry are used in self-assessing everyday functioning: (1) what are you doing now and (2) what could you do in the future? For people with schizophrenia, a related question is how perceived impairments in everyday functioning are associated with subjective illness burden.

People with schizophrenia report illness burden consistent with their self-reported disability, suggesting their reports in these domains are not random.⁸ Studies have consistently found, however, that these patients report:
   • less impairment on average in their everyday functioning than observed by clinicians
   • less subjective illness burden com­pared with individuals with much less severe illnesses.

Their reports also fail to correlate with cli­nicians’ observations.9 Patients with schizo­phrenia who have never been employed may report greater vocational potential than those employed full-time. Interestingly, patients who were previously—but not currently—employed reported the least vocational potential.¹⁰ These data suggest that experience may be a factor: individuals who have never worked have no context for their self-assessments, whereas people who are persistently unemployed may have a perspective on the challenges associated with employment.

In our research,⁹ high-contact clinicians (ie, case manager, psychiatrist, therapist, or residential facility manager) were bet­ter able than family or friends to generate ratings from an assessment questionnaire that correlated with performance-based measures of patients’ ability to perform everyday functional skills. The ratings were generated across multiple functional status scales, suggesting that the rater was more important than the specific scale. We concluded that high-contact clinicians can generate ratings of everyday functioning that are convergent with patients’ abilities, even when they have no information about actual performance scores.

Cognitive performance. When self-reported cognitive abilities are correlated with the results of performance on neuro­psychological assessments, the results are quite consistent. Patients provide reports that do not correlate with their objective performance.¹¹ Interestingly, when clini­cians were asked to use the same strategies as patients to generate ratings of cognitive impairment, clinician ratings had consider­ably greater evidence of validity. In several studies, patients’ ratings of their cognitive performance did not correlate with their neuropsychological test performance, even though they had just been tested on the assessment battery. Ratings by clinicians or other high-contact informants (who were unaware of patients’ test performance) were much more strongly related to patients’ objective test performance, compared with patient self-reports.¹²

The convergence of clinician ratings of cognitive performance with objective test data has been impressive. Correlation coef­ficients of at least r = 0.5, reflecting a moder­ate to large relationships between clinician ratings and objective performance, have been detected. Individual cognitive test domains, such as working memory and processing speed, often do not correlate with each other or with aspects of everyday functioning to that extent.¹³ These data sug­gest that a clinician assessment of cognitive performance, when focused on the correct aspects of cognitive functioning, can be a highly useful proxy for extensive neuropsy­chological testing.

Social cognitive performance. Introspective accuracy for social cognitive judg­ments can be assessed similarly to the strategies used to assess the domains of everyday functioning and cognitive perfor­mance. Patients are asked to complete a typi­cal social cognitive task, such as determining emotions from facial stimuli or examin­ing the eye region of the face, to determine the mental state of the depicted person. Immediately after responding to each stimu­lus, participants rate their confidence in the correctness of that response.

Consistent with the pattern of introspec­tive accuracy for everyday functioning, patients with schizophrenia tend to make more high-confidence errors than healthy individuals on social cognitive tasks. That is, the patients are less likely to realize when they are wrong in their judgments of social stimuli. A similar pattern has been found for mental state attribution,¹⁴ rec­ognition of facial emotion from the self,¹⁵ and recognition of facial emotion from others.¹⁶ These high-confidence errors also are more likely to occur for more difficult stimuli, such as faces that display only mildly emotional expressions. These dif­ficulties appear to be specific to judgments in an immediate evaluation situation. When asked to determine if the behavior of another individual is socially appropri­ate, individuals with schizophrenia are as able as healthy individuals to recognize social mistakes.¹⁷ This work suggests that, at least within the domain of social cogni­tion, introspective accuracy impairment is not caused by generalized poor judgment, just as self-assessments of disability and illness burden are generated at random.

Choosing a reliable informant
If a clinician has not had adequate time or exposure to a patient to make a cogni­tive or functional judgment, what should the strategy be? If asking the patient is uninformative, who should be asked? Our group has gathered information that may help clinicians identify informants who can provide ratings of cognitive perfor­mance and everyday functioning that are convergent with objective evidence.

In a systematic study of validity of reports of various informants, we com­pared correlations between reports of competence of everyday functioning with objective measures of cognitive test per­formance and ability to perform everyday functional skills. Our findings:
   • Patient reports of everyday function­ing were not correlated with performance-based measures for any of 6 rating scales.⁹
   • Clinician reports of everyday func­tioning were correlated with objective per­formance across 4 of 6 rating scales.
   • Correlations between ratings gener­ated by friend or relative informants and other information were almost shocking in their lack of validity (Table 2).⁹

 

We concluded that ratings generated by a generic informant—someone who simply knows the patient and is willing to provide ratings—are highly likely to be uninformative. If a friend or relative provides information of limited useful­ness, the report could easily lead to clinical decisions with high potential for bad out­comes. For example, attempts could fail to transition someone with impaired every­day living skills to independent living, or a patient whose potential is underesti­mated might not be offered opportunities to achieve attainable functional goals.

We found that the closer the rater was to a full caregiver role, the better and more accurate the information obtained. Caregivers who had regular contact with patients had much more valid rat­ings when performance on functionally relevant objective measures was consid­ered. Patients with caregivers had greater impairments in everyday outcomes, how­ever, suggesting that this subset was more impaired than the overall sample. For patients without caregivers, other sources of information—including careful obser­vation by high-contact clinicians—seem to be required to generate a valid assessment of functioning.

Direct functional implications of impaired introspective accuracy
Clinical effects of reduced awareness of ill­ness include reduced adherence to medi­cation, followed by relapse, disturbed behavior, leading to emergency room treat­ments or acute admissions, and—more rarely—disturbed behavior associated with violence or self-harm. Relapses such as these can adversely affect brain structure and function, with declines in cognitive functioning early in the illness.

Our recent study¹⁸ quantifies the direct impact of impairments in introspective accuracy on everyday functioning. We asked 214 individuals with schizophrenia to self-evaluate their cognitive ability with a systematic rating scale and to self-report their everyday functioning in social, voca­tional, and everyday activities domains. We used performance-based measures to assess their cognitive abilities and everyday functional skills. Concurrently, high-contact clinicians rated these same abilities with the same rating scales. We then predicted everyday functioning, as rated by the cli­nicians, with the discrepancies between self-assessed and clinician-assessed func­tioning, and patients’ scores on the perfor­mance-based measures.

Impaired introspective accuracy, as indexed by difference scores between cli­nician ratings and self-reports, was a more potent predictor of everyday functional deficits in social, vocational, and every­day activities domains than scores on performance-based measures of cognitive abilities and functional skills. Even when we analyzed only deficits in introspective accuracy for cognition as the predictor of everyday outcomes in these 3 real-world functional domains, the results were the same. Impaired introspective accuracy was the single best predictor of everyday func­tioning in all 3 domains, with actual abili­ties considerably less important.

Patient characteristics that predict introspective accuracy
Patient characteristics associated with impairments in introspective accuracy (Table 3)^19,20 are easy to identify and assess. Subjective reports of depression have a bell-shaped relationship with introspec­tive accuracy. A self-reported score of 0 by a disabled schizophrenia patient suggests some unawareness of an unfortunate life situation; mild to moderate scores are asso­ciated with more accurate self-assessment; and more severe scores, as seen in other conditions, often predict overestimation of disability.¹⁹

Psychosis and negative symptoms are associated with reduced introspective accu­racy and global over-reporting of functional competence.²⁰ Patients who have never worked have no way to comprehend the specific challenges associated with obtain­ing and sustaining employment. Patients who had a job and have not been able to return work may perceive barriers as more substantial than they are.

Tips to manage impairments in introspective accuracy
Ensure that assessment information is valid. If a patient has limited ability to self-assess, seek other sources of data. If a patient has psychotic symptoms, denies being depressed, or has limited life experi­ence, the clinician should adjust her (his) interpretation of the self-report accord­ingly, because these factors are known to adversely affect the accuracy of self-assessment. Consider informants’ level and quality of contact with the patient, as well as any motivation or bias that might influence the accuracy of their reports. Other professionals, such as occupational therapists, can provide useful information as reference points for treatment planning.

Consider treatments aimed at increasing introspective accuracy, such as structured training and exposure to self-assessment situations,⁶ and interventions aimed at increasing organization and skills perfor­mance. Cognitive remediation therapies, although not widely available, have poten­tial to improve functioning, with excellent persistence over time.²¹

Related Resources
• Harvey PD, ed. Cognitive impairment in schizophrenia: characteristics, assessment and treatment. Cambridge, United Kingdom: Cambridge University Press; 2013.
• Gould F, McGuire LS, Durand D, et al. Self-assessment in schizophrenia: accuracy of assessment of cognition and everyday functioning [published online February 2, 2015]. Neuropsychology.
• Dunning D. Self-insight: detours and roadblocks on the path to knowing thyself. New York, NY: Psychology Press; 2012.

 

Acknowledgment
This paper was supported by Grants MH078775 to Dr. Harvey and MH093432 to Drs. Harvey and Pinkham from the National Institute of Mental Health.

Disclosures
Dr. Harvey has received consulting fees from AbbVie, Boehringer Ingelheim, Forum Pharmaceuticals, Genentech, Otsuka America Pharmaceuticals, Roche, Sanofi, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals. Dr. Pinkham has served as a consultant for Otsuka America Pharmaceuticals.

Lack of insight or “unawareness of illness” occurs within a set of self-assessment problems commonly seen in schizophrenia.¹ In the clinical domain, people who do not realize they are ill typically are unwilling to accept treatment, including medication, with potential for worsened illness. They also may have difficulty self-assess­ing everyday function and functional potential, cognition, social cognition, and attitude, often to a variable degree across these domains (Table 1).^1-3

Self-assessment of performance can be clinically help­ful whether performance is objectively good or bad. Those with poor performance could be helped to attempt to match their aspirations to accomplishments and improve over time. Good performers could have their functioning bolstered by recognizing their competence. Thus, even a population whose performance often is poor could ben­efit from accurate self-assessment or experience additional challenges from inaccurate self-evaluation.

This article discusses patient characteristics associated with impairments in self-assessment and the most accu­rate sources of information for clinicians about patient functioning. Our research shows that an experienced psy­chiatrist is well positioned to make accurate judgments of functional potential and cognitive abilities for people with schizophrenia.

Patterns in patients with impaired self-assessment
Healthy individuals routinely overestimate their abilities and their attractiveness to others.⁴ Feedback that deflates these exag­gerated estimates increases the accuracy of their self-assessments. Mildly depressed individuals typically are the most accurate judges of their true functioning; those with more severe levels of depression tend to underestimate their competence. Thus, sim­ply being an inaccurate self-assessor is not “abnormal.” These response biases are con­sistent and predictable in healthy people.

People with severe mental illness pose a different challenge. As in the following cases, their reports manifest minimal cor­relation with other sources of information, including objective information about performance.

CASE 1
JR, age 28, is referred for occupational therapy because he has never worked since graduat­ing from high school. He tells the therapist his cognitive abilities are average and intact, although his scores on a comprehensive cog­nitive assessment suggest performance at the first percentile of normal distribution or less. His self-reported Beck Depression Inventory (BDI) score is 4. He says he would like to work as a certified public accountant, because he believes he has an aptitude for math. He admits he has no idea what the job entails, but he is quite motivated to set up an interview as soon as possible.

CASE 2
LM, age 48, says his “best job” was managing an auto parts store for 18 months after he earned an associate’s degree and until his second psychotic episode. His most recent work was approximately 12 years ago at an oil-change facility. He agrees to discuss employment but feels his vocational skills are too deteriorated for him to succeed and requests an assessment for Alzheimer’s disease. His cognitive perfor­mance averages in the 10th percentile of the overall population, and his BDI score is 18. Tests of his ability to perform vocational skills sug­gest he is qualified for multiple jobs, including his previous technician position.

Individuals with schizophrenia who report no depression and no work history routinely overestimate their functional potential, whereas those with a history of unsuccessful vocational attempts often underestimate their functional potential. Inaccurate self-assessment can contrib­ute to reduced functioning—in JR’s case because of unrealistic assessment of the match between skills and vocational poten­tial, and in LM’s case because of overly  pessimistic self-evaluation. For people with schizophrenia, inability to self-evaluate can have a bidirectional adverse impact on func­tioning: overestimation may lead to trying tasks that are too challenging, and under­estimation may lead to reduced effort and motivation to take on functional tasks.

Metacognition and introspective accuracy
“Metacognition” refers to self-assessment of the quality and accuracy of performance on cognitive tests.^5-7 Problem-solving tests— such as the Wisconsin Card Sorting test (WCST), in which the person being assessed needs to solve the test through performance feedback—are metacognition tests. When errors are made, the strategy in use needs to be discarded; when responses are correct, the strategy is retained. People with schizo­phrenia have disproportionate difficulties with the WCST, and deficits are especially salient when the test is modified to measure self-assessment of performance and ability to use feedback to change strategies.

“Introspective accuracy” is used to describe the wide-ranging self-assessment impairments in severe mental illness. Theories of metacognition implicate a broad spectrum, of which self-assessment is 1 component, whereas introspective accuracy more specifically indicates judg­ments of accuracy. Because self-assessment is focused on the self, and hence is intro­spective, this conceptualization can be applied to self-evaluations of:
   • achievement in everyday functioning (“Did I complete that task well?”)
   • potential for achievement in everyday functioning (“I could do that job”)
   • cognitive performance (“Yes, I remembered all of those words”)
   • social cognition (“He really is angry”).

 

Domains of impaired introspective accuracy
Everyday functioning. The 3 global domains of everyday functioning are social outcomes, productive/vocational out­comes, and everyday activities, including residential independence/support for peo­ple with severe mental illness. Two areas of inquiry are used in self-assessing everyday functioning: (1) what are you doing now and (2) what could you do in the future? For people with schizophrenia, a related question is how perceived impairments in everyday functioning are associated with subjective illness burden.

People with schizophrenia report illness burden consistent with their self-reported disability, suggesting their reports in these domains are not random.⁸ Studies have consistently found, however, that these patients report:
   • less impairment on average in their everyday functioning than observed by clinicians
   • less subjective illness burden com­pared with individuals with much less severe illnesses.

Their reports also fail to correlate with cli­nicians’ observations.9 Patients with schizo­phrenia who have never been employed may report greater vocational potential than those employed full-time. Interestingly, patients who were previously—but not currently—employed reported the least vocational potential.¹⁰ These data suggest that experience may be a factor: individuals who have never worked have no context for their self-assessments, whereas people who are persistently unemployed may have a perspective on the challenges associated with employment.

In our research,⁹ high-contact clinicians (ie, case manager, psychiatrist, therapist, or residential facility manager) were bet­ter able than family or friends to generate ratings from an assessment questionnaire that correlated with performance-based measures of patients’ ability to perform everyday functional skills. The ratings were generated across multiple functional status scales, suggesting that the rater was more important than the specific scale. We concluded that high-contact clinicians can generate ratings of everyday functioning that are convergent with patients’ abilities, even when they have no information about actual performance scores.

Cognitive performance. When self-reported cognitive abilities are correlated with the results of performance on neuro­psychological assessments, the results are quite consistent. Patients provide reports that do not correlate with their objective performance.¹¹ Interestingly, when clini­cians were asked to use the same strategies as patients to generate ratings of cognitive impairment, clinician ratings had consider­ably greater evidence of validity. In several studies, patients’ ratings of their cognitive performance did not correlate with their neuropsychological test performance, even though they had just been tested on the assessment battery. Ratings by clinicians or other high-contact informants (who were unaware of patients’ test performance) were much more strongly related to patients’ objective test performance, compared with patient self-reports.¹²

The convergence of clinician ratings of cognitive performance with objective test data has been impressive. Correlation coef­ficients of at least r = 0.5, reflecting a moder­ate to large relationships between clinician ratings and objective performance, have been detected. Individual cognitive test domains, such as working memory and processing speed, often do not correlate with each other or with aspects of everyday functioning to that extent.¹³ These data sug­gest that a clinician assessment of cognitive performance, when focused on the correct aspects of cognitive functioning, can be a highly useful proxy for extensive neuropsy­chological testing.

Social cognitive performance. Introspective accuracy for social cognitive judg­ments can be assessed similarly to the strategies used to assess the domains of everyday functioning and cognitive perfor­mance. Patients are asked to complete a typi­cal social cognitive task, such as determining emotions from facial stimuli or examin­ing the eye region of the face, to determine the mental state of the depicted person. Immediately after responding to each stimu­lus, participants rate their confidence in the correctness of that response.

Consistent with the pattern of introspec­tive accuracy for everyday functioning, patients with schizophrenia tend to make more high-confidence errors than healthy individuals on social cognitive tasks. That is, the patients are less likely to realize when they are wrong in their judgments of social stimuli. A similar pattern has been found for mental state attribution,¹⁴ rec­ognition of facial emotion from the self,¹⁵ and recognition of facial emotion from others.¹⁶ These high-confidence errors also are more likely to occur for more difficult stimuli, such as faces that display only mildly emotional expressions. These dif­ficulties appear to be specific to judgments in an immediate evaluation situation. When asked to determine if the behavior of another individual is socially appropri­ate, individuals with schizophrenia are as able as healthy individuals to recognize social mistakes.¹⁷ This work suggests that, at least within the domain of social cogni­tion, introspective accuracy impairment is not caused by generalized poor judgment, just as self-assessments of disability and illness burden are generated at random.

Choosing a reliable informant
If a clinician has not had adequate time or exposure to a patient to make a cogni­tive or functional judgment, what should the strategy be? If asking the patient is uninformative, who should be asked? Our group has gathered information that may help clinicians identify informants who can provide ratings of cognitive perfor­mance and everyday functioning that are convergent with objective evidence.

In a systematic study of validity of reports of various informants, we com­pared correlations between reports of competence of everyday functioning with objective measures of cognitive test per­formance and ability to perform everyday functional skills. Our findings:
   • Patient reports of everyday function­ing were not correlated with performance-based measures for any of 6 rating scales.⁹
   • Clinician reports of everyday func­tioning were correlated with objective per­formance across 4 of 6 rating scales.
   • Correlations between ratings gener­ated by friend or relative informants and other information were almost shocking in their lack of validity (Table 2).⁹

 

We concluded that ratings generated by a generic informant—someone who simply knows the patient and is willing to provide ratings—are highly likely to be uninformative. If a friend or relative provides information of limited useful­ness, the report could easily lead to clinical decisions with high potential for bad out­comes. For example, attempts could fail to transition someone with impaired every­day living skills to independent living, or a patient whose potential is underesti­mated might not be offered opportunities to achieve attainable functional goals.

We found that the closer the rater was to a full caregiver role, the better and more accurate the information obtained. Caregivers who had regular contact with patients had much more valid rat­ings when performance on functionally relevant objective measures was consid­ered. Patients with caregivers had greater impairments in everyday outcomes, how­ever, suggesting that this subset was more impaired than the overall sample. For patients without caregivers, other sources of information—including careful obser­vation by high-contact clinicians—seem to be required to generate a valid assessment of functioning.

Direct functional implications of impaired introspective accuracy
Clinical effects of reduced awareness of ill­ness include reduced adherence to medi­cation, followed by relapse, disturbed behavior, leading to emergency room treat­ments or acute admissions, and—more rarely—disturbed behavior associated with violence or self-harm. Relapses such as these can adversely affect brain structure and function, with declines in cognitive functioning early in the illness.

Our recent study¹⁸ quantifies the direct impact of impairments in introspective accuracy on everyday functioning. We asked 214 individuals with schizophrenia to self-evaluate their cognitive ability with a systematic rating scale and to self-report their everyday functioning in social, voca­tional, and everyday activities domains. We used performance-based measures to assess their cognitive abilities and everyday functional skills. Concurrently, high-contact clinicians rated these same abilities with the same rating scales. We then predicted everyday functioning, as rated by the cli­nicians, with the discrepancies between self-assessed and clinician-assessed func­tioning, and patients’ scores on the perfor­mance-based measures.

Impaired introspective accuracy, as indexed by difference scores between cli­nician ratings and self-reports, was a more potent predictor of everyday functional deficits in social, vocational, and every­day activities domains than scores on performance-based measures of cognitive abilities and functional skills. Even when we analyzed only deficits in introspective accuracy for cognition as the predictor of everyday outcomes in these 3 real-world functional domains, the results were the same. Impaired introspective accuracy was the single best predictor of everyday func­tioning in all 3 domains, with actual abili­ties considerably less important.

Patient characteristics that predict introspective accuracy
Patient characteristics associated with impairments in introspective accuracy (Table 3)^19,20 are easy to identify and assess. Subjective reports of depression have a bell-shaped relationship with introspec­tive accuracy. A self-reported score of 0 by a disabled schizophrenia patient suggests some unawareness of an unfortunate life situation; mild to moderate scores are asso­ciated with more accurate self-assessment; and more severe scores, as seen in other conditions, often predict overestimation of disability.¹⁹

Psychosis and negative symptoms are associated with reduced introspective accu­racy and global over-reporting of functional competence.²⁰ Patients who have never worked have no way to comprehend the specific challenges associated with obtain­ing and sustaining employment. Patients who had a job and have not been able to return work may perceive barriers as more substantial than they are.

Tips to manage impairments in introspective accuracy
Ensure that assessment information is valid. If a patient has limited ability to self-assess, seek other sources of data. If a patient has psychotic symptoms, denies being depressed, or has limited life experi­ence, the clinician should adjust her (his) interpretation of the self-report accord­ingly, because these factors are known to adversely affect the accuracy of self-assessment. Consider informants’ level and quality of contact with the patient, as well as any motivation or bias that might influence the accuracy of their reports. Other professionals, such as occupational therapists, can provide useful information as reference points for treatment planning.

Consider treatments aimed at increasing introspective accuracy, such as structured training and exposure to self-assessment situations,⁶ and interventions aimed at increasing organization and skills perfor­mance. Cognitive remediation therapies, although not widely available, have poten­tial to improve functioning, with excellent persistence over time.²¹

Related Resources
• Harvey PD, ed. Cognitive impairment in schizophrenia: characteristics, assessment and treatment. Cambridge, United Kingdom: Cambridge University Press; 2013.
• Gould F, McGuire LS, Durand D, et al. Self-assessment in schizophrenia: accuracy of assessment of cognition and everyday functioning [published online February 2, 2015]. Neuropsychology.
• Dunning D. Self-insight: detours and roadblocks on the path to knowing thyself. New York, NY: Psychology Press; 2012.

 

Acknowledgment
This paper was supported by Grants MH078775 to Dr. Harvey and MH093432 to Drs. Harvey and Pinkham from the National Institute of Mental Health.

Disclosures
Dr. Harvey has received consulting fees from AbbVie, Boehringer Ingelheim, Forum Pharmaceuticals, Genentech, Otsuka America Pharmaceuticals, Roche, Sanofi, Sunovion Pharmaceuticals, and Takeda Pharmaceuticals. Dr. Pinkham has served as a consultant for Otsuka America Pharmaceuticals.

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Substances use during adolescence is common in the United States. Data from the 2014 Monitoring the Future Survey estimated that among 12th graders, 60.2% used alcohol, 35.1% used mari­juana, and 13.9% used a prescription drug for nonmedical use within the previous year.¹ An estimated 11.4% of adolescents meet DSM-IV threshold criteria for a substance use disorder (SUD).² Substance use in adolescents often co-occurs with psychological distress and psychi­atric illness. Adolescents with a psychiatric disorder are at increased risk for developing a SUD; conversely, high rates of psychiatric illness are seen in adolescents with a SUD.^3,4 In one study, 82% of adolescents hospitalized for SUD treatment were found to have a co-occurring axis I disorder.⁵ Furthermore, co-occurring psychiatric illness and SUD complicates treatment course and prognosis. Adolescents with co-occurring psychiatric illness and SUD often benefit from an inte­grated, multimodal treatment approach that includes psychotherapy, pharmacologic interventions, family involvement, and collaboration with community supports.

In this article, we focus on pharmacologic management of non-nicotinic SUDs in adolescents, with an emphasis on those with comor­bid psychiatric illness.

Screening and assessment of substance use
It is important to counsel children with a psychiatric illness and their parents about the increased risk for SUD before a patient transitions to adolescence. Discussions about substance abuse should begin during the 5th grade because data suggests that adolescent sub­stance use often starts in middle school (6th to 9th grade). Clinicians should routinely screen adolescent patients for substance use. Nonproprietary screening tools available through the National Institute on Alcohol and Alcoholism and the National Institute on Drug Abuse are listed in Table 1.^6-8 The Screening to Brief Intervention (S2BI) is a newer tool that has been shown to be highly effective in identifying adolescents at risk for substance abuse and differentiating severity of illness.⁸ The S2BI includes screening ques­tions that assess for use of 8 substances in the past year.

Adolescents with psychiatric illness who are identified to be at risk for problems asso­ciated with substance use should be evalu­ated further for the presence or absence of a SUD. The number of criteria a patient endorses over the past year (Table 2⁹) is used to assess SUD severity—mild, moderate, or severe. Additional considerations include substance use patterns such as type, site, quantity, frequency, context, and combina­tions of substances.

It is important to be curious and non­judgmental when evaluating substance use patterns with adolescents to obtain a com­prehensive assessment. Teenagers often are creative and inventive in their efforts to maximize intoxication, which can put them at risk for complications associated with acute intoxication. Rapidly evolving meth­ods of ingesting highly concentrated forms of tetrahydrocannabinol (“wax,” “dabs”) are an example of use patterns that are ahead of what is reported in the literature.

Any substance use in an adolescent with a psychiatric illness is of concern and should be monitored closely because of the potential impact of substance use on the co-occurring psychiatric illness and pos­sible interactions between the abused sub­stance and prescribed medication.

Treatment interventions
Although this review will focus on phar­macotherapy, individual, group, and fam­ily psychotherapies are a critical part of a treatment plan for adolescents with comor­bid psychiatric illness and SUD (Table 3). Collaboration with community supports, including school and legal offi­cials, can help reinforce contingencies and assist with connecting a teen with posi­tive prosocial activities. Involvement with mutual help organizations, such as Alcoholics Anonymous, can facilitate adolescent engagement with a positive sober network.¹⁰

Pharmacologic strategies for treating co-occurring psychiatric illness and SUD include medication to:
   • decrease substance use and promote abstinence
   • alleviate withdrawal symptoms (medi­cation to treat withdrawal symptoms and agonist treatments)
   • block the effect of substance use (antag­onist agents)
   • decrease likelihood of substance use with aversive agents
   • target comorbid psychiatric illness.

Medication to decrease substance use and promote abstinence. One strategy is to target cravings and urges to use sub­stances with medication. Naltrexone is an opiate antagonist FDA-approved for treating alcohol and opioid use disorders in adults and is available as a daily oral medication and a monthly injectable depot preparation (extended-release naltrexone). Two small open-label studies showed decreased alcohol use with naltrexone treatment in adolescents with alcohol use disorder.^11,12 In a randomized double-blind placebo controlled (RCT) crossover study of 22 adolescent problem drinkers, nal­trexone, 50 mg/d, reduced the likelihood of drinking and heavy drinking (P ≤ .03).¹³ Acamprosate, another anti-craving medi­cation FDA-approved for treating alcohol use disorder in adults, has no data on the safety or efficacy for adolescent alcohol use disorder.

There is limited research on agents that decrease use and promote abstinence from non-nicotinic substances other than alco­hol. There is one pilot RCT that evaluated N-acetylcysteine (NAC)—an over-the-counter supplement that modulates the glutamate system—for treating adoles­cent Cannabis dependence. Treatment with NAC, 2,400 mg/d, was well tolerated and had twice the odds of increasing negative urine cannabinoid tests during treatment than placebo.¹⁴ Although NAC treatment was associated with decreased Cannabis use, it did not significantly decrease crav­ings compared with placebo.¹⁵

 

Medication to alleviate withdrawal symptoms. Some patients may find the physical discomfort and psychological dis­tress associated with substance withdrawal so intolerable that to avoid it they continue to use drugs or alcohol. Medication to treat withdrawal symptoms and agonist treat­ments can be used to alleviate discomfort and distress associated with withdrawal. Agonist treatments, such as methadone and buprenorphine, bind to the same receptors as the target substance, which allows the patient to shift to controlled use of a prescribed substitute. Agonist treatments are used for short detoxifi­cation and over longer periods of time for maintenance treatment. Methadone, which decreases craving and withdrawal symptoms from opiates by binding to the μ-opiate receptor and blocking other sub­stances from binding, is frequently used for detoxification and maintenance treat­ment in adults. There is limited data on methadone substitution therapy for adolescents in the United States.¹⁶ Methadone maintenance for adolescents in the United States is restricted to severe cases of opioid use disorder. Federal guidelines specify that adolescents age <18 can only receive methadone if they have had 2 unsuccess­ful detoxification attempts or outpatient psychosocial treatments and have met DSM criteria for an opioid use disorder for 1 year.¹⁷

Buprenorphine is a partial μ-opiate receptor agonist that is FDA-approved for use in adolescents age ≥16 with opioid dependence. Although a waiver from the U.S. Drug Enforcement Administration is required to prescribe buprenorphine, it generally can be administered in outpa­tient settings with relative ease compared with methadone.

Marsch et al¹⁸ examined the efficacy of buprenorphine compared with clonidine for detoxification over 1 month in 36 ado­lescents with opioid dependence. Clonidine is an α-2 adrenergic agonist that often is used during detoxification from opioids.¹⁹ Although both buprenorphine and cloni­dine relieved withdrawal symptoms, a significantly higher percentage of patients receiving buprenorphine completed treat­ment (72%) compared with those taking clonidine (39%) (P < .05).¹⁸ Detoxification with buprenorphine also was associated with a higher percentage of negative urine drug screens (64% vs 32%, P = .01), and those receiving buprenorphine were more likely to continue on naltrexone mainte­nance for continued medication-assisted treatment after detoxification compared with those randomized to clonidine.

Woody et al²⁰ compared use of buprenor­phine/naloxone for opioid detoxification vs short-term maintenance. Patients age 16 to 21 were randomized to detoxification over 2 weeks vs stabilization and maintenance for 9 weeks and taper over 3 weeks. Maintenance treatment with buprenorphine/naloxone was associated with less opioid use, less injection drug use, and less need for addic­tion treatment outside of that received through the study compared with detoxifica­tion treatment. When buprenorphine/nalox­one was discontinued both the detoxification and maintenance groups had high rates of positive urine toxicology screens at 1-year follow up (mean 48% to 72%). These data suggests maintenance with buprenorphine/ naloxone for adolescents and young adults is more effective than short-term detoxifi­cation for stabilizing opioid use disorders, although optimal treatment duration is unclear. Clinically, it is important to continue buprenorphine/naloxone maintenance until the patient has stabilized in recovery and has acquired coping skills to manage urges, crav­ings, and psychological distress (eg, anger, stress) that often arise during a slow taper of agonist treatment.

Antagonist treatment to block the effect of substance use
As an opioid receptor antagonist, naltrex­one is effective for treating opioid use dis­order because it blocks the action of opioids. Fishman et al²¹ published a descriptive series of 16 adolescents and young adults followed over 4 months who received the injectable depot preparation (extended-release) nal­trexone while in residential treatment, and then discharged to outpatient care. Most patients who received extended-release nal­trexone remained in outpatient treatment (63%) and reduced their opioid use or were abstinent at 4 months (56%). One barrier to naltrexone treatment is the need to be absti­nent from opioids for 7 to 10 days to prevent precipitated opioid withdrawal. Therefore, naltrexone is a good option for adolescents who present for treatment early and are not physiologically dependent on opioids or are receiving treatment in a structured environ­ment after detoxification, such as residential treatment or sober living.

Aversive agents to diminish substance use. Aversive agents produce an unpleas­ant reaction when a target substance is consumed. Disulfiram is prototypic aver­sive agent that prevents the breakdown of acetaldehyde, a toxic metabolite of alcohol. Patients who drink alcohol while taking disulfiram may experience adverse effects, including tachycardia, shortness of breath, nausea, dizziness, and confusion. There have been 2 studies examining the efficacy of disulfiram in adolescents with alcohol use disorder. Niederhofer et al²² found that disulfiram treatment significantly increased cumulative abstinence in a small RCT (P = .012). In another small randomized, open-label, 3-month study of adolescents who received disulfiram or naltrexone in addition to weekly psychotherapy, disul­firam was superior to naltrexone in mean days abstinent from alcohol, 84 days vs 51 days, respectively (P = .0001).²³ Often adolescents are not willing to adhere to disulfiram because they are concerned about the aversive reaction when combined with alcohol use. Consider prescribing disulfiram for adolescents who are about to go “on pass” from a therapeutic school or residen­tial SUD treatment center and will be return­ing to an environment where they may be tempted to use alcohol.

 

Pharmacotherapy to treat co-occurring psychiatric illness
Continued treatment of a psychiatric illness that co-occurs with SUD is important. As we recommended, consider psychosocial treatments for both the SUD and comorbid psychopathology. Several single-site RCTs have evaluated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) fluox­etine and sertraline for depressive disorders in adolescents with a co-occurring SUD.^24-28 Most studies have shown improvement in depressive symptoms and substance use in medication and placebo groups.^24,25,27,28 However, treatment with fluoxetine, 20 mg/d, or sertraline, 100 mg/d, when compared with placebo was associated with improved depressive symptoms in 1 of 3 studies and had no significant differ­ence in SUD outcome. The authors of these studies believe that the general improve­ment in depression and the SUD was related to use of cognitive-behavioral ther­apy (CBT) and/or motivational enhance­ment therapy.^24,25,27,28

Research on the use of mood stabilizers for adolescents with mood dysregulation and a SUD is limited but has suggested benefit associated with pharmacotherapy (Table 4).^29-32 Two RCTs and 1 open-label study demonstrated reductions in sub­stance use with mood stabilizer treatment in adolescents with co-occurring SUD and mood dysregulation.^29-32 The effect of phar­macotherapy on mood dysregulation rat­ings are less clear because there was no change in severity of affective symptoms observed in a small RCT of lithium (average blood level 0.9 mEq/L)²⁹; and improvement in affective symptoms was noted in topira­mate (300 mg/d) and placebo groups when both groups were treated with concurrent quetiapine.³² Because of the high risk of SUD and severe morbidity in juvenile bipo­lar disorder and severe mood dysregula­tion,³³ larger RCTs are warranted.

Several studies have evaluated the impact of stimulant and nonstimulant treat­ments for attention-deficit/hyperactiv­ity disorder (ADHD) in adolescents with a co-occurring SUD.^34-39 The largest and only multisite study evaluated the efficacy of osmotic (extended) release methylphe­nidate (OROS-MPH) vs placebo for ado­lescents who also were receiving CBT for SUD.³⁶ In this 16-week RCT, the OROS-MPH and placebo groups showed improvement in self-reported ADHD symptoms with no difference between groups. Parent report of ADHD symptoms did indicate a greater reduction in symptoms in the OROS-MPH group compared with placebo. Both groups had a decrease in self-reported days of sub­stance use over the past month with no dif­ferences between groups. Pharmacotherapy trials for ADHD that have included psy­chotherapy highlight the effectiveness of CBT for SUD and co-occurring psychiatric illness.^36,39,40

Although conduct disorder and anxiety disorders commonly co-occur with SUD, there has been less research evaluating the impact of pharmacotherapy on treating these disorders. Riggs et al^25,34,35,41 evaluated the impact of pharmacotherapy targeted to co-occurring ADHD and major depressive disorder in the context of conduct disorder and SUD. When evaluated in an outpatient setting, the presence of a treatment inter­vention to address the co-occurring SUD was an important component that led to a reduction in conduct symptoms.^25,35 There have been no comprehensive studies on the impact of pharmacotherapy for treat­ing anxiety and SUD in adolescents.

Recommendations for clinical management
Although more research is needed to evaluate the role of pharmacotherapy for adolescents with co-occurring psychiatric illness and a SUD, recommended practice is to continue pharmacotherapy and closely monitor response to treatment when at-risk substance use begins in patients with co-occurring psychiatric illness. In ado­lescents with a threshold SUD, continue pharmacotherapy for unstable mood dis­orders with first-line choices of SSRIs for unipolar depression and second-generation antipsychotics for bipolar spectrum illness. Suggested conservative pharmacological interventions for anxiety disorders include SSRIs and buspirone, which have been shown to be effective for treating anxiety in children and adolescents.^42,43 For patients with comorbid ADHD and SUD, if pos­sible, it is recommended to first stabilize substance use (low-level use or abstinence) and consider treating ADHD immediately thereafter with a nonstimulant such as ato­moxetine, which has data on efficacy and safety in context to substance use; and/or an α-agonist or an extended-release stimu­lant. Because of the potential for misuse and toxicity associated with concurrent substance use, benzodiazepines should be considered a last treatment of choice for adolescents with anxiety disorders and a SUD. Similarly, the use of immediate-release stimulants should be avoided in patients with ADHD and a SUD. When pre­scribing medications that could be misused or toxic when combined with a substance, it is important to evaluate the risk and benefit of continued use of a particular medication and consider prescribing lower quantities to decrease risk for misuse (1- to 2-week supply). Adolescents often are reluctant to engage in SUD treatment and one strat­egy to consider is to make continued pre­scription of any medication contingent on engaging in SUD treatment. Enlist parents in helping to monitor, store, and administer their child’s medication to improve adher­ence and decrease the potential for misuse, diversion, and complications associated with substance intoxication.

 

Bottom Line
It is important to screen for substance use in adolescents with co-occurring
psychiatric illness and vice versa. When at-risk or hazardous substance use is
detected there are effective psychosocial and pharmacologic interventions that
can be used to treat adolescent substance use disorders alone and in combination
with certain psychiatric disorders.

Related Resources
• National Institute on Drug Abuse. www.drugabuse.gov.
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.

Drug Brand Names
Acamprosate • Campral
Atomoxetine • Strattera
Buprenorphine• Subutex
Buprenorphine/naloxone • Suboxone
Buspirone • Buspar
Clonidine • Catapres
Disulfiram • Antabuse
Fluoxetine • Prozac
Lithium • Lithobid, Eskalith
Methadone • Dolophine
Naltrexone • ReVia, Vivitrol
Osmotic (extended) release methylphenidate • Concerta
Sertraline • Zoloft
Topiramate • Topamax
Quetiapine • Seroquel
Valproic acid • Depakote

Disclosures
Dr. Yule received grant support from the 2012 American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Faculty supported by Lilly USA, LLC, and receives grant support from the 2014 Louis V. Gerstner III Research Scholar Award. Dr. Wilens has received grant support from the National Institute on Drug Abuse (NIDA); has been a consultant for Euthymics/Neurovance, NIDA, Ironshore Pharmaceuticals and Development, Theravance Biopharma, Tris Pharma, the U.S. National Football League (ERM Associates), U.S. Minor/Major League Baseball, and Bay Cove Human Services (Clinical Services).

Too few psychiatrists. A growing number of patients. A new federal law, technological advances, and a genera­tional shift in the way people communicate. Add them together and you have the perfect environment for telepsy­chiatry—the remote practice of psychiatry by means of tele­medicine—to take root (Box 1). Although telepsychiatry has, in various forms, been around since the 1950s,¹ only recently has it expanded into almost all areas of psychiatric practice.

Here are some observations from my daily work on why I see this method of delivering mental health care is poised to expand in 2015 and beyond. Does telepsychiatry make sense for you?

Lack of supply is a big driver
There are simply not enough psychiatrists where they are needed, which is the primary driver of the expansion of telepsychiatry. With 77% of counties in the United States reporting a shortage of psychiatrists² and the “graying” of the psychiatric workforce,³ a more efficient way to make use of a psychiatrist’s time is needed. Telepsychiatry elimi­nates travel time and allows psychiatrists to visit distant sites virtually.

The shortage of psychiatric practitioners that we see today is only going to become worse. The Patient Protection and Affordable Care Act of 2010 includes mental health care and substance abuse treatment among its 10 essential benefits; just as important, new rules arising from the Mental Health Parity and Addiction Equity Act of 2008 limit restrictions on access to mental health care when insurance provides such cover­age.⁴ These legislative initiatives likely will lead to increased demand for psychiatrists in all care settings—from outpatient consults to acute inpatient admissions.


Why so attractive an option?
The shortage of psychiatrists creates limita­tions on access to care. Fortunately, telemed­icine has entered a new age, ushered in by widely available teleconferencing technol­ogy. Specialists from dermatology to surgery currently are using telemedicine; psychia­try is a good fit for telemedicine because of (1) the limited amount of “touch” required to make a psychiatric assessment, (2) signifi­cant improvements in video quality in recent years, and (3) a decrease in the stigma associ­ated with visiting a psychiatrist.

A generation raised on the Internet is entering the health care marketplace. These consumers and clinicians are accustomed to using video for many daily activities, and they seek health information from the Web. Visiting a psychiatrist through teleconferenc­ing isn’t strange or alienating to this genera­tion; their comfort with technology allows them to have intimate exchanges on video.

Subspecialty particulars
The earliest adopters, not surprisingly, are in areas where the strain of shortage has been felt most, with pediatric, geriatric, and correctional psychiatrists leading the way. In these fields, a substantial literature supports the use of telepsychiatry from a number of practice perspectives.

Pediatric psychiatry. The literature shows that children, families, and clinicians are, on the whole, satisfied with telepsychia­try.⁵ Children and adolescents who have been shown to benefit from telepsychia­try include those with depression,⁶ post­traumatic stress disorder, and eating disorders.⁷ Based on a case series, some authors have asserted that telepsychiatry might be preferable to in-person treatment (Box 2).⁸

Geriatric psychiatry. Research shows that geriatric patients, who are most likely to feel threatened by new technology, accept tele­psychiatry visits.⁹ For psychiatrists treating geriatric patients, telepsychiatry can sig­nificantly lower costs by cutting commut­ing¹⁰ and make more accessible for patients whose age makes them unable to drive.

Correctional psychiatry. Clinicians work­ing in correctional psychiatry have been at the forefront of experimentation with tele­psychiatry. The technology is a natural fit for this setting:  
   • Prisons often are located in remote locations.  
   • Psychiatrists can be reluctant to pro­vide on-site services because of safety concerns.

With correctional telepsychiatry, not only are patient outcomes comparable with in-person psychiatry, but the cost of delivering care can be significantly lower.¹¹ With the U.S. Department of Justice reporting that 50% of inmates have a diagnosable mental disorder, including substance abuse,¹² the need for access to a psychiatrist in the cor­rectional system is acute.

Telepsychiatry can confidently be pro­vided in a number of settings:  
   • emergency rooms  
   • nursing homes  
   • offices of primary care physicians  
   • in-home care.

Clinical services in these settings have been offered, studied, and reviewed.¹³

Can confidentiality and security be assured?
As with any new medical tool, the risk and benefits must be weighed care­ fully. The most obvious risk is to privacy. Telepsychiatry visits, like all patient encounters, must be secure and confiden­tial. Given the growing suspicion among the public and professionals who use com­puters that all data are at risk, clinicians must take appropriate cautions and, at the same time, warn patients of the risks. Readily available videoconferencing soft­ware, such as Skype, does not provide the level of security that patients expect from health care providers.¹⁴

 

Other common concerns about telepsy­chiatry are stable access to videoconferenc­ing and the safety from hackers of necessary hardware. Medical device companies have created hardware and software for use in telepsychiatry that provide a Health Insurance Portability and Accountability Act-compliant high-quality, stable, video­conferencing visit.

Do patients benefit?
Clinically, patients have fared well when they receive care through telepsychiatry. In some studies, however, clinicians have expressed some dissatisfaction with the technology¹³— understandable, given the value that psychi­atry traditionally has put on sitting with the patient. As Knoedler¹⁵ described it, making the switch to telepsychiatry from in-person contact can engender loneliness in some phy­sicians; not only is patient contact shifted to videoconferencing, but the psychiatrist loses the supportive environment of a busy clinical practice. Knoedler also pointed out that, on the other hand, telepsychiatry offers practi­tioners the opportunity to evaluate and treat people who otherwise would not have men­tal health care.

Obstacles—practical, knotty ones
Reimbursement and licensing. These are 2 pressing problems of telepsychiatry, although recent policy developments will help expand telepsychiatry and make it more appealing to physicians:
   • Medicare reimburses for telepsychiatry in non-metropolitan areas.
   • In 41 states, Medicaid has included tele­psychiatry as a benefit.¹⁶
   • Nine states offer a specific medical license for practicing telepsychiatry¹⁷ (in the remaining states, a full medical license must be obtained before one can provide telemedi­cine services).
   • The Joint Commission has included lan­guage in its regulations that could expedite privileging of telepsychiatrists.¹⁸

Even with such advancements, problems with licensure, credentialing, privacy, secu­rity, confidentiality, informed consent, and professional liability remain.¹⁹ I urge you to do your research on these key areas before plunging in.

Changes to models of care. The risk that telepsychiatry poses to various models of care has to be considered. Telepsychiatry is a dramatic innovation, but it should be used to support only high-quality, evidence-based care to which patients are entitled.²⁰ With new technology—as with new medi­cations—use must be carefully monitored and scrutinized.

Although evidence of the value of telepsy­chiatry is growing, many methods of long-distance practice are still in their infancy. Data must be collected and poor outcomes assessed honestly to ensure that the “more-good-than-harm” mandate is met.
 

Good reasons to call this shift ‘inevitable’
The future of telepsychiatry includes expansion into new areas of practice. The move to providing services to patients where they happen to be—at work or home— seems inevitable:
   • In rural areas, practitioners can com­municate with patients so that they are cared for in their homes, without the expense of transportation.
   • Employers can invest in workplace health clinics that use telemedicine ser­vices to reduce absenteeism.
   • For psychiatrists, the ability to provide services to patients across a wide region, from a single convenient location, and at lower cost is an attractive prospect.

To conclude: telepsychiatry holds potential to provide greater reimburse­ment and improved quality of life for psy­chiatrists and patients: It allows physicians to choose where they live and work, and limits the number of unreimbursed com­mutes, and gives patients access to psychi­atric care locally, without disruptive travel and delays.

Bottom Line
The exchange of medical information from 1 site to another by means of electronic communication has great potential to improve the health of patients and to alleviate the shortage of psychiatric practitioners across regions and settings. Pediatric, geriatric, and correctional psychiatry stand to benefit because of the nature of the patients and locations.

Related Resources
• American Telemedicine Association. Practice guidelines for video-based online mental health services. http://www. americantelemed.org/docs/default-source/standards/practice-guidelines-for-video-based-online-mental-health-services. pdf?sfvrsn=6. Published May 2013. Accessed February 10, 2015.
• Freudenberg N, Yellowlees PM. Telepsychiatry as part of a com­prehensive care plan. Virtual Mentor. 2014;16(12):964-968.
• Kornbluh R. Telepsychiatry is a tool that we must exploit. Clinical Psychiatry News. August 7, 2014. http://www. clinicalpsychiatrynews.com/home/article/telepsychiatry-is-a-tool-that-we-must-exploit/28c87bec298e0aa208309fa 9bc48dedc.html.
• University of Colorado Denver. Telemental Health Guide. http:// www.tmhguide.org.

 

Disclosure
Dr. Kornbluh reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Too few psychiatrists. A growing number of patients. A new federal law, technological advances, and a genera­tional shift in the way people communicate. Add them together and you have the perfect environment for telepsy­chiatry—the remote practice of psychiatry by means of tele­medicine—to take root (Box 1). Although telepsychiatry has, in various forms, been around since the 1950s,¹ only recently has it expanded into almost all areas of psychiatric practice.

Here are some observations from my daily work on why I see this method of delivering mental health care is poised to expand in 2015 and beyond. Does telepsychiatry make sense for you?

Lack of supply is a big driver
There are simply not enough psychiatrists where they are needed, which is the primary driver of the expansion of telepsychiatry. With 77% of counties in the United States reporting a shortage of psychiatrists² and the “graying” of the psychiatric workforce,³ a more efficient way to make use of a psychiatrist’s time is needed. Telepsychiatry elimi­nates travel time and allows psychiatrists to visit distant sites virtually.

The shortage of psychiatric practitioners that we see today is only going to become worse. The Patient Protection and Affordable Care Act of 2010 includes mental health care and substance abuse treatment among its 10 essential benefits; just as important, new rules arising from the Mental Health Parity and Addiction Equity Act of 2008 limit restrictions on access to mental health care when insurance provides such cover­age.⁴ These legislative initiatives likely will lead to increased demand for psychiatrists in all care settings—from outpatient consults to acute inpatient admissions.


Why so attractive an option?
The shortage of psychiatrists creates limita­tions on access to care. Fortunately, telemed­icine has entered a new age, ushered in by widely available teleconferencing technol­ogy. Specialists from dermatology to surgery currently are using telemedicine; psychia­try is a good fit for telemedicine because of (1) the limited amount of “touch” required to make a psychiatric assessment, (2) signifi­cant improvements in video quality in recent years, and (3) a decrease in the stigma associ­ated with visiting a psychiatrist.

A generation raised on the Internet is entering the health care marketplace. These consumers and clinicians are accustomed to using video for many daily activities, and they seek health information from the Web. Visiting a psychiatrist through teleconferenc­ing isn’t strange or alienating to this genera­tion; their comfort with technology allows them to have intimate exchanges on video.

Subspecialty particulars
The earliest adopters, not surprisingly, are in areas where the strain of shortage has been felt most, with pediatric, geriatric, and correctional psychiatrists leading the way. In these fields, a substantial literature supports the use of telepsychiatry from a number of practice perspectives.

Pediatric psychiatry. The literature shows that children, families, and clinicians are, on the whole, satisfied with telepsychia­try.⁵ Children and adolescents who have been shown to benefit from telepsychia­try include those with depression,⁶ post­traumatic stress disorder, and eating disorders.⁷ Based on a case series, some authors have asserted that telepsychiatry might be preferable to in-person treatment (Box 2).⁸

Geriatric psychiatry. Research shows that geriatric patients, who are most likely to feel threatened by new technology, accept tele­psychiatry visits.⁹ For psychiatrists treating geriatric patients, telepsychiatry can sig­nificantly lower costs by cutting commut­ing¹⁰ and make more accessible for patients whose age makes them unable to drive.

Correctional psychiatry. Clinicians work­ing in correctional psychiatry have been at the forefront of experimentation with tele­psychiatry. The technology is a natural fit for this setting:  
   • Prisons often are located in remote locations.  
   • Psychiatrists can be reluctant to pro­vide on-site services because of safety concerns.

With correctional telepsychiatry, not only are patient outcomes comparable with in-person psychiatry, but the cost of delivering care can be significantly lower.¹¹ With the U.S. Department of Justice reporting that 50% of inmates have a diagnosable mental disorder, including substance abuse,¹² the need for access to a psychiatrist in the cor­rectional system is acute.

Telepsychiatry can confidently be pro­vided in a number of settings:  
   • emergency rooms  
   • nursing homes  
   • offices of primary care physicians  
   • in-home care.

Clinical services in these settings have been offered, studied, and reviewed.¹³

Can confidentiality and security be assured?
As with any new medical tool, the risk and benefits must be weighed care­ fully. The most obvious risk is to privacy. Telepsychiatry visits, like all patient encounters, must be secure and confiden­tial. Given the growing suspicion among the public and professionals who use com­puters that all data are at risk, clinicians must take appropriate cautions and, at the same time, warn patients of the risks. Readily available videoconferencing soft­ware, such as Skype, does not provide the level of security that patients expect from health care providers.¹⁴

 

Other common concerns about telepsy­chiatry are stable access to videoconferenc­ing and the safety from hackers of necessary hardware. Medical device companies have created hardware and software for use in telepsychiatry that provide a Health Insurance Portability and Accountability Act-compliant high-quality, stable, video­conferencing visit.

Do patients benefit?
Clinically, patients have fared well when they receive care through telepsychiatry. In some studies, however, clinicians have expressed some dissatisfaction with the technology¹³— understandable, given the value that psychi­atry traditionally has put on sitting with the patient. As Knoedler¹⁵ described it, making the switch to telepsychiatry from in-person contact can engender loneliness in some phy­sicians; not only is patient contact shifted to videoconferencing, but the psychiatrist loses the supportive environment of a busy clinical practice. Knoedler also pointed out that, on the other hand, telepsychiatry offers practi­tioners the opportunity to evaluate and treat people who otherwise would not have men­tal health care.

Obstacles—practical, knotty ones
Reimbursement and licensing. These are 2 pressing problems of telepsychiatry, although recent policy developments will help expand telepsychiatry and make it more appealing to physicians:
   • Medicare reimburses for telepsychiatry in non-metropolitan areas.
   • In 41 states, Medicaid has included tele­psychiatry as a benefit.¹⁶
   • Nine states offer a specific medical license for practicing telepsychiatry¹⁷ (in the remaining states, a full medical license must be obtained before one can provide telemedi­cine services).
   • The Joint Commission has included lan­guage in its regulations that could expedite privileging of telepsychiatrists.¹⁸

Even with such advancements, problems with licensure, credentialing, privacy, secu­rity, confidentiality, informed consent, and professional liability remain.¹⁹ I urge you to do your research on these key areas before plunging in.

Changes to models of care. The risk that telepsychiatry poses to various models of care has to be considered. Telepsychiatry is a dramatic innovation, but it should be used to support only high-quality, evidence-based care to which patients are entitled.²⁰ With new technology—as with new medi­cations—use must be carefully monitored and scrutinized.

Although evidence of the value of telepsy­chiatry is growing, many methods of long-distance practice are still in their infancy. Data must be collected and poor outcomes assessed honestly to ensure that the “more-good-than-harm” mandate is met.
 

Good reasons to call this shift ‘inevitable’
The future of telepsychiatry includes expansion into new areas of practice. The move to providing services to patients where they happen to be—at work or home— seems inevitable:
   • In rural areas, practitioners can com­municate with patients so that they are cared for in their homes, without the expense of transportation.
   • Employers can invest in workplace health clinics that use telemedicine ser­vices to reduce absenteeism.
   • For psychiatrists, the ability to provide services to patients across a wide region, from a single convenient location, and at lower cost is an attractive prospect.

To conclude: telepsychiatry holds potential to provide greater reimburse­ment and improved quality of life for psy­chiatrists and patients: It allows physicians to choose where they live and work, and limits the number of unreimbursed com­mutes, and gives patients access to psychi­atric care locally, without disruptive travel and delays.

Bottom Line
The exchange of medical information from 1 site to another by means of electronic communication has great potential to improve the health of patients and to alleviate the shortage of psychiatric practitioners across regions and settings. Pediatric, geriatric, and correctional psychiatry stand to benefit because of the nature of the patients and locations.

Related Resources
• American Telemedicine Association. Practice guidelines for video-based online mental health services. http://www. americantelemed.org/docs/default-source/standards/practice-guidelines-for-video-based-online-mental-health-services. pdf?sfvrsn=6. Published May 2013. Accessed February 10, 2015.
• Freudenberg N, Yellowlees PM. Telepsychiatry as part of a com­prehensive care plan. Virtual Mentor. 2014;16(12):964-968.
• Kornbluh R. Telepsychiatry is a tool that we must exploit. Clinical Psychiatry News. August 7, 2014. http://www. clinicalpsychiatrynews.com/home/article/telepsychiatry-is-a-tool-that-we-must-exploit/28c87bec298e0aa208309fa 9bc48dedc.html.
• University of Colorado Denver. Telemental Health Guide. http:// www.tmhguide.org.

 

Disclosure
Dr. Kornbluh reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Too few psychiatrists. A growing number of patients. A new federal law, technological advances, and a genera­tional shift in the way people communicate. Add them together and you have the perfect environment for telepsy­chiatry—the remote practice of psychiatry by means of tele­medicine—to take root (Box 1). Although telepsychiatry has, in various forms, been around since the 1950s,¹ only recently has it expanded into almost all areas of psychiatric practice.

Here are some observations from my daily work on why I see this method of delivering mental health care is poised to expand in 2015 and beyond. Does telepsychiatry make sense for you?

Lack of supply is a big driver
There are simply not enough psychiatrists where they are needed, which is the primary driver of the expansion of telepsychiatry. With 77% of counties in the United States reporting a shortage of psychiatrists² and the “graying” of the psychiatric workforce,³ a more efficient way to make use of a psychiatrist’s time is needed. Telepsychiatry elimi­nates travel time and allows psychiatrists to visit distant sites virtually.

The shortage of psychiatric practitioners that we see today is only going to become worse. The Patient Protection and Affordable Care Act of 2010 includes mental health care and substance abuse treatment among its 10 essential benefits; just as important, new rules arising from the Mental Health Parity and Addiction Equity Act of 2008 limit restrictions on access to mental health care when insurance provides such cover­age.⁴ These legislative initiatives likely will lead to increased demand for psychiatrists in all care settings—from outpatient consults to acute inpatient admissions.


Why so attractive an option?
The shortage of psychiatrists creates limita­tions on access to care. Fortunately, telemed­icine has entered a new age, ushered in by widely available teleconferencing technol­ogy. Specialists from dermatology to surgery currently are using telemedicine; psychia­try is a good fit for telemedicine because of (1) the limited amount of “touch” required to make a psychiatric assessment, (2) signifi­cant improvements in video quality in recent years, and (3) a decrease in the stigma associ­ated with visiting a psychiatrist.

A generation raised on the Internet is entering the health care marketplace. These consumers and clinicians are accustomed to using video for many daily activities, and they seek health information from the Web. Visiting a psychiatrist through teleconferenc­ing isn’t strange or alienating to this genera­tion; their comfort with technology allows them to have intimate exchanges on video.

Subspecialty particulars
The earliest adopters, not surprisingly, are in areas where the strain of shortage has been felt most, with pediatric, geriatric, and correctional psychiatrists leading the way. In these fields, a substantial literature supports the use of telepsychiatry from a number of practice perspectives.

Pediatric psychiatry. The literature shows that children, families, and clinicians are, on the whole, satisfied with telepsychia­try.⁵ Children and adolescents who have been shown to benefit from telepsychia­try include those with depression,⁶ post­traumatic stress disorder, and eating disorders.⁷ Based on a case series, some authors have asserted that telepsychiatry might be preferable to in-person treatment (Box 2).⁸

Geriatric psychiatry. Research shows that geriatric patients, who are most likely to feel threatened by new technology, accept tele­psychiatry visits.⁹ For psychiatrists treating geriatric patients, telepsychiatry can sig­nificantly lower costs by cutting commut­ing¹⁰ and make more accessible for patients whose age makes them unable to drive.

Correctional psychiatry. Clinicians work­ing in correctional psychiatry have been at the forefront of experimentation with tele­psychiatry. The technology is a natural fit for this setting:  
   • Prisons often are located in remote locations.  
   • Psychiatrists can be reluctant to pro­vide on-site services because of safety concerns.

With correctional telepsychiatry, not only are patient outcomes comparable with in-person psychiatry, but the cost of delivering care can be significantly lower.¹¹ With the U.S. Department of Justice reporting that 50% of inmates have a diagnosable mental disorder, including substance abuse,¹² the need for access to a psychiatrist in the cor­rectional system is acute.

Telepsychiatry can confidently be pro­vided in a number of settings:  
   • emergency rooms  
   • nursing homes  
   • offices of primary care physicians  
   • in-home care.

Clinical services in these settings have been offered, studied, and reviewed.¹³

Can confidentiality and security be assured?
As with any new medical tool, the risk and benefits must be weighed care­ fully. The most obvious risk is to privacy. Telepsychiatry visits, like all patient encounters, must be secure and confiden­tial. Given the growing suspicion among the public and professionals who use com­puters that all data are at risk, clinicians must take appropriate cautions and, at the same time, warn patients of the risks. Readily available videoconferencing soft­ware, such as Skype, does not provide the level of security that patients expect from health care providers.¹⁴

 

Other common concerns about telepsy­chiatry are stable access to videoconferenc­ing and the safety from hackers of necessary hardware. Medical device companies have created hardware and software for use in telepsychiatry that provide a Health Insurance Portability and Accountability Act-compliant high-quality, stable, video­conferencing visit.

Do patients benefit?
Clinically, patients have fared well when they receive care through telepsychiatry. In some studies, however, clinicians have expressed some dissatisfaction with the technology¹³— understandable, given the value that psychi­atry traditionally has put on sitting with the patient. As Knoedler¹⁵ described it, making the switch to telepsychiatry from in-person contact can engender loneliness in some phy­sicians; not only is patient contact shifted to videoconferencing, but the psychiatrist loses the supportive environment of a busy clinical practice. Knoedler also pointed out that, on the other hand, telepsychiatry offers practi­tioners the opportunity to evaluate and treat people who otherwise would not have men­tal health care.

Obstacles—practical, knotty ones
Reimbursement and licensing. These are 2 pressing problems of telepsychiatry, although recent policy developments will help expand telepsychiatry and make it more appealing to physicians:
   • Medicare reimburses for telepsychiatry in non-metropolitan areas.
   • In 41 states, Medicaid has included tele­psychiatry as a benefit.¹⁶
   • Nine states offer a specific medical license for practicing telepsychiatry¹⁷ (in the remaining states, a full medical license must be obtained before one can provide telemedi­cine services).
   • The Joint Commission has included lan­guage in its regulations that could expedite privileging of telepsychiatrists.¹⁸

Even with such advancements, problems with licensure, credentialing, privacy, secu­rity, confidentiality, informed consent, and professional liability remain.¹⁹ I urge you to do your research on these key areas before plunging in.

Changes to models of care. The risk that telepsychiatry poses to various models of care has to be considered. Telepsychiatry is a dramatic innovation, but it should be used to support only high-quality, evidence-based care to which patients are entitled.²⁰ With new technology—as with new medi­cations—use must be carefully monitored and scrutinized.

Although evidence of the value of telepsy­chiatry is growing, many methods of long-distance practice are still in their infancy. Data must be collected and poor outcomes assessed honestly to ensure that the “more-good-than-harm” mandate is met.
 

Good reasons to call this shift ‘inevitable’
The future of telepsychiatry includes expansion into new areas of practice. The move to providing services to patients where they happen to be—at work or home— seems inevitable:
   • In rural areas, practitioners can com­municate with patients so that they are cared for in their homes, without the expense of transportation.
   • Employers can invest in workplace health clinics that use telemedicine ser­vices to reduce absenteeism.
   • For psychiatrists, the ability to provide services to patients across a wide region, from a single convenient location, and at lower cost is an attractive prospect.

To conclude: telepsychiatry holds potential to provide greater reimburse­ment and improved quality of life for psy­chiatrists and patients: It allows physicians to choose where they live and work, and limits the number of unreimbursed com­mutes, and gives patients access to psychi­atric care locally, without disruptive travel and delays.

Bottom Line
The exchange of medical information from 1 site to another by means of electronic communication has great potential to improve the health of patients and to alleviate the shortage of psychiatric practitioners across regions and settings. Pediatric, geriatric, and correctional psychiatry stand to benefit because of the nature of the patients and locations.

Related Resources
• American Telemedicine Association. Practice guidelines for video-based online mental health services. http://www. americantelemed.org/docs/default-source/standards/practice-guidelines-for-video-based-online-mental-health-services. pdf?sfvrsn=6. Published May 2013. Accessed February 10, 2015.
• Freudenberg N, Yellowlees PM. Telepsychiatry as part of a com­prehensive care plan. Virtual Mentor. 2014;16(12):964-968.
• Kornbluh R. Telepsychiatry is a tool that we must exploit. Clinical Psychiatry News. August 7, 2014. http://www. clinicalpsychiatrynews.com/home/article/telepsychiatry-is-a-tool-that-we-must-exploit/28c87bec298e0aa208309fa 9bc48dedc.html.
• University of Colorado Denver. Telemental Health Guide. http:// www.tmhguide.org.

 

Disclosure
Dr. Kornbluh reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

 

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Ms. T’s MMSE score was 26/30, down from 29/30 at baseline. Her score fell below the cutoff score of 27 for mild cogni­tive impairment for someone with at least 8 years of completed education. Her results were abnormal mainly in the memory domain (3-item recall), raising the ques­tion of a possible prodromal state of AD although the acute nature of the change made delirium or mild NCD high in the differential.

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

 

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

 

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Laboratory work-up should include:
   •comprehensive metabolic panel (CMP) to assess for electrolyte derangements and liver or kidney disease
   •urinalysis if there are signs of urinary tract infection (low threshold for test­ing in patients age >65 even if they are asymptomatic)
   •urine drug screen or serum alcohol level if substance use is suspected
   •complete blood count (CBC) if there are reports of infection (white blood cell count) or blood loss/bruising to ensure that anemia or thrombocytopenia is not playing a role
   •thyroid-stimulating hormone (TSH) because thyroid disorders can cause neuro­psychiatric as well as somatic symptoms.⁹

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

 

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

 

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

 

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Ms. T’s MMSE score was 26/30, down from 29/30 at baseline. Her score fell below the cutoff score of 27 for mild cogni­tive impairment for someone with at least 8 years of completed education. Her results were abnormal mainly in the memory domain (3-item recall), raising the ques­tion of a possible prodromal state of AD although the acute nature of the change made delirium or mild NCD high in the differential.

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

 

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

 

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Laboratory work-up should include:
   •comprehensive metabolic panel (CMP) to assess for electrolyte derangements and liver or kidney disease
   •urinalysis if there are signs of urinary tract infection (low threshold for test­ing in patients age >65 even if they are asymptomatic)
   •urine drug screen or serum alcohol level if substance use is suspected
   •complete blood count (CBC) if there are reports of infection (white blood cell count) or blood loss/bruising to ensure that anemia or thrombocytopenia is not playing a role
   •thyroid-stimulating hormone (TSH) because thyroid disorders can cause neuro­psychiatric as well as somatic symptoms.⁹

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

 

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

 

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

“Mr. Smith seems somewhat confused today” is one of the most serious and concerning pre-visit reports you can receive from your staff or the patient’s family. Such a descriptor can be confusing—pardon the pun—not only for the patient, but to even seasoned mental health providers.

The term confusion can be code for diagnoses ranging from delirium^a to a progressive neurocognitive disorder (NCD) such as major NCD due to Alzheimer’s disease (AD), or even a more challenging prob­lem such as beclouded dementia (delirium superimposed on demen­tia/NCD). It is essential for all mental health professionals to have an evidence-based approach when encountering signs or symptoms of confusion.

^aICD-10 code R41.0 encompasses Confusion, Other Specified Delirium, or Unspecified Delirium.

CASE REPORT
Ms. T, age 62, has hypothyroidism and bipolar I disorder, most recently depressed, with comorbid generalized anxiety disorder. She has been tak­ing lithium, 600 mg/d, to control her mood symptoms. Her daughter-in-law reports that Ms. T has been exhibiting increasing signs of confusion. During the office evaluation, Ms. T minimizes her symptoms, only describ­ing mild issues with forgetfulness while cooking and concern over increas­ing anxiety. Her daughter-in-law plays a voicemail message from earlier in the week, in which Ms. T’s speech is halting, disorganized, and in a word, confused. I decide to use the mnemonic decision chart MR. MIND (Table 1) to get to the bottom of her recent confusion.

 

Measure cognition
It is nice to receive advanced warning about a cognitive change or a change in activities of daily living; however, many patients present with subtle, sub-acute changes that are more difficult to assess. When encountering a broad symptom such as “confusion”—which has an equally broad differential diagnosis—systematic assess­ment of the current cognitive state com­pared with the patient’s baseline becomes the first order of business. However, this requires that the patient has had a baseline cognitive assessment.

In my practice, I often administer one of the validated neurocognitive screening instruments when a patient first begins care—even a brief test such as the Mini- Cog (3-item recall plus clock drawing test), which is comparable to longer screening tests at least for NCD/dementia.¹ During a presentation for confusion, a more detailed neurocognitive assessment instrument would be recommended, allowing one to marry the clinical impression with a validated, objective measure. Formal neu­ropsychological testing by a clinical neuro­psychologist is the gold standard, but such testing is time-consuming and expensive and often not readily available. The screen­ing instrument I use for a more thorough evaluation depends on the clinical scenario.

The Six-Item Screener is used in some emergency settings because it is short but boasts a higher sensitivity than the Mini- Cog (94% vs 75%) with similar specificity when screening for cognitive impairment.² The Mini-Mental State Examination (MMSE) is a valuable instrument, although, recently, the Saint Louis University Mental Status Examination has been thought to be better at detecting mild NCD than the MMSE; more data are needed to substan­tiate this claim.³ The Montreal Cognitive Assessment is another validated screening tool that has been shown to be superior to the MMSE in terms of screening for mild cognitive impairment.⁴ The best delirium-specific assessment tool is the Confusion Assessment Method (Table 2).⁵

Ms. T’s MMSE score was 26/30, down from 29/30 at baseline. Her score fell below the cutoff score of 27 for mild cogni­tive impairment for someone with at least 8 years of completed education. Her results were abnormal mainly in the memory domain (3-item recall), raising the ques­tion of a possible prodromal state of AD although the acute nature of the change made delirium or mild NCD high in the differential.

Review medications
A review of the medication list is not just a Joint Commission mandate (medication reconciliation during each encounter) but is important whenever confusion is noted. Polypharmacy can be a concern, but is not as concerning as the class of medication prescribed, particularly anticholinergic and sedative medications in patients age >65. The Drug Burden Index can be helpful in assessing this risk.⁶ Medications such as the benzodiazepine-receptor agonists, tri­cyclic antidepressants, and antipsychotics should be discontinued if possible, keeping in mind that the addition or subtraction of medications must be done prudently and only after reviewing the evidence and in consultation with the patient. A detailed medication review is as important for confused outpatients as it is for an inpatient case (steps 2 and 3 of the inpatient algo­rithm outlined in Table 3).⁷

 

In Ms. T’s case, the primary concern on her medication list was that her medical team was prescribing levothyroxine, 112 mcg/d, and desiccated thyroid (combination thy­roxine and triiodothyronine in the form of 20 mg Armour Thyroid), despite a lack of data for such combination therapy. Earlier, I had discontinued lorazepam, leaving lithium, 600 mg/d, quetiapine, 400 mg/d, and escitalopram, 10 mg/d, as her remain­ing psychotropics. Her other medications included atorvastatin, 40 mg/d, for hyper-lipidemia and metformin, 750 mg/d, for type 2 diabetes mellitus.

 

Medical illness
An organic basis must rank high in the dif­ferential diagnosis if medications are not the culprit. There are myriad medical disorders that can lead to confusion (Table 4).⁸ In an outpatient psychiatric setting, labo­ratory and radiology testing might not be readily available. It then becomes impor­tant to collaborate with a patient’s medical team if any of the following are met:
   •there is high suspicion of a medical cause
   •there could be delays in performing a medical workup
   •a physical examination is needed.

Laboratory work-up should include:
   •comprehensive metabolic panel (CMP) to assess for electrolyte derangements and liver or kidney disease
   •urinalysis if there are signs of urinary tract infection (low threshold for test­ing in patients age >65 even if they are asymptomatic)
   •urine drug screen or serum alcohol level if substance use is suspected
   •complete blood count (CBC) if there are reports of infection (white blood cell count) or blood loss/bruising to ensure that anemia or thrombocytopenia is not playing a role
   •thyroid-stimulating hormone (TSH) because thyroid disorders can cause neuro­psychiatric as well as somatic symptoms.⁹

Other laboratory testing could be valu­able depending on the clinical scenario. These include tests such as:
   •drug level monitoring (lithium, val­proic acid, etc.) to assess for toxicity
   •HIV and rapid plasma reagin for sus­pected sexually transmitted infections
   •vitamin levels in patients with poor nutrition or post bariatric surgery
   •erythrocyte sedimentation rate or C-reactive protein, or both, if there are signs of inflammation
   •bacterial culture if blood or tissue infec­tion is a concern.

Esoteric tests include ceruloplasmin (Wilson’s disease), heavy metals screen, and even tests such as anti-gliadin anti­bodies because the prevalence of gluten sensitivity and celiac disease appear to be on the rise and have been associated with neuropsychiatric problems including encephalopathy.¹⁰

Brain imaging is an important consider­ation when a medical differential diagnosis for confusion is formulated. Unfortunately, there is little evidence-based guidance as to when brain imaging should be performed, often leading to overuse of tests such as CT, especially in emergency settings when con­fusion is noted. From a clinical standpoint, a head CT scan often is best ordered for patients who demonstrate an acute change in mental status, are age >70, are receiving anticoagulation, or have sustained trauma to the head. The key concern would be intracranial hemorrhage. However, some data suggest that the best use of head CT is for patients who have an impaired level of consciousness or a new focal neurologic deficit.¹¹

Apart from more acute changes, a brain MRI study is more helpful than a head CT when evaluating the brain parenchyma for more sub-acute diagnoses such as multiple sclerosis or a brain tumor. T2-weighted hyperintensities seen on an MRI are thought to predict an increased risk of stroke, dementia, and death.

Their discov­ery should prompt a detailed evaluation for risk factors of stroke and dementia/NCD.¹²

In Ms. T’s case, she was taking lithium, so it was logical to obtain a trough lith­ium level 12 hours after the last dose and to check kidney function (serum creati­nine to estimate the glomerular filtration rate), which were in the therapeutic/nor­mal range. Her serum lithium level was 0.7 mEq/L. Brain imaging was not ordered, but several other labs (CMP, CBC, hemoglo­bin A1c [HgbA1c], and TSH) were drawn. These labs were notable for HgbA1c of 5.1% (normal <5.7%) and TSH of 0.5 mIU/L (normal level, 1.5 mIU/L), which is low for someone taking thyroid replacement.

I requested that Ms. T stop Armour Thyroid to address the suppressed TSH. I also requested that she stop metfor­min because, although hypoglycemia from metformin monotherapy is uncom­mon, it can happen in older patients. Hypoglycemia associated with metformin also can occur in situations when caloric intake is deficient or when metformin is used in combination with other drugs such as sulfonylureas (ie, glipizide), beta-adrenergic blocking drugs, angiotensin-converting enzyme inhibitors, or even nonsteroidal anti-inflammatory drugs.¹³

Identifying overlapping psychiatric (or psychological) illness
Symptoms of depression, anxiety, psycho­sis, and even dissociation can present as con­fusion. The term pseudodementia describes patients who exhibit cognitive symptoms consistent with NCD but could improve once the underlying mood, thought, anxi­ety, or personality disorder is treated.

For example, a patient with depression typically exhibits neurovegetative symp­toms—such as poor sleep or appetite— amotivation, and low energy. All of these can lead to abrupt-onset cognitive changes, which are a hallmark of pseudodementia rather than the more insidious pattern of mild NCD. In cases of pseudodementia, neurocognitive testing will show impair­ment that often rapidly improves after the primary psychiatric (or psychological) issue is rectified. Making a diagnosis of pseu­dodementia at the initial presentation is difficult because neurocognitive tests such as the MMSE often fail to separate depres­sion from true cognitive changes.¹⁴ Such a diagnosis typically requires hindsight. Yet, one must also keep in mind that pseudode­mentia may be part of a NCD prodrome.¹⁵

 

Conversion disorder as well as the disso­ciative disorders and substance-related dis­orders are notorious for causing confusion. In Ms. T’s case, pseudodementia stemming from her underlying bipolar disorder and anxiety figured prominently in the differ­ential diagnosis, but she did not have any other overt psychopathology, personality disorder, or signs of malingering to further complicate her picture.

Notebook. I recommend that my patients keep a small notebook to record medical data ranging from blood pressure and gly­cemic measurements to details about sleep and dietary intake. Such data comprise the necessary metrics to properly assess target conditions and then track changes once treatment is initiated. This exercise not only yields much-needed detail about the patient’s condition for the clinician; the act of journaling also can be therapeutic for the writer through a process known as experi­mental disclosure, in which writing down one’s thoughts and observations has a posi­tive impact on the writer’s physical health and psychology.¹⁶

Diagnosis. The first rule in medicine (perhaps the second, behind primum non nocere) is to determine what you are treat­ing before beginning treatment (decernite quid tractemus, prius cura ministrandi, for Latin buffs). This means trying to fash­ion the best diagnostic label, even if it is merely a place-holder, while assessment of the confused state continues. DSM-5 has attempted to remove stigma from several neuropsychiatric disorders. On the cog­nition front, the new name for dementia is “neurocognitive disorder (NCD),” the umbrella term that focuses on the decline from a previous level of cognitive func­tioning. NCD has been divided into mild or major cognitive impairment headings either “with” or “without behavioral dis­turbance” subspecifiers.¹⁷

Aside from NCD, there are several other diagnoses in the differential for confusion. Delirium remains the most prominent and focuses on disturbances in attention and orientation that develops over a short period of time, with a change seen in an additional cognitive domain, such as memory, but not in the context of a severely reduced level of arousal such as coma. Subjective cognitive impairment (SCI) is when subjective complaints of cog­nitive impairment are hallmark compared with objective findings—with evidence suggesting that the presence of SCI could predict a 4.5 times higher rate of develop­ing mild cognitive impairment (MCI) over 7 years.¹⁸ MCI was originally used to describe the early prodrome of AD, minus functional decline.


Treatment
After even a provisional diagnosis comes the final, all-important challenge: treating the neuropsychiatric symptoms (NPS) of the confused patient. NPS are nearly universal in NCD/delirium throughout the course of illness. There are no FDA-approved treat­ments for the NPS associated with these conditions. In terms of treating delirium, the best approach is to treat the underlying medical condition. For control of behavior, which can range from agitated to psychotic to hypoactive, nonpharmacotherapeutic interventions are paramount; they include making sure that the patient is at the appro­priate level of care, which, for the confused outpatient, could mean hospitalization. Ensuring proper nutrition, hydration, sen­sory care (hearing aids, glasses, etc.), and stability in ambulation must be done before considering pharmacotherapy.

Antipsychotic use has been the mainstay of drug treatment of behavioral dyscontrol. Haloperidol has been the traditional go-to medication because there is no evidence that low-dose haloperidol (<3 mg/d) has any different efficacy compared with the atypical antipsychotics or has a greater fre­quency of adverse drug effects. However, high-dose haloperidol (>4.5 mg/d) was associated with a greater incidence of adverse effects, mainly parkinsonism, than atypical antipsychotics.¹⁹ Neither the typi­cal nor atypical antipsychotics have shown mortality benefit—the real outcome mea­sure of interest.

In terms of treating major (or minor) NCD, there are only 2 FDA-approved medication classes: cholinesterase inhibi­tors (donepezil, galantamine, rivastig­mine, etc.) and memantine. However, these medication classes—even when combined together—have only shown marginal benefit in terms of improving cognition. Worse, even when given early in the course of illness they do not reduce the rate of NCD. For pseudodementia, selec­tive serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors tend to form the mainstay of treating underlying depression or anxiety leading to cognitive changes. Preliminary data suggest that some SSRIs might improve cognition in terms of process­ing speed, verbal learning, and memory.²⁰ More studies are needed before definitive conclusions can be drawn.

For the confused patient, a personalized therapeutic program, in which multiple interventions are considered at once (tar­geting all areas of the patient’s life) is gain­ing research traction. For example, a novel, comprehensive program involving mul­tiple modalities designed to achieve meta­bolic enhancement for neurodegeneration (MEND) recently has shown robust benefit for patients with AD, MCI, and SCI.²¹ Using an individual approach to improve diet, activity, sleep, metabolic status including body mass index, and several other mark­ers that affect neural plasticity, researchers demonstrated symptom improvement in 9 of 10 study patients.

 

Yet, some of the interventions, such as the use of statins for hyperlipidemia, remain controversial, with some studies suggesting that they help cognition,^22,23 and others showing no association.²⁴ The researchers caution that further research is warranted before costly dementia pre­vention trials with statins are undertaken. It does not appear that there are current MEND-type research projects in delirium but it’s to be hoped that we will see these in the future.

In the case of Ms. T, the cause of delir­ium vs mild NCD was thought to be mul­tifactorial. Discontinuing Armour Thyroid and metformin—symptoms of hypoglyce­mia emerged as a leading concern—were simple adjustments that led to resolution of the most concerning elements of her confusion. She continued her other psy­chotropics, although there might be mild residual cognitive issues that warrant close observation.

Related Resources
• Lin JS, O’Connor E, Rossum RC, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality (US); 2013.
• Grover S, Kate N. Assessment scales for delirium: a review. World J Psychiatry. 2012;2(4):58-70.

Drug Brand Names
Atorvastatin • Lipitor                           Lithium • Eskalith, Lithobid
Donepezil • Aricept                              Lorazepam • Ativan
Escitalopram • Lexapro                        Memantine • Namenda
Flumazenil • Romazicon                       Metformin • Glucophage
Galantamine • Razadyne                      Naloxone • Narcan
Glipizide • Glucotrol                             Physostigmine • Antilirium
Haloperidol • Haldol                             Quetiapine • Seroquel
Levothyroxine • Levoxyl, Synthroid       Rivastigmine • Exelon
Lithium • Eskalith, Lithobid                   Valproic acid • Depakene

Disclosure
Dr. Raj is a speaker for Actavis Pharmaceuticals, AstraZeneca, and Merck.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Levomilnacipran is unique because it is more of an NSRI, so to speak, than an SNRI: That is, the drug’s uptake inhibition of norepinephrine is more potent than its serotonin inhibition. Theoretically, levomilnacipran should help improve cognitive functions linked to the action of norepinephrine, such as concentration and motivation, and in turn, improve social function. The FDA also has approved levomilnacipran for treating functional impairment in depression.⁹

Adverse effects. The norepinephrine uptake inhibition of levomilnacipran might be responsible for observed increases in heart rate and blood pressure in some patients, and dose-dependent urinary hesitancy and erectile dysfunction in others. The drug has no significant effect on weight in depressed patients, compared with placebo.

Continue to: The benefits of levomilnacipran

 

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

The downstream effect of this multi­modal action is an increase in dopamine, norepinephrine, and acetylcholine activ­ity in the prefrontal cortex.¹⁰ These down­stream effects are thought to help restore some cognitive deficits associated with depression.¹¹

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

 

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

 

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral