Current Psychiatry

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

CASE: Unclear diagnosis

Police find Ms. S, age 31, extremely intoxicated and drinking alcohol in her car in a city park parking lot. In the emergency room, she becomes increasingly somnolent and clinicians intubate her trachea to protect her airway. Lab testing shows she has elevated acetaminophen and lithium serum levels, and she is transferred to our hospital for further management after being started on N-acetylcysteine to treat acetaminophen toxicity. Her “ex-fiancé,” the father of her 2 children, saw her earlier the day of the episode and says she was distraught, intoxicated, and had several empty pill bottles in her purse.

In our hospital, Ms. S’ lithium level increases from 2.3 mEq/L to a peak of 5.32 mEq/L, and she undergoes hemodialysis. On hospital day 2, her serum lithium level is trending downward. After Ms. S is able to breathe spontaneously, her trachea is extubated and her hemodialysis line is removed. A psychiatric consultation is obtained, but she is unable to provide a coherent history and the treating clinicians believe she has delirium caused by multiple factors.

On hospital day 3, Ms. S’ delirium clears enough for her to engage in an interview, and she is transferred to our inpatient psychiatry ward for further monitoring and stabilization.

She reports that she was diagnosed with bipolar disorder (BD) at age 12, when she faced multiple psychosocial stressors, including physical abuse by her mother’s boyfriend. She took several psychotropics—although she cannot remember which ones—until age 14, when she stopped all medications until the year before her current hospitalization. Although throughout adolescence and adulthood Ms. S experienced chronic irritability, anxiety, impulsive behavior, poor self-esteem, abusive relationships, self-cutting, and depressed mood, she maintains that she felt worse when she was taking psychotropics and doubts the BD diagnosis. She attributes her longstanding mood issues to low self-worth, a “codependent nature,” and a tendency to gravitate toward abusive relationships. Although she admits to experimenting with several illicit drugs during adolescence, she denies more recent substance use and states she drinks alcohol only once every few months.

The authors’ observations

BD is underdiagnosed in several patient populations, such as individuals previously diagnosed with MDD.^1-3 Misdiagnosis can have severe implications, including delay in receiving treatment with effective medications (eg, mood stabilizers) or use of agents that can induce mania or rapid-cycling, such as antidepressants. Perhaps in response to this concern, in recent years clinicians increasingly have diagnosed BD in adolescents and adults. An analysis of a national database of physician practices found a 40-fold increase in office visits for BD among youth and a near doubling among adults from 1994 to 2003.⁴

Although underdiagnosis of BD remains important, some researchers have suggested that overdiagnosis may be more prevalent and equally harmful. In a study of 180 patients being treated for depression in a family care clinic, there was a 21.6% initial underdiagnosis rate among those eventually found to have BD.¹ However, among 43 patients with a prior BD diagnosis, the diagnosis was not confirmed in 33%.¹ In a study of 700 psychiatric outpatients in Rhode Island, only 43% of 145 patients who reported a prior BD diagnosis had that diagnosis confirmed.⁵ Three times as many patients were overdiagnosed with BD as underdiagnosed.

Are there characteristics common to individuals incorrectly diagnosed with BD? In a study that compared patients who had been mistakenly diagnosed with BD with those who had not been diagnosed with BD, the overdiagnosis group was significantly more likely to be diagnosed with a personality disorder, in particular borderline or antisocial personality disorder.⁶ Only lifetime and current BPD, current posttraumatic stress disorder (PTSD), and lifetime impulse control disorders were independently associated with BD overdiagnosis. The odds ratio for overdiagnosis of BD in patients found to have BPD was 3.7.

EVALUATION: Rethink the diagnosis

In the last few months, Ms. S had complained to her primary care provider (PCP) of worsening anxiety and depressed mood. She was the victim of ongoing physical and emotional abuse by her ex-fiancé and was concerned that she may lose custody of her 2 sons. Approximately 8 months before admission, Ms. S’ PCP prescribed lithium, 450 mg, 3 times a day, for “mood stabilization” and depression because she’d already been diagnosed with BD. This was the first mood stabilizer she’d taken since she was 14. She also was taking unknown doses of hydrocodone/acetaminophen, cyclobenzaprine, and tramadol for pain and temazepam for insomnia. Ms. S continued to suffer from labile and depressed mood, and fought with her ex-fiancé and legal authorities to maintain custody of her 2 children until she was found in the park.

Throughout her hospitalization she denies that she attempted suicide that day, and maintains that this incident was caused by unintentional mismanagement of her medications. Although she continues to have a sense of low self-worth, she denies feeling depressed; in contrast, she says she feels like she has a “new lease on life.” During several interviews she cannot provide a history of any prolonged (ie, several days) episodes of elevated mood, increased goal-directed behavior, decreased need for sleep, tangential thought, pressured speech, or other symptoms that suggest hypomania or mania. She does not endorse prolonged periods of neurovegetative symptoms that would indicate a major depressive episode.

We feel that Ms. S’ symptoms of affective dysregulation, impulsivity, and interpersonal dysfunction are consistent with BPD, and we determine that she meets 6 of the 9 DSM-IV-TR diagnostic features of BPD (≥5 are required for a BPD diagnosis) (Table 1).⁷ Ms. S describes efforts to avoid abandonment, unstable and intense interpersonal relationships, marked and persistent unstable self-image, recurrent suicidal and self-mutilating behavior, affective instability, and chronic feelings of emptiness. She is discharged to follow up with a psychotherapist and family practitioner. She is not continued on any psychotropic medications.

The authors’ observations

Although it can be difficult to accurately diagnose psychiatric illness during a brief inpatient hospitalization, several clinicians who cared for Ms. S felt that her presentation was more consistent with BPD than BD. Her case is an example of the potential harm of incorrectly diagnosing personality-disordered patients with BD. Ms. S is impulsive and used lithium—a medication that is the standard of care for BD—in an overdose, which lead to a costly and dangerous hospitalization marked by a difficult tracheal intubation and hemodialysis.

Table 1

DSM-IV-TR diagnostic criteria for borderline personality disorder

Distinguishing BD and BPD

There is considerable overlap in symptoms of BD and BPD. Although the episodic nature of BD is well differentiated from the more chronic course of BPD, many hypomania and mania symptoms are similar to those of BPD (Table 2).⁷ For example, patients with BD or BPD may exhibit impulsive behavior and labile moods. Substance use, risky and self-destructive behaviors, and inflammatory interpersonal relationships can occur in both disorders. Some researchers have suggested that pathophysiologically, BPD may fall on a spectrum of bipolar illness, and have proposed a clinical entity they call bipolar type IV or ultra-rapid cycling BD.^2,8,9 There may be more co-occurrence of BD with BPD than would be expected by chance¹⁰; 1 review of BPD studies found the rate of comorbid BD ranged from 5.6% to 19%.¹¹ However, because of differences in several factors—including phenomenology, family prevalence, longitudinal course, and medication response—some researchers have concluded that evidence does not support categorizing BPD as part of a bipolar spectrum.^10-14 Nonetheless, BPD and other personality disorders often co-occur with axis I disorders, including MDD, BD, or PTSD.

Some research has suggested that the increasing availability and marketing campaigns of medications to treat BD may promote diagnosis of the disorder.¹⁵ Zimmerman¹⁵ hypothesizes that physicians may be more likely to diagnose a condition that responds to medication (ie, BD) than one that is less responsive (ie, BPD). Financial compensation for treating axis I disorders is significantly better than for treating personality disorders.¹⁶ The inpatient setting confers barriers to accurately diagnosing personality disorders, including limits on the amount of time that clinicians can spend with patients or ability to communicate with sources of collateral information. A patient’s observed personality and behaviors while hospitalized may not accurately reflect his or her personality and behaviors in that patient’s “natural” environment.

Several diagnostic strategies can help distinguish BPD from BD. For BD to be the primary diagnosis, a patient must have had a hypomanic or manic episode. Sustained episodes of elation or extreme irritability without evident stressors suggest BD rather than BPD.¹⁰ According to Gunderson et al,¹⁰ “repeated angry outbursts, suicide attempts, or acts of deliberate self harm that are reactive to interpersonal stress and reflect extreme rejection sensitivity are axiomatic of borderline personality disorder.” In a review of clinical practice, Gunderson¹⁷ found that hypersensitivity to rejection and fearful preoccupation with expected abandonment are the most distinctive characteristics of BPD patients. He suggested that clinicians can establish the diagnosis by asking patients directly if they believe the criteria for BPD characterize them, which also can help a patient to accept the diagnosis.

Finally, during a short hospitalization, it can be helpful to obtain collateral information from the patient’s friends and family or further characterize the time course of symptoms and diagnostic features in the patient’s natural environment. Clinicians who are reluctant to diagnose BPD in an inpatient setting could suggest the presence of borderline traits or discuss the possibility of the BPD diagnosis in documentation (eg, in the assessment or formulation). Doing so would avoid a premature BPD diagnosis and allow outpatient providers to confirm or rule out personality disorder diagnoses over time. It is important to screen patients with BPD for co-occurring axis I disorders, including BD, MDD, PTSD, and substance abuse.

A false-positive BD diagnosis in patients with BPD has serious treatment implications. Antipsychotics, antidepressants, and anticonvulsants have been used to target BPD symptoms such as affective dysregulation, impulsivity, and cognitive/perceptual abnormalities, but no medications are FDA-approved for treating BPD. American Psychiatric Association guidelines recommend symptom-based pharmacologic strategies for BPD,¹⁸ although some researchers believe that these recommendations are out-of-date and not evidence-based.^17,19 Some evidence suggests pharmacotherapy can have modest short-term benefits on specific BPD symptoms, but no data suggest that medication can reduce the severity of BPD or lead to remission.^19-23 Just 1 randomized controlled trial (N = 17) has examined lithium for BPD and found no effect on mood.^11,24

Misdiagnosis of BD in the context of BPD may create unrealistic expectations regarding the potential efficacy of medications for relieving symptoms. Patients may be diverted from potentially helpful psychotherapeutic treatments—such as DBT or mentalization therapy—which evidence suggests can effectively reduce symptoms, the need for additional treatments, and self-harm or suicidal behaviors.^10,17,19 Evidence from long-term longitudinal studies suggests that psychosocial or psychotherapeutic treatment may protect against suicide in BPD patients.²⁵

Table 2

DSM-IV-TR diagnostic criteria for a manic episode

Related Resources

• National Education Alliance Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.
• Hoffman PD, Steiner-Grossman P. Borderline personality disorder: meeting the challenges to successful treatment. Philadelphia, PA: Haworth Press; 2008.

Drug Brand Names

• Cyclobenzaprine • Flexeril
• Hydrocodone/acetaminophen • Lorcet, Vicodin, others
• Lithium • Eskalith, Lithobid
• Temazepam • Restoril
• Tramadol • Ultram

Disclosure

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

Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

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

Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

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

Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

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

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.