Evidence-Based Reviews

With panic attacks, alarming physiologic symptoms mount swiftly—tachycardia, chest pain, sweating, trembling, smothering or choking, dizziness, fear of losing control or going crazy—even fear of dying.¹ Patients constantly fear the next attack, worry about its consequences, and change their behaviors to avoid or withdraw from anxiety-provoking situations.

To relieve their suffering, cognitive-behavioral therapy (CBT) may offer benefits you would not realize with medication alone. CBT can:

• improve long-term patient outcomes
• enhance medication management
• boost treatment response when medication alone is inadequate
• ease drug discontinuation.²

Whether you or a CBT-trained psychotherapist guides the sessions, you can achieve optimal results for your patients with panic disorder.

How Effective is CBT?

Panic disorder is chronic, often disabling, and characterized by spontaneous, unpredictable panic attacks (Boxes 1 and 2^3-11). When treated with CBT, about three-quarters of patients become panic-free and maintain treatment gains at follow-up, and one-half become both panic-free and free of excess anxiety.⁹

Typical therapy is 12 individual, once-weekly visits for psycho-education, relaxation, and breathing training; cognitive restructuring; and exposure therapies.

Briefer protocols, “reduced therapist contact,”¹² and group therapy¹³ also can help patients and in some studies have been as beneficial as 12 weeks of individual therapy. Although trained psychotherapists have higher success rates than nonbehaviorists when treating panic patients, nonbehaviorists also can provide effective therapy after relatively brief training.¹⁴

American Psychiatric Association¹⁵ treatment guidelines recommend medications—such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and benzodiazepines—as well as CBT as first-line therapies for panic disorder. Other treatment guidelines concur¹⁶ and note that CBT is more cost-effective than medications.

In comparison studies, CBT has been at least as effective for panic symptoms as SSRIs,^17,18 TCAs,¹⁹ and alprazolam.²⁰ Antidepressants are the preferred drug for panic disorder¹⁶ because they lack benzodiazepines’ dependence and abuse potential.

Providing medication during CBT may maintain patients’ therapeutic gains better than CBT alone if the medication is continued after CBT is completed. Interestingly, patients who use benzodiazepines during CBT may have higher relapse rates than those who do not use benzodiazepines, particularly when the benzodiazepines are withdrawn.⁹

CBT produces improvement rates similar to those of pharmacologic treatment at one-quarter to one-half the cost in the first year. Patients also appear to have better clinical outcomes if they receive CBT while SSRIs or benzodiazepines are being discontinued, compared with simply stopping the medications.⁸

Box 1

Box 2

CBT Candidates

To diagnose panic disorder, conduct a thorough psychiatric evaluation that includes assessing for comorbid mental and substance use disorders. The history and physical exam are essential to rule out medical causes of the patient’s symptoms, such as heart disease causing dizziness or palpitations. Asking patients to keep panic attack records can help you identify panic symptoms’ frequency and triggers.⁹

An assessment tool such as the Albany Panic and Phobia Questionnaire (Figure) can be a useful starting point. It has 27 items and three subscales to quantify a patient’s fear of agoraphobic situations, social phobia situations, and situations that produce bodily sensations (interoceptive symptoms). Items on the interoceptive subscale include activities such as exercising vigorously, ingesting caffeine, and experiencing intense emotion.²¹ Using the Anxiety Sensitivity Index is another assessment option.²²

Not all patients with panic attacks respond well to CBT; predictors of poor response in clinical trials have included:

• severe baseline panic symptoms, personality disorders, and possibly depressed mood
• marital dissatisfaction
• low motivation for treatment.^2,9

Figure Patient assessment: Albany Panic and Phobia Questionnaire

Source: Reprinted with permission from Rapee RM, Craske MG, Barlow DH. Assessment instrument for panic disorder that includes fear of sensation-producing activities: The Albany Panic and Phobia Questionnaire. Anxiety 1995;1:114-22. Copyright 1995, Wiley-Liss, Inc.

Cognitive Therapies for Panic Disorder

Psychoeducation. Begin by defining and explaining anxiety, panic attacks, panic disorder, and any comorbid psychopathology the patient may have (agoraphobia, depression). Explain panic symptoms as physiologic and psychological responses to stressors.

Address the patient’s fears that anxiety’s physiologic symptoms represent a serious or undiagnosed medical disorder or that a panic attack could cause serious harm. Assign self-help and reading materials to reinforce this discussion (see Related resources). Finally, explain the rationale for using CBT to treat panic symptoms.

Use cognitive restructuring to address faulty or irrational information-processing patterns that underlie pathologic anxiety. Identify automatic thought patterns (such as catastrophizing, overgeneralization, all-or-nothing thinking, and personalization), then provide a careful “reality check,” in which you systematically substitute a more-rational thought process.

Have the patient keep a self-monitoring diary to help you assess thought patterns and re-direct irrational thoughts. A diary may identify anxiety-provoking scenarios on which to focus therapy. Encourage patients to document anxiety events using the “triple-column” technique:²³

• column 1: circumstances of the anxiety or panic
• column 2: their emotional state at the time
• column 3: any thoughts they can identify.

Instruct them to log this data while experiencing symptoms or immediately afterward. Later, during the intervention phase, patients can record how they tried to restructure their thoughts and any consequent mood changes. Review diary entries with them during subsequent sessions.

Exposure Therapy

Graduated exposure and response prevention (ERP) is the core component of CBT for panic disorder. ERP exercises require the patient to confront anxiety-producing stimuli while agreeing not to engage in maladaptive behavior that avoids, prematurely reduces, or prevents the anxiety. The stimuli may be external cues—such as bridges, stores, or heights—or interoceptive cues such as dizziness, tachycardia, or tachypnea.

Creating fear hierarchies. To begin, we recommend that you work with the patient to create lists of all external situations and interoceptive stimuli that cause him or her anxiety. Separating the stimuli into two lists helps patients recognize that their bodily stimuli are at least as important as environmental stimuli in promoting a panic attack.

The patient then rates each stimulus using a Subjective Units of Distress scale (SUDS)—assigning 0 to 100 points from no anxiety to overwhelming anxiety—and ranks items on the lists from mildest to worst anxiety. Instruct patients to rate the distress they would feel if they could not escape from the stimuli.

First experience. After the hierarchies are created, the therapist introduces the patient to exposure therapy by choosing an item that causes mild to moderate anxiety. Starting at this anxiety level, patients are likely to succeed with their first exercise without feeling overwhelmed. The therapist teaches the patient about the process, then begins the exposure by helping the patient create and confront the very scenario (or a representation of that scenario) that causes anxiety.

When working on interoceptive cues, various exercises can be used to reproduce bother-some bodily symptoms, such as:

• running up a flight of stairs or running in place to generate tachycardia
• purposefully hyperventilating to produce lightheadedness.
• spinning in place to create dizziness.

The patient agrees not to actively attempt to escape the scenario but to tolerate and perhaps even focus on the anxiety (Box 3). Using “safety cues”—such as leaning against a wall or keeping eyes closed—is also forbidden. Patients soon see that the anxiety does not last indefinitely but begins to diminish fairly rapidly.

Reaching the goal. After repeated exposure sessions, anxiety associated with a stimulus begins to extinguish. Having experienced the success of tolerating a previously difficult stimuli and feeling much less anxious, the patient is ready to take on increasingly difficult tasks. The therapist also assigns the patient “homework” to practice exposure exercises already mastered during sessions. As exposure therapy progresses, the patient takes a larger role in designing and executing sessions. The goal is for the patient to learn to become his or her own behaviorist and to intervene early when panic symptoms begin.

Box 3

Other Behavioral Techniques

Imaginal exposure sessions can be created using visualizations of feared stimuli, gradually presented as with in vivo exposure. For example, as you recount a target scenario, ask the patient to imagine a progression of events or bodily cues that have led to panic attacks. The patient supplies SUDS ratings and refrains from imagining an avoidance or maladaptive response. You can tape-record the session for homework and assign the patient to listen to it and participate daily.

Imaginal exposure may help treat phobic avoidance (such as agoraphobic symptoms), but study results have been disappointing in panic symptoms.²⁴ However, this approach may help reluctant patients initiate in vivo exposure therapy.

Relaxation training—such as progressive muscle relaxation, visual imagery, or autogenic protocols—has shown mixed results in treating panic.^25,26 Relaxation may help patients cope with panic’s physiologic arousal, but it is not suitable as a singular intervention.

Breathing retraining. Because hyperventilation and panic symptoms are related, instruction and practice in slow, diaphragmatic breathing has long been a component of CBT for panic symptoms. Little evidence supports breathing retraining,⁹ although Meuret et al^27,28 have described a respiratory feedback paradigm that may reduce panic symptoms in appropriately selected patients.

Many studies that have assessed breathing retraining as monotherapy for panic have had methodologic flaws.²⁷

Building a Therapeutic Alliance

Successful therapists have been found to use empathic listening more than directives and explanations in the first therapy session.⁹ They understand the suffering from panic disorder and the value of listening as patients explain their symptoms, thoughts, and feelings. The rapport built during this initial interaction can help sustain motivation as the therapist then takes charge of subsequent sessions.

Among important skills for CBT therapists, Seligman²⁹ includes empathy, caring, warmth, and active listening, as well as the ability to:

• be a teacher, scientist, and co-investigator
• demystify treatment
• engage clients as “active, knowledgeable, and responsible partners” in their therapy.

Finally, although CBT clinicians suggest tasks and interventions for this “shared endeavor,” patients are primarily responsible for change.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
• Craske M, Barlow D, Cary NC. Mastery of your anxiety and panic, (3rd ed). Therapist guide and client workbook. Oxford, UK: Oxford University Press; 2000.
• Otto MW. Stopping anxiety medication: panic control therapy for benzodiazepine discontinuation. Therapist guide and patient workbook. Oxford, UK: Oxford University Press; 2004.
• The Panic Center. Patient diaries and other self-help resources. www.paniccenter.net

With panic attacks, alarming physiologic symptoms mount swiftly—tachycardia, chest pain, sweating, trembling, smothering or choking, dizziness, fear of losing control or going crazy—even fear of dying.¹ Patients constantly fear the next attack, worry about its consequences, and change their behaviors to avoid or withdraw from anxiety-provoking situations.

To relieve their suffering, cognitive-behavioral therapy (CBT) may offer benefits you would not realize with medication alone. CBT can:

• improve long-term patient outcomes
• enhance medication management
• boost treatment response when medication alone is inadequate
• ease drug discontinuation.²

Whether you or a CBT-trained psychotherapist guides the sessions, you can achieve optimal results for your patients with panic disorder.

How Effective is CBT?

Panic disorder is chronic, often disabling, and characterized by spontaneous, unpredictable panic attacks (Boxes 1 and 2^3-11). When treated with CBT, about three-quarters of patients become panic-free and maintain treatment gains at follow-up, and one-half become both panic-free and free of excess anxiety.⁹

Typical therapy is 12 individual, once-weekly visits for psycho-education, relaxation, and breathing training; cognitive restructuring; and exposure therapies.

Briefer protocols, “reduced therapist contact,”¹² and group therapy¹³ also can help patients and in some studies have been as beneficial as 12 weeks of individual therapy. Although trained psychotherapists have higher success rates than nonbehaviorists when treating panic patients, nonbehaviorists also can provide effective therapy after relatively brief training.¹⁴

American Psychiatric Association¹⁵ treatment guidelines recommend medications—such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and benzodiazepines—as well as CBT as first-line therapies for panic disorder. Other treatment guidelines concur¹⁶ and note that CBT is more cost-effective than medications.

In comparison studies, CBT has been at least as effective for panic symptoms as SSRIs,^17,18 TCAs,¹⁹ and alprazolam.²⁰ Antidepressants are the preferred drug for panic disorder¹⁶ because they lack benzodiazepines’ dependence and abuse potential.

Providing medication during CBT may maintain patients’ therapeutic gains better than CBT alone if the medication is continued after CBT is completed. Interestingly, patients who use benzodiazepines during CBT may have higher relapse rates than those who do not use benzodiazepines, particularly when the benzodiazepines are withdrawn.⁹

CBT produces improvement rates similar to those of pharmacologic treatment at one-quarter to one-half the cost in the first year. Patients also appear to have better clinical outcomes if they receive CBT while SSRIs or benzodiazepines are being discontinued, compared with simply stopping the medications.⁸

Box 1

Box 2

CBT Candidates

To diagnose panic disorder, conduct a thorough psychiatric evaluation that includes assessing for comorbid mental and substance use disorders. The history and physical exam are essential to rule out medical causes of the patient’s symptoms, such as heart disease causing dizziness or palpitations. Asking patients to keep panic attack records can help you identify panic symptoms’ frequency and triggers.⁹

An assessment tool such as the Albany Panic and Phobia Questionnaire (Figure) can be a useful starting point. It has 27 items and three subscales to quantify a patient’s fear of agoraphobic situations, social phobia situations, and situations that produce bodily sensations (interoceptive symptoms). Items on the interoceptive subscale include activities such as exercising vigorously, ingesting caffeine, and experiencing intense emotion.²¹ Using the Anxiety Sensitivity Index is another assessment option.²²

Not all patients with panic attacks respond well to CBT; predictors of poor response in clinical trials have included:

• severe baseline panic symptoms, personality disorders, and possibly depressed mood
• marital dissatisfaction
• low motivation for treatment.^2,9

Figure Patient assessment: Albany Panic and Phobia Questionnaire

Source: Reprinted with permission from Rapee RM, Craske MG, Barlow DH. Assessment instrument for panic disorder that includes fear of sensation-producing activities: The Albany Panic and Phobia Questionnaire. Anxiety 1995;1:114-22. Copyright 1995, Wiley-Liss, Inc.

Cognitive Therapies for Panic Disorder

Psychoeducation. Begin by defining and explaining anxiety, panic attacks, panic disorder, and any comorbid psychopathology the patient may have (agoraphobia, depression). Explain panic symptoms as physiologic and psychological responses to stressors.

Address the patient’s fears that anxiety’s physiologic symptoms represent a serious or undiagnosed medical disorder or that a panic attack could cause serious harm. Assign self-help and reading materials to reinforce this discussion (see Related resources). Finally, explain the rationale for using CBT to treat panic symptoms.

Use cognitive restructuring to address faulty or irrational information-processing patterns that underlie pathologic anxiety. Identify automatic thought patterns (such as catastrophizing, overgeneralization, all-or-nothing thinking, and personalization), then provide a careful “reality check,” in which you systematically substitute a more-rational thought process.

Have the patient keep a self-monitoring diary to help you assess thought patterns and re-direct irrational thoughts. A diary may identify anxiety-provoking scenarios on which to focus therapy. Encourage patients to document anxiety events using the “triple-column” technique:²³

• column 1: circumstances of the anxiety or panic
• column 2: their emotional state at the time
• column 3: any thoughts they can identify.

Instruct them to log this data while experiencing symptoms or immediately afterward. Later, during the intervention phase, patients can record how they tried to restructure their thoughts and any consequent mood changes. Review diary entries with them during subsequent sessions.

Exposure Therapy

Graduated exposure and response prevention (ERP) is the core component of CBT for panic disorder. ERP exercises require the patient to confront anxiety-producing stimuli while agreeing not to engage in maladaptive behavior that avoids, prematurely reduces, or prevents the anxiety. The stimuli may be external cues—such as bridges, stores, or heights—or interoceptive cues such as dizziness, tachycardia, or tachypnea.

Creating fear hierarchies. To begin, we recommend that you work with the patient to create lists of all external situations and interoceptive stimuli that cause him or her anxiety. Separating the stimuli into two lists helps patients recognize that their bodily stimuli are at least as important as environmental stimuli in promoting a panic attack.

The patient then rates each stimulus using a Subjective Units of Distress scale (SUDS)—assigning 0 to 100 points from no anxiety to overwhelming anxiety—and ranks items on the lists from mildest to worst anxiety. Instruct patients to rate the distress they would feel if they could not escape from the stimuli.

First experience. After the hierarchies are created, the therapist introduces the patient to exposure therapy by choosing an item that causes mild to moderate anxiety. Starting at this anxiety level, patients are likely to succeed with their first exercise without feeling overwhelmed. The therapist teaches the patient about the process, then begins the exposure by helping the patient create and confront the very scenario (or a representation of that scenario) that causes anxiety.

When working on interoceptive cues, various exercises can be used to reproduce bother-some bodily symptoms, such as:

• running up a flight of stairs or running in place to generate tachycardia
• purposefully hyperventilating to produce lightheadedness.
• spinning in place to create dizziness.

The patient agrees not to actively attempt to escape the scenario but to tolerate and perhaps even focus on the anxiety (Box 3). Using “safety cues”—such as leaning against a wall or keeping eyes closed—is also forbidden. Patients soon see that the anxiety does not last indefinitely but begins to diminish fairly rapidly.

Reaching the goal. After repeated exposure sessions, anxiety associated with a stimulus begins to extinguish. Having experienced the success of tolerating a previously difficult stimuli and feeling much less anxious, the patient is ready to take on increasingly difficult tasks. The therapist also assigns the patient “homework” to practice exposure exercises already mastered during sessions. As exposure therapy progresses, the patient takes a larger role in designing and executing sessions. The goal is for the patient to learn to become his or her own behaviorist and to intervene early when panic symptoms begin.

Box 3

Other Behavioral Techniques

Imaginal exposure sessions can be created using visualizations of feared stimuli, gradually presented as with in vivo exposure. For example, as you recount a target scenario, ask the patient to imagine a progression of events or bodily cues that have led to panic attacks. The patient supplies SUDS ratings and refrains from imagining an avoidance or maladaptive response. You can tape-record the session for homework and assign the patient to listen to it and participate daily.

Imaginal exposure may help treat phobic avoidance (such as agoraphobic symptoms), but study results have been disappointing in panic symptoms.²⁴ However, this approach may help reluctant patients initiate in vivo exposure therapy.

Relaxation training—such as progressive muscle relaxation, visual imagery, or autogenic protocols—has shown mixed results in treating panic.^25,26 Relaxation may help patients cope with panic’s physiologic arousal, but it is not suitable as a singular intervention.

Breathing retraining. Because hyperventilation and panic symptoms are related, instruction and practice in slow, diaphragmatic breathing has long been a component of CBT for panic symptoms. Little evidence supports breathing retraining,⁹ although Meuret et al^27,28 have described a respiratory feedback paradigm that may reduce panic symptoms in appropriately selected patients.

Many studies that have assessed breathing retraining as monotherapy for panic have had methodologic flaws.²⁷

Building a Therapeutic Alliance

Successful therapists have been found to use empathic listening more than directives and explanations in the first therapy session.⁹ They understand the suffering from panic disorder and the value of listening as patients explain their symptoms, thoughts, and feelings. The rapport built during this initial interaction can help sustain motivation as the therapist then takes charge of subsequent sessions.

Among important skills for CBT therapists, Seligman²⁹ includes empathy, caring, warmth, and active listening, as well as the ability to:

• be a teacher, scientist, and co-investigator
• demystify treatment
• engage clients as “active, knowledgeable, and responsible partners” in their therapy.

Finally, although CBT clinicians suggest tasks and interventions for this “shared endeavor,” patients are primarily responsible for change.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
• Craske M, Barlow D, Cary NC. Mastery of your anxiety and panic, (3rd ed). Therapist guide and client workbook. Oxford, UK: Oxford University Press; 2000.
• Otto MW. Stopping anxiety medication: panic control therapy for benzodiazepine discontinuation. Therapist guide and patient workbook. Oxford, UK: Oxford University Press; 2004.
• The Panic Center. Patient diaries and other self-help resources. www.paniccenter.net

With panic attacks, alarming physiologic symptoms mount swiftly—tachycardia, chest pain, sweating, trembling, smothering or choking, dizziness, fear of losing control or going crazy—even fear of dying.¹ Patients constantly fear the next attack, worry about its consequences, and change their behaviors to avoid or withdraw from anxiety-provoking situations.

To relieve their suffering, cognitive-behavioral therapy (CBT) may offer benefits you would not realize with medication alone. CBT can:

• improve long-term patient outcomes
• enhance medication management
• boost treatment response when medication alone is inadequate
• ease drug discontinuation.²

Whether you or a CBT-trained psychotherapist guides the sessions, you can achieve optimal results for your patients with panic disorder.

How Effective is CBT?

Panic disorder is chronic, often disabling, and characterized by spontaneous, unpredictable panic attacks (Boxes 1 and 2^3-11). When treated with CBT, about three-quarters of patients become panic-free and maintain treatment gains at follow-up, and one-half become both panic-free and free of excess anxiety.⁹

Typical therapy is 12 individual, once-weekly visits for psycho-education, relaxation, and breathing training; cognitive restructuring; and exposure therapies.

Briefer protocols, “reduced therapist contact,”¹² and group therapy¹³ also can help patients and in some studies have been as beneficial as 12 weeks of individual therapy. Although trained psychotherapists have higher success rates than nonbehaviorists when treating panic patients, nonbehaviorists also can provide effective therapy after relatively brief training.¹⁴

American Psychiatric Association¹⁵ treatment guidelines recommend medications—such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and benzodiazepines—as well as CBT as first-line therapies for panic disorder. Other treatment guidelines concur¹⁶ and note that CBT is more cost-effective than medications.

In comparison studies, CBT has been at least as effective for panic symptoms as SSRIs,^17,18 TCAs,¹⁹ and alprazolam.²⁰ Antidepressants are the preferred drug for panic disorder¹⁶ because they lack benzodiazepines’ dependence and abuse potential.

Providing medication during CBT may maintain patients’ therapeutic gains better than CBT alone if the medication is continued after CBT is completed. Interestingly, patients who use benzodiazepines during CBT may have higher relapse rates than those who do not use benzodiazepines, particularly when the benzodiazepines are withdrawn.⁹

CBT produces improvement rates similar to those of pharmacologic treatment at one-quarter to one-half the cost in the first year. Patients also appear to have better clinical outcomes if they receive CBT while SSRIs or benzodiazepines are being discontinued, compared with simply stopping the medications.⁸

Box 1

Box 2

CBT Candidates

To diagnose panic disorder, conduct a thorough psychiatric evaluation that includes assessing for comorbid mental and substance use disorders. The history and physical exam are essential to rule out medical causes of the patient’s symptoms, such as heart disease causing dizziness or palpitations. Asking patients to keep panic attack records can help you identify panic symptoms’ frequency and triggers.⁹

An assessment tool such as the Albany Panic and Phobia Questionnaire (Figure) can be a useful starting point. It has 27 items and three subscales to quantify a patient’s fear of agoraphobic situations, social phobia situations, and situations that produce bodily sensations (interoceptive symptoms). Items on the interoceptive subscale include activities such as exercising vigorously, ingesting caffeine, and experiencing intense emotion.²¹ Using the Anxiety Sensitivity Index is another assessment option.²²

Not all patients with panic attacks respond well to CBT; predictors of poor response in clinical trials have included:

• severe baseline panic symptoms, personality disorders, and possibly depressed mood
• marital dissatisfaction
• low motivation for treatment.^2,9

Figure Patient assessment: Albany Panic and Phobia Questionnaire

Source: Reprinted with permission from Rapee RM, Craske MG, Barlow DH. Assessment instrument for panic disorder that includes fear of sensation-producing activities: The Albany Panic and Phobia Questionnaire. Anxiety 1995;1:114-22. Copyright 1995, Wiley-Liss, Inc.

Cognitive Therapies for Panic Disorder

Psychoeducation. Begin by defining and explaining anxiety, panic attacks, panic disorder, and any comorbid psychopathology the patient may have (agoraphobia, depression). Explain panic symptoms as physiologic and psychological responses to stressors.

Address the patient’s fears that anxiety’s physiologic symptoms represent a serious or undiagnosed medical disorder or that a panic attack could cause serious harm. Assign self-help and reading materials to reinforce this discussion (see Related resources). Finally, explain the rationale for using CBT to treat panic symptoms.

Use cognitive restructuring to address faulty or irrational information-processing patterns that underlie pathologic anxiety. Identify automatic thought patterns (such as catastrophizing, overgeneralization, all-or-nothing thinking, and personalization), then provide a careful “reality check,” in which you systematically substitute a more-rational thought process.

Have the patient keep a self-monitoring diary to help you assess thought patterns and re-direct irrational thoughts. A diary may identify anxiety-provoking scenarios on which to focus therapy. Encourage patients to document anxiety events using the “triple-column” technique:²³

• column 1: circumstances of the anxiety or panic
• column 2: their emotional state at the time
• column 3: any thoughts they can identify.

Instruct them to log this data while experiencing symptoms or immediately afterward. Later, during the intervention phase, patients can record how they tried to restructure their thoughts and any consequent mood changes. Review diary entries with them during subsequent sessions.

Exposure Therapy

Graduated exposure and response prevention (ERP) is the core component of CBT for panic disorder. ERP exercises require the patient to confront anxiety-producing stimuli while agreeing not to engage in maladaptive behavior that avoids, prematurely reduces, or prevents the anxiety. The stimuli may be external cues—such as bridges, stores, or heights—or interoceptive cues such as dizziness, tachycardia, or tachypnea.

Creating fear hierarchies. To begin, we recommend that you work with the patient to create lists of all external situations and interoceptive stimuli that cause him or her anxiety. Separating the stimuli into two lists helps patients recognize that their bodily stimuli are at least as important as environmental stimuli in promoting a panic attack.

The patient then rates each stimulus using a Subjective Units of Distress scale (SUDS)—assigning 0 to 100 points from no anxiety to overwhelming anxiety—and ranks items on the lists from mildest to worst anxiety. Instruct patients to rate the distress they would feel if they could not escape from the stimuli.

First experience. After the hierarchies are created, the therapist introduces the patient to exposure therapy by choosing an item that causes mild to moderate anxiety. Starting at this anxiety level, patients are likely to succeed with their first exercise without feeling overwhelmed. The therapist teaches the patient about the process, then begins the exposure by helping the patient create and confront the very scenario (or a representation of that scenario) that causes anxiety.

When working on interoceptive cues, various exercises can be used to reproduce bother-some bodily symptoms, such as:

• running up a flight of stairs or running in place to generate tachycardia
• purposefully hyperventilating to produce lightheadedness.
• spinning in place to create dizziness.

The patient agrees not to actively attempt to escape the scenario but to tolerate and perhaps even focus on the anxiety (Box 3). Using “safety cues”—such as leaning against a wall or keeping eyes closed—is also forbidden. Patients soon see that the anxiety does not last indefinitely but begins to diminish fairly rapidly.

Reaching the goal. After repeated exposure sessions, anxiety associated with a stimulus begins to extinguish. Having experienced the success of tolerating a previously difficult stimuli and feeling much less anxious, the patient is ready to take on increasingly difficult tasks. The therapist also assigns the patient “homework” to practice exposure exercises already mastered during sessions. As exposure therapy progresses, the patient takes a larger role in designing and executing sessions. The goal is for the patient to learn to become his or her own behaviorist and to intervene early when panic symptoms begin.

Box 3

Other Behavioral Techniques

Imaginal exposure sessions can be created using visualizations of feared stimuli, gradually presented as with in vivo exposure. For example, as you recount a target scenario, ask the patient to imagine a progression of events or bodily cues that have led to panic attacks. The patient supplies SUDS ratings and refrains from imagining an avoidance or maladaptive response. You can tape-record the session for homework and assign the patient to listen to it and participate daily.

Imaginal exposure may help treat phobic avoidance (such as agoraphobic symptoms), but study results have been disappointing in panic symptoms.²⁴ However, this approach may help reluctant patients initiate in vivo exposure therapy.

Relaxation training—such as progressive muscle relaxation, visual imagery, or autogenic protocols—has shown mixed results in treating panic.^25,26 Relaxation may help patients cope with panic’s physiologic arousal, but it is not suitable as a singular intervention.

Breathing retraining. Because hyperventilation and panic symptoms are related, instruction and practice in slow, diaphragmatic breathing has long been a component of CBT for panic symptoms. Little evidence supports breathing retraining,⁹ although Meuret et al^27,28 have described a respiratory feedback paradigm that may reduce panic symptoms in appropriately selected patients.

Many studies that have assessed breathing retraining as monotherapy for panic have had methodologic flaws.²⁷

Building a Therapeutic Alliance

Successful therapists have been found to use empathic listening more than directives and explanations in the first therapy session.⁹ They understand the suffering from panic disorder and the value of listening as patients explain their symptoms, thoughts, and feelings. The rapport built during this initial interaction can help sustain motivation as the therapist then takes charge of subsequent sessions.

Among important skills for CBT therapists, Seligman²⁹ includes empathy, caring, warmth, and active listening, as well as the ability to:

• be a teacher, scientist, and co-investigator
• demystify treatment
• engage clients as “active, knowledgeable, and responsible partners” in their therapy.

Finally, although CBT clinicians suggest tasks and interventions for this “shared endeavor,” patients are primarily responsible for change.

Related resources

• Anxiety Disorders Association of America. www.adaa.org.
• Craske M, Barlow D, Cary NC. Mastery of your anxiety and panic, (3rd ed). Therapist guide and client workbook. Oxford, UK: Oxford University Press; 2000.
• Otto MW. Stopping anxiety medication: panic control therapy for benzodiazepine discontinuation. Therapist guide and patient workbook. Oxford, UK: Oxford University Press; 2004.
• The Panic Center. Patient diaries and other self-help resources. www.paniccenter.net

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Table 1

4 situations where serum valproate monitoring may be clinically useful

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Table 1

4 situations where serum valproate monitoring may be clinically useful

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Table 1

4 situations where serum valproate monitoring may be clinically useful

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Police officers bring Mr. A, age 25, to the emergency department (ED) in handcuffs after an alleged assault at work. He is calm but will provide no information about himself. ED staff don’t know if he has been using illicit substances, is on medications, or has any medical conditions.

Mr. A says the FBI is after him, but he makes no threats to ED staff. He talks about milking cows on a farm and of hearing animal sounds, though he lives in the city. After about 30 minutes, he consents to a lab draw and provides a urine sample.

Because no charges are pending and Mr. A is semi-cooperative, police remove his handcuffs and leave him in the care of two ED security officers. He is given something to eat and drink and seems fairly content. He asks how long he will need to stay in the room but does not demand to leave.

In a fast-paced ED, physicians might not notice signs of psychiatric illness, such as Mr. A’s paranoid and delusional thinking. By being familiar with techniques to manage patients’ psychiatric emergencies, you can help your ED colleagues:

• establish working psychiatric diagnoses and medical causes of psychiatric symptoms in the fast-paced ED
• maintain a safe ED environment for patients and clinicians.

What ed patients want

To understand how ED patients feel, put yourself in Mr. A’s shoes. You were at work and began to hallucinate. You believed your boss was out to harm you, and in fear you made comments perceived as threatening.

The next thing you know, you’re in a police car with handcuffs on. All of your coworkers witnessed your embarrassment. Now you are in a small ED room, wondering what’s going to happen next. Are you going to be put in a straight jacket and a padded room?

Patients may experience anxiety-provoking thoughts whether they come to the ED voluntarily or involuntarily. Fear and confusion can affect their behavior in the ED, and how providers respond to patients in crisis can escalate or de-escalate an already-difficult situation.

Psychiatric illness in the ed

Mr. A may have a psychiatric disorder, as do at least 3% of patients seen in EDs.¹ This figure may be low, however:

• Kunen et al² asserted that EDs are underdiagnosing psychiatric disorders, given a U.S. Department of Health and Human Services 1999 estimate that 20% to 28% of Americans have psychiatric illnesses. Using ED discharge records across 6 months in three emergency departments, the authors found the psychiatric diagnosis rate to be 5.27% in 33,000 ED visits.
• Another study, done in a university teaching hospital ED, showed that ED physicians trained to focus on patients’ presenting problems often missed comorbid medical or psychiatric illnesses.

In the randomized, controlled trial by Schriger et al,³ 218 patients with nonspecific complaints suggesting occult psychiatric illness (such as chronic headache, abdominal pain, or back pain) completed the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. This 27-item self-report asks questions about mood, alcohol use, obsessive-compulsive symptoms, phobias, and somatoform symptoms.

Participants were then randomly assigned to “report” or “nonreport” groups, depending on whether or not ED physicians received their PRIME-MD scores. Even when informed of patients’ psychiatric symptoms, ED physicians rarely diagnosed or treated psychiatric disorders. Lack of mental status documentation and psychiatric interviews was apparent, the authors noted.

Case continued: a toxic cocktail

Mr. A’s urine drug screen and lab results are positive for benzodiazepines, methamphetamines, and cannabis. The staff decide Mr. A will require further observation and detoxification, and he is told this. A bed is not available at the hospital, however, and calls to nearby facilities find no empty beds.

As time passes, Mr. A shows signs of agitation and arousal. He paces the examination room—his jaw clenched and his face flushed—and begins raising his voice, asking to be discharged.

Recommendations. Unpleasantness is sometimes unavoidable, but no one in the ED has tried to create an alliance with Mr. A (Box). Try to make patients’ ED experiences as positive as possible. Make it clear that you share a common goal: to help the patient feel better. In fact, psychiatric patients and emergency psychiatrists have similar ideas about what constitutes quality ED care. When surveyed,⁴ ED patients said they preferred:

• verbal interventions compared with medications
• a collaborative approach with ED physicians
• having medications selected for their specific problems, medication experiences, and choices
• benzodiazepines rather than conventional antipsychotics such as haloperidol.

Box

A pragmatic workup

Medical illnesses such as delirium, stroke, drug toxicity, or urinary tract infections can trigger or worsen psychiatric illness (Table 1).⁵ Comorbidities such as diabetes, hypertension, obesity, and heart disease are common in patients with psychiatric disorders, and psychotropics can cause or exacerbate these conditions.

In the high-pressure ED, a sufficient workup for complicated medical conditions lies somewhere between extensive/unnecessary and inadequate. Thus, determining an exact diagnosis is not as important as establishing a diagnostic category to guide emergency treatment.

Think of psychiatric disorders as they are organized in DSM-IV-TR—mood, anxiety, psychotic, substance use/withdrawal/intoxication, cognitive, adjustment, somatoform, and personality disorders—and whether they are primary or secondary to a general medical condition or substance use. For example:

• Anxiety disorder secondary to a general medical condition means the history, physical exam, or lab reports suggest a medical condition is the direct physiologic cause of the mood disturbance.
• Methamphetamine-induced psychotic disorder would be the diagnosis if methamphetamines are presumed to be causing a patient’s psychotic symptoms.

Hospitalization. ED staff often develop a treatment plan based on a patient’s clinical picture and a working diagnosis. The plan hinges on deciding if the patient needs to be admitted to the hospital. Admission may be warranted for life-threatening medical conditions or safety issues, such as threats to self or others or inability to care for oneself at home. Other issues come into play—such as starting or changing medications and follow-up to ensure continuity of care—if you decide to discharge the patient.

Even after medical clearance, patients in the psychiatric emergency service may have underlying medical illnesses (Table 2).⁶

Table 1

Medical disorders that can cause psychiatric symptoms

Table 2

Reasonable medical assessment in psychiatric emergencies

Overwhelming demand

In the study of ED patient preferences,⁴ one-fifth of patients said they went to the ED because they lacked access to routine mental health care. Therefore, besides psychiatric conditions caused by medical illnesses, ED physicians can see patients with any primary psychiatric diagnosis, including mood and anxiety disorders and psychosis.

Under pressures of time and limited collateral information, ED staff must:

• individualize psychiatric treatment
• consider use of medications and/or restraints
• rule out life-threatening causes for psychiatric symptoms
• stabilize patients and prevent injury to self and others.

These tasks are becoming increasingly difficult as more and more patients present to emergency rooms. Nationally, ED visits increased from 19 million in 1992 to 108 million in 2000, according to the U.S. Department of Health and Human Services.¹

Psychiatric patients are seeking ED care in greater numbers, and the number of those staying longer than anticipated (“boarding”) also has increased, according to a 2004 survey of 340 physicians by the American College of Emergency Physicians, American Psychiatric Association, National Mental Health Association, and National Alliance for the Mentally Ill. Surveyed physicians blamed inadequate Medicaid funding and bed shortages for the increasing ED visits.⁷

In crowded emergency rooms, where patients wait longer and longer to be seen, the influx of acutely ill psychiatric patients increases the risks of agitation, violence, and injury, as well as litigation.⁸

Case continued: going up in smoke

Recognizing Mr. A’s arousal, ED staff tries to reassure him and offers him food, something to drink, a phone Call, and a magazine. When these attempts fail to de-escalate his agitation, staff offers to make him more comfortable by giving oral lorazepam, which he adamantly refuses. He is told again that he must stay until a transfer facility is found for him.

Mr. A then demands to go outside “for a smoke.” When he is told ED patients cannot leave to smoke and is offered nicotine replacement, he begins to scream and lunges at one of the security officers. He is extremely strong, and additional officers are summoned. He retreats inside the room, slams the door, shatters the door window with a chair, and begins punching the broken glass. He slides to the floor in a vasovagal reaction at the sight of his bleeding hands but soon becomes combative again.

Staff give Mr. A IM haloperidol, 10 mg, and lorazepam, 2 mg, to manage his extreme agitation and place him in physical restraints to protect him and others. Within 25 to 30 minutes he is calm, and a safe environment has been re-established. The lacerations on his hands are sutured, and he is admitted to an inpatient psychiatric hospital for further stabilization and treatment.

No place for complacency

Mr. A’s experience illustrates how situations can become dangerous when precautions are not taken. Five steps can help you prepare and protect yourself when evaluating patients in the ED:

• seek the patient history
• evaluate the context in which the patient is being assessed
• identify arousal states (fear, anger, confusion, and humiliation)
• structure the interview for safety
• keep your guard up during the clinical encounter.⁹

Risk is high when law enforcement officers bring a patient to the ED. Be on guard, even if the patient is 80 years old and in a wheelchair. Complacency has no place in the ED; prepare as much as you can before interviewing the patient.

When restraints are needed. Involuntary medication and/or restraints may be necessary when reasonable interventions have failed, the patient will not cooperate, and he or she is exhibiting behavior/symptoms that could result in injury. Approximately 10% to 20% of psychiatric patients require physical or chemical restraint in the ED.¹⁰

Expert consensus guidelines suggest starting with verbal intervention, voluntary medication, and show of force, although emergency medication may be a reasonable first treatment (Algorithm).¹¹ Offer oral medication first; IM medications carry risks including acute dystonia and akathisia, although these can be treated.

Lorazepam, 1 to 2 mg oral/IM, combined with haloperidol, 2 to 5 mg oral/IM, is a reasonable start in most cases. If the patient remains extremely agitated, the same medications and dosages can be repeated 30 to 60 minutes after the initial administration.¹²

Conventional oral/IM agents are usually more readily available in the ED than atypical antipsychotics, which must be ordered from the pharmacy. Recent FDA black-box warnings also emphasize that atypical antipsychotics are approved only for treating schizophrenia, acute manic and mixed episodes of bipolar I disorder, and for maintenance treatment in bipolar disorder. When compared with placebo, atypical antipsychotics have been associated with:

• increased risk for cerebrovascular events in elderly patients with dementia
• death in elderly patients with dementia-related psychosis.

Atypicals may be more appropriate than conventional antipsychotics for emergency treatment of agitation and aggression in some patients with complicating medical conditions or histories. For example, avoid high-potency conventional antipsychotics in patients with a history of extrapyramidal side effects and in those with mental retardation/developmental delay.¹¹ Similarly, avoid benzodiazepines in patients with chronic obstructive pulmonary disease (COPD) or a history of drug-seeking behavior or drug abuse.

Of course not all psychiatric interventions in the ED are involuntary. For example, the ED physician may start an antidepressant for a patient diagnosed with mild to moderate depression for whom hospitalization is not indicated. Characteristics of patients who may be good candidates for starting antidepressants in the ED include a clear diagnosis, no substance abuse, low suicide risk, no psychosis or agitation, available social supports, clear follow-up plan, desire to begin treatment, and ability to pay for and obtain medications.¹³

Algorithm Consensus guideline for treating a behavioral emergency

• Allen MH, Currier GW, Hughes DH, et al. The Expert Consensus Guideline Series: Treatment of behavioral emergencies. Postgrad Med 2001;May(Spec No):1-88.
• American College of Emergency Physicians. www.acep.org
• National Alliance on Mental Illness. www.nami.org

Drug brand names

• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan

Disclosure

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

Police officers bring Mr. A, age 25, to the emergency department (ED) in handcuffs after an alleged assault at work. He is calm but will provide no information about himself. ED staff don’t know if he has been using illicit substances, is on medications, or has any medical conditions.

Mr. A says the FBI is after him, but he makes no threats to ED staff. He talks about milking cows on a farm and of hearing animal sounds, though he lives in the city. After about 30 minutes, he consents to a lab draw and provides a urine sample.

Because no charges are pending and Mr. A is semi-cooperative, police remove his handcuffs and leave him in the care of two ED security officers. He is given something to eat and drink and seems fairly content. He asks how long he will need to stay in the room but does not demand to leave.

In a fast-paced ED, physicians might not notice signs of psychiatric illness, such as Mr. A’s paranoid and delusional thinking. By being familiar with techniques to manage patients’ psychiatric emergencies, you can help your ED colleagues:

• establish working psychiatric diagnoses and medical causes of psychiatric symptoms in the fast-paced ED
• maintain a safe ED environment for patients and clinicians.

What ed patients want

To understand how ED patients feel, put yourself in Mr. A’s shoes. You were at work and began to hallucinate. You believed your boss was out to harm you, and in fear you made comments perceived as threatening.

The next thing you know, you’re in a police car with handcuffs on. All of your coworkers witnessed your embarrassment. Now you are in a small ED room, wondering what’s going to happen next. Are you going to be put in a straight jacket and a padded room?

Patients may experience anxiety-provoking thoughts whether they come to the ED voluntarily or involuntarily. Fear and confusion can affect their behavior in the ED, and how providers respond to patients in crisis can escalate or de-escalate an already-difficult situation.

Psychiatric illness in the ed

Mr. A may have a psychiatric disorder, as do at least 3% of patients seen in EDs.¹ This figure may be low, however:

• Kunen et al² asserted that EDs are underdiagnosing psychiatric disorders, given a U.S. Department of Health and Human Services 1999 estimate that 20% to 28% of Americans have psychiatric illnesses. Using ED discharge records across 6 months in three emergency departments, the authors found the psychiatric diagnosis rate to be 5.27% in 33,000 ED visits.
• Another study, done in a university teaching hospital ED, showed that ED physicians trained to focus on patients’ presenting problems often missed comorbid medical or psychiatric illnesses.

In the randomized, controlled trial by Schriger et al,³ 218 patients with nonspecific complaints suggesting occult psychiatric illness (such as chronic headache, abdominal pain, or back pain) completed the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. This 27-item self-report asks questions about mood, alcohol use, obsessive-compulsive symptoms, phobias, and somatoform symptoms.

Participants were then randomly assigned to “report” or “nonreport” groups, depending on whether or not ED physicians received their PRIME-MD scores. Even when informed of patients’ psychiatric symptoms, ED physicians rarely diagnosed or treated psychiatric disorders. Lack of mental status documentation and psychiatric interviews was apparent, the authors noted.

Case continued: a toxic cocktail

Mr. A’s urine drug screen and lab results are positive for benzodiazepines, methamphetamines, and cannabis. The staff decide Mr. A will require further observation and detoxification, and he is told this. A bed is not available at the hospital, however, and calls to nearby facilities find no empty beds.

As time passes, Mr. A shows signs of agitation and arousal. He paces the examination room—his jaw clenched and his face flushed—and begins raising his voice, asking to be discharged.

Recommendations. Unpleasantness is sometimes unavoidable, but no one in the ED has tried to create an alliance with Mr. A (Box). Try to make patients’ ED experiences as positive as possible. Make it clear that you share a common goal: to help the patient feel better. In fact, psychiatric patients and emergency psychiatrists have similar ideas about what constitutes quality ED care. When surveyed,⁴ ED patients said they preferred:

• verbal interventions compared with medications
• a collaborative approach with ED physicians
• having medications selected for their specific problems, medication experiences, and choices
• benzodiazepines rather than conventional antipsychotics such as haloperidol.

Box

A pragmatic workup

Medical illnesses such as delirium, stroke, drug toxicity, or urinary tract infections can trigger or worsen psychiatric illness (Table 1).⁵ Comorbidities such as diabetes, hypertension, obesity, and heart disease are common in patients with psychiatric disorders, and psychotropics can cause or exacerbate these conditions.

In the high-pressure ED, a sufficient workup for complicated medical conditions lies somewhere between extensive/unnecessary and inadequate. Thus, determining an exact diagnosis is not as important as establishing a diagnostic category to guide emergency treatment.

Think of psychiatric disorders as they are organized in DSM-IV-TR—mood, anxiety, psychotic, substance use/withdrawal/intoxication, cognitive, adjustment, somatoform, and personality disorders—and whether they are primary or secondary to a general medical condition or substance use. For example:

• Anxiety disorder secondary to a general medical condition means the history, physical exam, or lab reports suggest a medical condition is the direct physiologic cause of the mood disturbance.
• Methamphetamine-induced psychotic disorder would be the diagnosis if methamphetamines are presumed to be causing a patient’s psychotic symptoms.

Hospitalization. ED staff often develop a treatment plan based on a patient’s clinical picture and a working diagnosis. The plan hinges on deciding if the patient needs to be admitted to the hospital. Admission may be warranted for life-threatening medical conditions or safety issues, such as threats to self or others or inability to care for oneself at home. Other issues come into play—such as starting or changing medications and follow-up to ensure continuity of care—if you decide to discharge the patient.

Even after medical clearance, patients in the psychiatric emergency service may have underlying medical illnesses (Table 2).⁶

Table 1

Medical disorders that can cause psychiatric symptoms

Table 2

Reasonable medical assessment in psychiatric emergencies

Overwhelming demand

In the study of ED patient preferences,⁴ one-fifth of patients said they went to the ED because they lacked access to routine mental health care. Therefore, besides psychiatric conditions caused by medical illnesses, ED physicians can see patients with any primary psychiatric diagnosis, including mood and anxiety disorders and psychosis.

Under pressures of time and limited collateral information, ED staff must:

• individualize psychiatric treatment
• consider use of medications and/or restraints
• rule out life-threatening causes for psychiatric symptoms
• stabilize patients and prevent injury to self and others.

These tasks are becoming increasingly difficult as more and more patients present to emergency rooms. Nationally, ED visits increased from 19 million in 1992 to 108 million in 2000, according to the U.S. Department of Health and Human Services.¹

Psychiatric patients are seeking ED care in greater numbers, and the number of those staying longer than anticipated (“boarding”) also has increased, according to a 2004 survey of 340 physicians by the American College of Emergency Physicians, American Psychiatric Association, National Mental Health Association, and National Alliance for the Mentally Ill. Surveyed physicians blamed inadequate Medicaid funding and bed shortages for the increasing ED visits.⁷

In crowded emergency rooms, where patients wait longer and longer to be seen, the influx of acutely ill psychiatric patients increases the risks of agitation, violence, and injury, as well as litigation.⁸

Case continued: going up in smoke

Recognizing Mr. A’s arousal, ED staff tries to reassure him and offers him food, something to drink, a phone Call, and a magazine. When these attempts fail to de-escalate his agitation, staff offers to make him more comfortable by giving oral lorazepam, which he adamantly refuses. He is told again that he must stay until a transfer facility is found for him.

Mr. A then demands to go outside “for a smoke.” When he is told ED patients cannot leave to smoke and is offered nicotine replacement, he begins to scream and lunges at one of the security officers. He is extremely strong, and additional officers are summoned. He retreats inside the room, slams the door, shatters the door window with a chair, and begins punching the broken glass. He slides to the floor in a vasovagal reaction at the sight of his bleeding hands but soon becomes combative again.

Staff give Mr. A IM haloperidol, 10 mg, and lorazepam, 2 mg, to manage his extreme agitation and place him in physical restraints to protect him and others. Within 25 to 30 minutes he is calm, and a safe environment has been re-established. The lacerations on his hands are sutured, and he is admitted to an inpatient psychiatric hospital for further stabilization and treatment.

No place for complacency

Mr. A’s experience illustrates how situations can become dangerous when precautions are not taken. Five steps can help you prepare and protect yourself when evaluating patients in the ED:

• seek the patient history
• evaluate the context in which the patient is being assessed
• identify arousal states (fear, anger, confusion, and humiliation)
• structure the interview for safety
• keep your guard up during the clinical encounter.⁹

Risk is high when law enforcement officers bring a patient to the ED. Be on guard, even if the patient is 80 years old and in a wheelchair. Complacency has no place in the ED; prepare as much as you can before interviewing the patient.

When restraints are needed. Involuntary medication and/or restraints may be necessary when reasonable interventions have failed, the patient will not cooperate, and he or she is exhibiting behavior/symptoms that could result in injury. Approximately 10% to 20% of psychiatric patients require physical or chemical restraint in the ED.¹⁰

Expert consensus guidelines suggest starting with verbal intervention, voluntary medication, and show of force, although emergency medication may be a reasonable first treatment (Algorithm).¹¹ Offer oral medication first; IM medications carry risks including acute dystonia and akathisia, although these can be treated.

Lorazepam, 1 to 2 mg oral/IM, combined with haloperidol, 2 to 5 mg oral/IM, is a reasonable start in most cases. If the patient remains extremely agitated, the same medications and dosages can be repeated 30 to 60 minutes after the initial administration.¹²

Conventional oral/IM agents are usually more readily available in the ED than atypical antipsychotics, which must be ordered from the pharmacy. Recent FDA black-box warnings also emphasize that atypical antipsychotics are approved only for treating schizophrenia, acute manic and mixed episodes of bipolar I disorder, and for maintenance treatment in bipolar disorder. When compared with placebo, atypical antipsychotics have been associated with:

• increased risk for cerebrovascular events in elderly patients with dementia
• death in elderly patients with dementia-related psychosis.

Atypicals may be more appropriate than conventional antipsychotics for emergency treatment of agitation and aggression in some patients with complicating medical conditions or histories. For example, avoid high-potency conventional antipsychotics in patients with a history of extrapyramidal side effects and in those with mental retardation/developmental delay.¹¹ Similarly, avoid benzodiazepines in patients with chronic obstructive pulmonary disease (COPD) or a history of drug-seeking behavior or drug abuse.

Of course not all psychiatric interventions in the ED are involuntary. For example, the ED physician may start an antidepressant for a patient diagnosed with mild to moderate depression for whom hospitalization is not indicated. Characteristics of patients who may be good candidates for starting antidepressants in the ED include a clear diagnosis, no substance abuse, low suicide risk, no psychosis or agitation, available social supports, clear follow-up plan, desire to begin treatment, and ability to pay for and obtain medications.¹³

Algorithm Consensus guideline for treating a behavioral emergency

• Allen MH, Currier GW, Hughes DH, et al. The Expert Consensus Guideline Series: Treatment of behavioral emergencies. Postgrad Med 2001;May(Spec No):1-88.
• American College of Emergency Physicians. www.acep.org
• National Alliance on Mental Illness. www.nami.org

Drug brand names

• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan

Disclosure

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

Police officers bring Mr. A, age 25, to the emergency department (ED) in handcuffs after an alleged assault at work. He is calm but will provide no information about himself. ED staff don’t know if he has been using illicit substances, is on medications, or has any medical conditions.

Mr. A says the FBI is after him, but he makes no threats to ED staff. He talks about milking cows on a farm and of hearing animal sounds, though he lives in the city. After about 30 minutes, he consents to a lab draw and provides a urine sample.

Because no charges are pending and Mr. A is semi-cooperative, police remove his handcuffs and leave him in the care of two ED security officers. He is given something to eat and drink and seems fairly content. He asks how long he will need to stay in the room but does not demand to leave.

In a fast-paced ED, physicians might not notice signs of psychiatric illness, such as Mr. A’s paranoid and delusional thinking. By being familiar with techniques to manage patients’ psychiatric emergencies, you can help your ED colleagues:

• establish working psychiatric diagnoses and medical causes of psychiatric symptoms in the fast-paced ED
• maintain a safe ED environment for patients and clinicians.

What ed patients want

To understand how ED patients feel, put yourself in Mr. A’s shoes. You were at work and began to hallucinate. You believed your boss was out to harm you, and in fear you made comments perceived as threatening.

The next thing you know, you’re in a police car with handcuffs on. All of your coworkers witnessed your embarrassment. Now you are in a small ED room, wondering what’s going to happen next. Are you going to be put in a straight jacket and a padded room?

Patients may experience anxiety-provoking thoughts whether they come to the ED voluntarily or involuntarily. Fear and confusion can affect their behavior in the ED, and how providers respond to patients in crisis can escalate or de-escalate an already-difficult situation.

Psychiatric illness in the ed

Mr. A may have a psychiatric disorder, as do at least 3% of patients seen in EDs.¹ This figure may be low, however:

• Kunen et al² asserted that EDs are underdiagnosing psychiatric disorders, given a U.S. Department of Health and Human Services 1999 estimate that 20% to 28% of Americans have psychiatric illnesses. Using ED discharge records across 6 months in three emergency departments, the authors found the psychiatric diagnosis rate to be 5.27% in 33,000 ED visits.
• Another study, done in a university teaching hospital ED, showed that ED physicians trained to focus on patients’ presenting problems often missed comorbid medical or psychiatric illnesses.

In the randomized, controlled trial by Schriger et al,³ 218 patients with nonspecific complaints suggesting occult psychiatric illness (such as chronic headache, abdominal pain, or back pain) completed the Primary Care Evaluation of Mental Disorders (PRIME-MD) questionnaire. This 27-item self-report asks questions about mood, alcohol use, obsessive-compulsive symptoms, phobias, and somatoform symptoms.

Participants were then randomly assigned to “report” or “nonreport” groups, depending on whether or not ED physicians received their PRIME-MD scores. Even when informed of patients’ psychiatric symptoms, ED physicians rarely diagnosed or treated psychiatric disorders. Lack of mental status documentation and psychiatric interviews was apparent, the authors noted.

Case continued: a toxic cocktail

Mr. A’s urine drug screen and lab results are positive for benzodiazepines, methamphetamines, and cannabis. The staff decide Mr. A will require further observation and detoxification, and he is told this. A bed is not available at the hospital, however, and calls to nearby facilities find no empty beds.

As time passes, Mr. A shows signs of agitation and arousal. He paces the examination room—his jaw clenched and his face flushed—and begins raising his voice, asking to be discharged.

Recommendations. Unpleasantness is sometimes unavoidable, but no one in the ED has tried to create an alliance with Mr. A (Box). Try to make patients’ ED experiences as positive as possible. Make it clear that you share a common goal: to help the patient feel better. In fact, psychiatric patients and emergency psychiatrists have similar ideas about what constitutes quality ED care. When surveyed,⁴ ED patients said they preferred:

• verbal interventions compared with medications
• a collaborative approach with ED physicians
• having medications selected for their specific problems, medication experiences, and choices
• benzodiazepines rather than conventional antipsychotics such as haloperidol.

Box

A pragmatic workup

Medical illnesses such as delirium, stroke, drug toxicity, or urinary tract infections can trigger or worsen psychiatric illness (Table 1).⁵ Comorbidities such as diabetes, hypertension, obesity, and heart disease are common in patients with psychiatric disorders, and psychotropics can cause or exacerbate these conditions.

In the high-pressure ED, a sufficient workup for complicated medical conditions lies somewhere between extensive/unnecessary and inadequate. Thus, determining an exact diagnosis is not as important as establishing a diagnostic category to guide emergency treatment.

Think of psychiatric disorders as they are organized in DSM-IV-TR—mood, anxiety, psychotic, substance use/withdrawal/intoxication, cognitive, adjustment, somatoform, and personality disorders—and whether they are primary or secondary to a general medical condition or substance use. For example:

• Anxiety disorder secondary to a general medical condition means the history, physical exam, or lab reports suggest a medical condition is the direct physiologic cause of the mood disturbance.
• Methamphetamine-induced psychotic disorder would be the diagnosis if methamphetamines are presumed to be causing a patient’s psychotic symptoms.

Hospitalization. ED staff often develop a treatment plan based on a patient’s clinical picture and a working diagnosis. The plan hinges on deciding if the patient needs to be admitted to the hospital. Admission may be warranted for life-threatening medical conditions or safety issues, such as threats to self or others or inability to care for oneself at home. Other issues come into play—such as starting or changing medications and follow-up to ensure continuity of care—if you decide to discharge the patient.

Even after medical clearance, patients in the psychiatric emergency service may have underlying medical illnesses (Table 2).⁶

Table 1

Medical disorders that can cause psychiatric symptoms

Table 2

Reasonable medical assessment in psychiatric emergencies

Overwhelming demand

In the study of ED patient preferences,⁴ one-fifth of patients said they went to the ED because they lacked access to routine mental health care. Therefore, besides psychiatric conditions caused by medical illnesses, ED physicians can see patients with any primary psychiatric diagnosis, including mood and anxiety disorders and psychosis.

Under pressures of time and limited collateral information, ED staff must:

• individualize psychiatric treatment
• consider use of medications and/or restraints
• rule out life-threatening causes for psychiatric symptoms
• stabilize patients and prevent injury to self and others.

These tasks are becoming increasingly difficult as more and more patients present to emergency rooms. Nationally, ED visits increased from 19 million in 1992 to 108 million in 2000, according to the U.S. Department of Health and Human Services.¹

Psychiatric patients are seeking ED care in greater numbers, and the number of those staying longer than anticipated (“boarding”) also has increased, according to a 2004 survey of 340 physicians by the American College of Emergency Physicians, American Psychiatric Association, National Mental Health Association, and National Alliance for the Mentally Ill. Surveyed physicians blamed inadequate Medicaid funding and bed shortages for the increasing ED visits.⁷

In crowded emergency rooms, where patients wait longer and longer to be seen, the influx of acutely ill psychiatric patients increases the risks of agitation, violence, and injury, as well as litigation.⁸

Case continued: going up in smoke

Recognizing Mr. A’s arousal, ED staff tries to reassure him and offers him food, something to drink, a phone Call, and a magazine. When these attempts fail to de-escalate his agitation, staff offers to make him more comfortable by giving oral lorazepam, which he adamantly refuses. He is told again that he must stay until a transfer facility is found for him.

Mr. A then demands to go outside “for a smoke.” When he is told ED patients cannot leave to smoke and is offered nicotine replacement, he begins to scream and lunges at one of the security officers. He is extremely strong, and additional officers are summoned. He retreats inside the room, slams the door, shatters the door window with a chair, and begins punching the broken glass. He slides to the floor in a vasovagal reaction at the sight of his bleeding hands but soon becomes combative again.

Staff give Mr. A IM haloperidol, 10 mg, and lorazepam, 2 mg, to manage his extreme agitation and place him in physical restraints to protect him and others. Within 25 to 30 minutes he is calm, and a safe environment has been re-established. The lacerations on his hands are sutured, and he is admitted to an inpatient psychiatric hospital for further stabilization and treatment.

No place for complacency

Mr. A’s experience illustrates how situations can become dangerous when precautions are not taken. Five steps can help you prepare and protect yourself when evaluating patients in the ED:

• seek the patient history
• evaluate the context in which the patient is being assessed
• identify arousal states (fear, anger, confusion, and humiliation)
• structure the interview for safety
• keep your guard up during the clinical encounter.⁹

Risk is high when law enforcement officers bring a patient to the ED. Be on guard, even if the patient is 80 years old and in a wheelchair. Complacency has no place in the ED; prepare as much as you can before interviewing the patient.

When restraints are needed. Involuntary medication and/or restraints may be necessary when reasonable interventions have failed, the patient will not cooperate, and he or she is exhibiting behavior/symptoms that could result in injury. Approximately 10% to 20% of psychiatric patients require physical or chemical restraint in the ED.¹⁰

Expert consensus guidelines suggest starting with verbal intervention, voluntary medication, and show of force, although emergency medication may be a reasonable first treatment (Algorithm).¹¹ Offer oral medication first; IM medications carry risks including acute dystonia and akathisia, although these can be treated.

Lorazepam, 1 to 2 mg oral/IM, combined with haloperidol, 2 to 5 mg oral/IM, is a reasonable start in most cases. If the patient remains extremely agitated, the same medications and dosages can be repeated 30 to 60 minutes after the initial administration.¹²

Conventional oral/IM agents are usually more readily available in the ED than atypical antipsychotics, which must be ordered from the pharmacy. Recent FDA black-box warnings also emphasize that atypical antipsychotics are approved only for treating schizophrenia, acute manic and mixed episodes of bipolar I disorder, and for maintenance treatment in bipolar disorder. When compared with placebo, atypical antipsychotics have been associated with:

• increased risk for cerebrovascular events in elderly patients with dementia
• death in elderly patients with dementia-related psychosis.

Atypicals may be more appropriate than conventional antipsychotics for emergency treatment of agitation and aggression in some patients with complicating medical conditions or histories. For example, avoid high-potency conventional antipsychotics in patients with a history of extrapyramidal side effects and in those with mental retardation/developmental delay.¹¹ Similarly, avoid benzodiazepines in patients with chronic obstructive pulmonary disease (COPD) or a history of drug-seeking behavior or drug abuse.

Of course not all psychiatric interventions in the ED are involuntary. For example, the ED physician may start an antidepressant for a patient diagnosed with mild to moderate depression for whom hospitalization is not indicated. Characteristics of patients who may be good candidates for starting antidepressants in the ED include a clear diagnosis, no substance abuse, low suicide risk, no psychosis or agitation, available social supports, clear follow-up plan, desire to begin treatment, and ability to pay for and obtain medications.¹³

Algorithm Consensus guideline for treating a behavioral emergency

• Allen MH, Currier GW, Hughes DH, et al. The Expert Consensus Guideline Series: Treatment of behavioral emergencies. Postgrad Med 2001;May(Spec No):1-88.
• American College of Emergency Physicians. www.acep.org
• National Alliance on Mental Illness. www.nami.org

Drug brand names

• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan

Disclosure

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

Using a cholinesterase inhibitor (ChEI) makes sense for any disorder with a significant cholinergic deficit, such as Alzheimer’s disease (AD) and other forms of mild-to-moderate dementia (Box 1).^1-3 Yet the ChEIs tacrine, donepezil, rivastigmine, and galantamine have pharmacologic differences, and individual patients respond differently to them.

To help you choose the safest, most effective treatment for each patient, we discuss:

• three cases that show how ChEIs differ in mechanism of action, administration, and side effects
  
• evidence of ChEIs’ efficacy in AD—for which they are approved—and in other dementias for which they have been tried
  
• when to switch agents, and how long to continue treatment.
  

Box 1

How Cheis Differ

Although dementia remains incurable, recognizing cognitive decline early allows you to start ChEI therapy before substantial neuronal loss occurs (Box 2).^3,4 The goal of early treatment is to improve or stabilize cognition, behavior, and activities of daily living for as long as possible.

In comparison studies,^5,6 ChEIs have shown differences in tolerability but not consistent differences in efficacy for mild to moderate AD—though these studies had methodologic limitations. Because the agents appear similarly effective, the initial ChEI choice often depends on how their differences might benefit your patient (Table 1). Consider the following cases:

Box 2

Similarities and differences among cholinesterase inhibitors

Case 1: Gradual Memory Loss

Mrs. J, age 76, has experienced a slow, insidious memory decline across 5 years. She has become socially withdrawn and shows some language difficulties. She has had peptic ulcer disease and often does not take medications as prescribed.

Her psychiatrist diagnoses probable AD and chooses donepezil with its easy dosing schedule because of Mrs. J’s history of nonadherence. Donepezil’s GI tolerability is also a factor in this choice because of the patient’s peptic ulcer disease.

Case 2: Dementia And Motor Deficits

Mr. L, age 82, has gradually developed memory loss and parkinsonian symptoms, including slowness of movement and shuffling gait. He has visual hallucinations of people and episodic confusion. His medications include warfarin and digoxin for atrial fibrillation and congestive heart failure.

Mr. L is diagnosed with probable dementia with Lewy bodies. His psychiatrist chooses rivastigmine because it has shown efficacy in this type of dementia and is not known to interact significantly with cardiovascular medications.

Case 3: Stroke, Then Rapid Decline

Mrs. D, age 68, has a history of hypertension and suffered a stroke in the past. Her family says her memory and behavior—anger outbursts and excessive irritability—have worsened rapidly across 2 years. Examination reveals some focal neurologic deficits.

Her psychiatrist diagnoses probable vascular dementia and chooses galantamine for its efficacy in patients with this dementia type. Mrs. D has no history of GI illness and will likely tolerate the drug’s GI side effects. Follow-up care will include monitoring for tolerability.

Mechanism. Donepezil inhibits the enzyme acetylcholinesterase, and rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase. Galantamine inhibits acetylcholinesterase and shows allosteric modulation of the presynaptic nicotinic receptor.

Data indicating that rivastigmine is particularly effective in patients with rapidly progressive illness is consistent with the possible advantage of inhibiting both butyrylcholinesterase and acetylcholinesterase. It has been argued that galantamine’s binding to nicotinic receptors modulates their function, which may enhance acetylcholine release.

Among the three agents, only rivastigmine shows a consistent, linear dose-response relationship. It is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite (autohydrolysis). Minimal metabolism occurs via the major cytochrome P (CYP)-450 isoenzymes. Donepezil and galantamine are metabolized by isoenzymes 2D6 and 3A4 and undergo glucuronidation.⁷

Drug interactions. Because rivastigmine avoids hepatic metabolism, interactions with drugs metabolized by CYP-450 isoenzymes have not been reported.⁸

Donepezil interacts with ketoconazole and quinidine, which inhibit donepezil metabolism and increase mean donepezil concentrations. Galantamine interacts with ketoconazole, paroxetine, and erythromycin, which increase mean galantamine concentrations.⁹

Administration. Donepezil and extended-release galantamine are given once daily because of their long half-lives, whereas regular galantamine and rivastigmine are taken twice daily with meals to minimize GI effects (Table 2). Nausea and vomiting can occur with any of the ChEIs but are more common and troublesome with rivastigmine and galantamine.

Table 2

How to use cholinesterase inhibitors for patients with dementia

Efficacy In Early AD

In controlled clinical trials, all four ChEIs have significantly improved cognition, behavior, and activities of daily living in patients with mild-to-moderate AD.^10-12 Tacrine—the first FDA-approved ChEI—is rarely used because its associated hepatoxicity requires ongoing liver enzyme monitoring.¹³ Among the other three:

Donepezil. A review of 16 trials involving 4,365 participants¹⁰ found significant benefits in cognitive functioning, activities of daily living, and behavior in persons with mild, moderate, or severe AD who were treated with donepezil for 12, 24, or 52 weeks.

Rivastigmine improved or maintained cognitive function, activities of daily living, and behavior for up to 52 weeks in patients with mild to moderate AD, according to a review of studies from 1995 to 2002.¹¹ GI irritation was the most common adverse effect. Giving rivastigmine for up to 2 years may reduce the cost of caring for patients with AD, mostly by delaying nursing home placement.

Galantamine has beneficial effects on cognition, global function, activities of daily living, and behavior in patients with AD, vascular dementia, and AD with cerebrovascular components, according to a review of clinical studies.¹² Adverse events are generally mild to moderate, transient, and gastrointestinal.

Efficacy In Other Dementias

In addition to their FDA-approved use for mildto-moderate AD, ChEIs also have been studied in persons with other types of dementia and mild cognitive impairment (MCI).

Dementia with Lewy bodies. Rivastigmine given with flexible titration from 6 to 12 mg/d improved behavior in 120 patients with Lewy body dementia.¹⁴ In the double-blind, multicenter study, patients taking rivastigmine, mean 9.7 mg/d for 20 weeks, were less apathetic and anxious and had fewer delusions and hallucinations than did those taking placebo. The drug was judged to be safe and well tolerated.

Vascular dementia. Patients with vascular dementia showed improved cognition and global function when treated with donepezil, 5 or 10 mg/d, for up to 24 weeks. Donepezil was well tolerated in this combined analysis of two randomized, placebo-controlled trials.¹⁵

Kumar et al¹⁶ compared two rivastigmine dosages in patients with mild-to-moderate AD, some of whom also had vascular dementia risk factors. Patients were randomly assigned to placebo, low-dose rivastigmine (1 to 4 mg/d), or high-dose rivastigmine (6 to 12 mg/d) for 26 weeks. Cognition, activities of daily living, and disease severity improved with rivastigmine in patients with or without vascular risk factors. Greater benefit was seen with high-dose than low-dose rivastigmine and in patients with AD plus vascular risk factors than in those with AD alone.

In a multicenter, double-blind trial,¹⁷ patients with vascular dementia or AD with vascular risk factors received galantamine, up to 24 mg/d, or placebo for 6 months. Compared with controls, those taking galantamine showed improved cognition, behavior, and function. The drug overall was well tolerated, with nausea and vomiting the most common side effects.

Parkinson’s dementia. Emre et al¹⁸ evaluated rivastigmine’s efficacy and safety in patients whose mild-to-moderate dementia developed at least 2 years after a clinical diagnosis of Parkinson’s disease (PD). Patients were randomly assigned to placebo or rivastigmine, 3 to 12 mg/d, for 24 weeks, and 410 of 541 enrollees completed the study. Compared with placebo, rivastigmine was associated with statistically significant improvements in cognition and global measures in dementia associated with PD but also with higher rates of nausea, vomiting, and tremor. PD’s motor symptoms did not change significantly in either group.

Mixed dementia states. As mentioned, galantamine improved cognitive and noncognitive abilities in patients with vascular dementia or AD with vascular risk factors in a 6-month, double-blind trial.¹⁷ Patients who received galantamine or placebo could then continue open-label galantamine, 24 mg/d, for another 6 months. In patients treated the full 12 months, galantamine continued to improve or maintain:

• cognition, based on Alzheimer’s Disease Assessment Scale-cognitive subscale scores
  
• functional ability, measured by the 40-item Disability Assessment for Dementia
  
• behavior, measured by the Neuro-psychiatric Inventory.¹⁹
  

After 12 months, the rivastigmine-treated patients were less behaviorally impaired than the matched patients, and their caregivers reported reduced stress. Rivastigmine did not prevent cognitive deterioration, as assessed with the Mini-Mental State Examination (MMSE).

Mild cognitive impairment. Persons with MCI have objective psychometric evidence of memory loss compared with their peers, but they are not significantly impaired in activities of daily living or other cognitive functions (language, abstract thinking, or problem-solving).

At this time, we do not recommend using ChEIs to treat MCI. These agents have shown little benefit and potential risk in patients who do not meet diagnostic criteria for dementia:

• Salloway et al²¹ tested donepezil’s efficacy and safety in 270 patients with MCI in a 24-week, double-blind, placebo-controlled trial. Donepezil was started at 5 mg/d for 42 days, then escalated to 10 mg/d. Compared with placebo, donepezil showed no significant effects on recall, but some improvements were seen in attention and psychomotor speed.
  
• In two unpublished placebo-controlled trials, galantamine did not improve memory when given for 2 years to elderly patients with MCI. A precaution was added to the drug’s prescribing information because 13 of the 1,026 patients taking galantamine died, compared with 1 of 1,022 taking placebo. Vascular disease caused one-half of the galantamine group deaths. No evidence of increased mortality risk has been seen in studies of galantamine in patients with mild-to-moderate AD, for which it is indicated.
  

Getting The Greatest Response

To gauge response to ChEI therapy, family reports about the patient are helpful—such as that cognition has improved or cognitive decline has not progressed as rapidly as before. Assessment tools such as the MMSE can document improvement or stabilization.

We recommend trying an initial ChEI for at least 6 months to determine its efficacy. If your patient cannot tolerate one ChEI or fails to respond to initial treatment, two consensus panels^22,23 recommend that you consider changing ChEIs:

• If switching because of intolerable side effects, wait at least 2 to 3 days after stopping the first ChEI before starting another.
  
• If switching because of poor response, you can start a different ChEI immediately after the first one is stopped.
  

Box 3

• Alzheimer’s Association. Information for health care professionals:
  • • Diagnosing Alzheimer’s www.alz.org/Health/Diagnose/overview.asp
    
  • • Treating cognitive symptoms www.alz.org/Health/Treating/symptoms.asp
    
  
  
• American Association for Geriatric Psychiatry. Information for older patients and their families on Alzheimer’s disease, other dementias. www.gmhfonline.org/gmhf/consumer/alzheimers.html.
  

• Tacrine • Cognex
  
• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Razadyne (was Reminyl)
  

Drs. Kamat and LeFevre report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg receives grant/research support from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Cyberonics, Eli Lilly and Co., Eunoe, Forest Pharmaceuticals, Novartis Pharmaceuticals Corp., Pfizer, and Wyeth Pharmaceuticals. He is a consultant to AstraZeneca Pharmaceuticals, Forest Pharmaceuticals, Janssen Pharmaceutica, KV Pharma, Novartis Pharmaceuticals Corp., Organon International, and Sanofi-Synthelabo.

Acknowledgment

The authors thank Anjali Baliga, MD, for her contribution and help in preparing this article

Using a cholinesterase inhibitor (ChEI) makes sense for any disorder with a significant cholinergic deficit, such as Alzheimer’s disease (AD) and other forms of mild-to-moderate dementia (Box 1).^1-3 Yet the ChEIs tacrine, donepezil, rivastigmine, and galantamine have pharmacologic differences, and individual patients respond differently to them.

To help you choose the safest, most effective treatment for each patient, we discuss:

• three cases that show how ChEIs differ in mechanism of action, administration, and side effects
  
• evidence of ChEIs’ efficacy in AD—for which they are approved—and in other dementias for which they have been tried
  
• when to switch agents, and how long to continue treatment.
  

Box 1

How Cheis Differ

Although dementia remains incurable, recognizing cognitive decline early allows you to start ChEI therapy before substantial neuronal loss occurs (Box 2).^3,4 The goal of early treatment is to improve or stabilize cognition, behavior, and activities of daily living for as long as possible.

In comparison studies,^5,6 ChEIs have shown differences in tolerability but not consistent differences in efficacy for mild to moderate AD—though these studies had methodologic limitations. Because the agents appear similarly effective, the initial ChEI choice often depends on how their differences might benefit your patient (Table 1). Consider the following cases:

Box 2

Similarities and differences among cholinesterase inhibitors

Case 1: Gradual Memory Loss

Mrs. J, age 76, has experienced a slow, insidious memory decline across 5 years. She has become socially withdrawn and shows some language difficulties. She has had peptic ulcer disease and often does not take medications as prescribed.

Her psychiatrist diagnoses probable AD and chooses donepezil with its easy dosing schedule because of Mrs. J’s history of nonadherence. Donepezil’s GI tolerability is also a factor in this choice because of the patient’s peptic ulcer disease.

Case 2: Dementia And Motor Deficits

Mr. L, age 82, has gradually developed memory loss and parkinsonian symptoms, including slowness of movement and shuffling gait. He has visual hallucinations of people and episodic confusion. His medications include warfarin and digoxin for atrial fibrillation and congestive heart failure.

Mr. L is diagnosed with probable dementia with Lewy bodies. His psychiatrist chooses rivastigmine because it has shown efficacy in this type of dementia and is not known to interact significantly with cardiovascular medications.

Case 3: Stroke, Then Rapid Decline

Mrs. D, age 68, has a history of hypertension and suffered a stroke in the past. Her family says her memory and behavior—anger outbursts and excessive irritability—have worsened rapidly across 2 years. Examination reveals some focal neurologic deficits.

Her psychiatrist diagnoses probable vascular dementia and chooses galantamine for its efficacy in patients with this dementia type. Mrs. D has no history of GI illness and will likely tolerate the drug’s GI side effects. Follow-up care will include monitoring for tolerability.

Mechanism. Donepezil inhibits the enzyme acetylcholinesterase, and rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase. Galantamine inhibits acetylcholinesterase and shows allosteric modulation of the presynaptic nicotinic receptor.

Data indicating that rivastigmine is particularly effective in patients with rapidly progressive illness is consistent with the possible advantage of inhibiting both butyrylcholinesterase and acetylcholinesterase. It has been argued that galantamine’s binding to nicotinic receptors modulates their function, which may enhance acetylcholine release.

Among the three agents, only rivastigmine shows a consistent, linear dose-response relationship. It is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite (autohydrolysis). Minimal metabolism occurs via the major cytochrome P (CYP)-450 isoenzymes. Donepezil and galantamine are metabolized by isoenzymes 2D6 and 3A4 and undergo glucuronidation.⁷

Drug interactions. Because rivastigmine avoids hepatic metabolism, interactions with drugs metabolized by CYP-450 isoenzymes have not been reported.⁸

Donepezil interacts with ketoconazole and quinidine, which inhibit donepezil metabolism and increase mean donepezil concentrations. Galantamine interacts with ketoconazole, paroxetine, and erythromycin, which increase mean galantamine concentrations.⁹

Administration. Donepezil and extended-release galantamine are given once daily because of their long half-lives, whereas regular galantamine and rivastigmine are taken twice daily with meals to minimize GI effects (Table 2). Nausea and vomiting can occur with any of the ChEIs but are more common and troublesome with rivastigmine and galantamine.

Table 2

How to use cholinesterase inhibitors for patients with dementia

Efficacy In Early AD

In controlled clinical trials, all four ChEIs have significantly improved cognition, behavior, and activities of daily living in patients with mild-to-moderate AD.^10-12 Tacrine—the first FDA-approved ChEI—is rarely used because its associated hepatoxicity requires ongoing liver enzyme monitoring.¹³ Among the other three:

Donepezil. A review of 16 trials involving 4,365 participants¹⁰ found significant benefits in cognitive functioning, activities of daily living, and behavior in persons with mild, moderate, or severe AD who were treated with donepezil for 12, 24, or 52 weeks.

Rivastigmine improved or maintained cognitive function, activities of daily living, and behavior for up to 52 weeks in patients with mild to moderate AD, according to a review of studies from 1995 to 2002.¹¹ GI irritation was the most common adverse effect. Giving rivastigmine for up to 2 years may reduce the cost of caring for patients with AD, mostly by delaying nursing home placement.

Galantamine has beneficial effects on cognition, global function, activities of daily living, and behavior in patients with AD, vascular dementia, and AD with cerebrovascular components, according to a review of clinical studies.¹² Adverse events are generally mild to moderate, transient, and gastrointestinal.

Efficacy In Other Dementias

In addition to their FDA-approved use for mildto-moderate AD, ChEIs also have been studied in persons with other types of dementia and mild cognitive impairment (MCI).

Dementia with Lewy bodies. Rivastigmine given with flexible titration from 6 to 12 mg/d improved behavior in 120 patients with Lewy body dementia.¹⁴ In the double-blind, multicenter study, patients taking rivastigmine, mean 9.7 mg/d for 20 weeks, were less apathetic and anxious and had fewer delusions and hallucinations than did those taking placebo. The drug was judged to be safe and well tolerated.

Vascular dementia. Patients with vascular dementia showed improved cognition and global function when treated with donepezil, 5 or 10 mg/d, for up to 24 weeks. Donepezil was well tolerated in this combined analysis of two randomized, placebo-controlled trials.¹⁵

Kumar et al¹⁶ compared two rivastigmine dosages in patients with mild-to-moderate AD, some of whom also had vascular dementia risk factors. Patients were randomly assigned to placebo, low-dose rivastigmine (1 to 4 mg/d), or high-dose rivastigmine (6 to 12 mg/d) for 26 weeks. Cognition, activities of daily living, and disease severity improved with rivastigmine in patients with or without vascular risk factors. Greater benefit was seen with high-dose than low-dose rivastigmine and in patients with AD plus vascular risk factors than in those with AD alone.

In a multicenter, double-blind trial,¹⁷ patients with vascular dementia or AD with vascular risk factors received galantamine, up to 24 mg/d, or placebo for 6 months. Compared with controls, those taking galantamine showed improved cognition, behavior, and function. The drug overall was well tolerated, with nausea and vomiting the most common side effects.

Parkinson’s dementia. Emre et al¹⁸ evaluated rivastigmine’s efficacy and safety in patients whose mild-to-moderate dementia developed at least 2 years after a clinical diagnosis of Parkinson’s disease (PD). Patients were randomly assigned to placebo or rivastigmine, 3 to 12 mg/d, for 24 weeks, and 410 of 541 enrollees completed the study. Compared with placebo, rivastigmine was associated with statistically significant improvements in cognition and global measures in dementia associated with PD but also with higher rates of nausea, vomiting, and tremor. PD’s motor symptoms did not change significantly in either group.

Mixed dementia states. As mentioned, galantamine improved cognitive and noncognitive abilities in patients with vascular dementia or AD with vascular risk factors in a 6-month, double-blind trial.¹⁷ Patients who received galantamine or placebo could then continue open-label galantamine, 24 mg/d, for another 6 months. In patients treated the full 12 months, galantamine continued to improve or maintain:

• cognition, based on Alzheimer’s Disease Assessment Scale-cognitive subscale scores
  
• functional ability, measured by the 40-item Disability Assessment for Dementia
  
• behavior, measured by the Neuro-psychiatric Inventory.¹⁹
  

After 12 months, the rivastigmine-treated patients were less behaviorally impaired than the matched patients, and their caregivers reported reduced stress. Rivastigmine did not prevent cognitive deterioration, as assessed with the Mini-Mental State Examination (MMSE).

Mild cognitive impairment. Persons with MCI have objective psychometric evidence of memory loss compared with their peers, but they are not significantly impaired in activities of daily living or other cognitive functions (language, abstract thinking, or problem-solving).

At this time, we do not recommend using ChEIs to treat MCI. These agents have shown little benefit and potential risk in patients who do not meet diagnostic criteria for dementia:

• Salloway et al²¹ tested donepezil’s efficacy and safety in 270 patients with MCI in a 24-week, double-blind, placebo-controlled trial. Donepezil was started at 5 mg/d for 42 days, then escalated to 10 mg/d. Compared with placebo, donepezil showed no significant effects on recall, but some improvements were seen in attention and psychomotor speed.
  
• In two unpublished placebo-controlled trials, galantamine did not improve memory when given for 2 years to elderly patients with MCI. A precaution was added to the drug’s prescribing information because 13 of the 1,026 patients taking galantamine died, compared with 1 of 1,022 taking placebo. Vascular disease caused one-half of the galantamine group deaths. No evidence of increased mortality risk has been seen in studies of galantamine in patients with mild-to-moderate AD, for which it is indicated.
  

Getting The Greatest Response

To gauge response to ChEI therapy, family reports about the patient are helpful—such as that cognition has improved or cognitive decline has not progressed as rapidly as before. Assessment tools such as the MMSE can document improvement or stabilization.

We recommend trying an initial ChEI for at least 6 months to determine its efficacy. If your patient cannot tolerate one ChEI or fails to respond to initial treatment, two consensus panels^22,23 recommend that you consider changing ChEIs:

• If switching because of intolerable side effects, wait at least 2 to 3 days after stopping the first ChEI before starting another.
  
• If switching because of poor response, you can start a different ChEI immediately after the first one is stopped.
  

Box 3

• Alzheimer’s Association. Information for health care professionals:
  • • Diagnosing Alzheimer’s www.alz.org/Health/Diagnose/overview.asp
    
  • • Treating cognitive symptoms www.alz.org/Health/Treating/symptoms.asp
    
  
  
• American Association for Geriatric Psychiatry. Information for older patients and their families on Alzheimer’s disease, other dementias. www.gmhfonline.org/gmhf/consumer/alzheimers.html.
  

• Tacrine • Cognex
  
• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Razadyne (was Reminyl)
  

Drs. Kamat and LeFevre report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg receives grant/research support from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Cyberonics, Eli Lilly and Co., Eunoe, Forest Pharmaceuticals, Novartis Pharmaceuticals Corp., Pfizer, and Wyeth Pharmaceuticals. He is a consultant to AstraZeneca Pharmaceuticals, Forest Pharmaceuticals, Janssen Pharmaceutica, KV Pharma, Novartis Pharmaceuticals Corp., Organon International, and Sanofi-Synthelabo.

Acknowledgment

The authors thank Anjali Baliga, MD, for her contribution and help in preparing this article

Using a cholinesterase inhibitor (ChEI) makes sense for any disorder with a significant cholinergic deficit, such as Alzheimer’s disease (AD) and other forms of mild-to-moderate dementia (Box 1).^1-3 Yet the ChEIs tacrine, donepezil, rivastigmine, and galantamine have pharmacologic differences, and individual patients respond differently to them.

To help you choose the safest, most effective treatment for each patient, we discuss:

• three cases that show how ChEIs differ in mechanism of action, administration, and side effects
  
• evidence of ChEIs’ efficacy in AD—for which they are approved—and in other dementias for which they have been tried
  
• when to switch agents, and how long to continue treatment.
  

Box 1

How Cheis Differ

Although dementia remains incurable, recognizing cognitive decline early allows you to start ChEI therapy before substantial neuronal loss occurs (Box 2).^3,4 The goal of early treatment is to improve or stabilize cognition, behavior, and activities of daily living for as long as possible.

In comparison studies,^5,6 ChEIs have shown differences in tolerability but not consistent differences in efficacy for mild to moderate AD—though these studies had methodologic limitations. Because the agents appear similarly effective, the initial ChEI choice often depends on how their differences might benefit your patient (Table 1). Consider the following cases:

Box 2

Similarities and differences among cholinesterase inhibitors

Case 1: Gradual Memory Loss

Mrs. J, age 76, has experienced a slow, insidious memory decline across 5 years. She has become socially withdrawn and shows some language difficulties. She has had peptic ulcer disease and often does not take medications as prescribed.

Her psychiatrist diagnoses probable AD and chooses donepezil with its easy dosing schedule because of Mrs. J’s history of nonadherence. Donepezil’s GI tolerability is also a factor in this choice because of the patient’s peptic ulcer disease.

Case 2: Dementia And Motor Deficits

Mr. L, age 82, has gradually developed memory loss and parkinsonian symptoms, including slowness of movement and shuffling gait. He has visual hallucinations of people and episodic confusion. His medications include warfarin and digoxin for atrial fibrillation and congestive heart failure.

Mr. L is diagnosed with probable dementia with Lewy bodies. His psychiatrist chooses rivastigmine because it has shown efficacy in this type of dementia and is not known to interact significantly with cardiovascular medications.

Case 3: Stroke, Then Rapid Decline

Mrs. D, age 68, has a history of hypertension and suffered a stroke in the past. Her family says her memory and behavior—anger outbursts and excessive irritability—have worsened rapidly across 2 years. Examination reveals some focal neurologic deficits.

Her psychiatrist diagnoses probable vascular dementia and chooses galantamine for its efficacy in patients with this dementia type. Mrs. D has no history of GI illness and will likely tolerate the drug’s GI side effects. Follow-up care will include monitoring for tolerability.

Mechanism. Donepezil inhibits the enzyme acetylcholinesterase, and rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase. Galantamine inhibits acetylcholinesterase and shows allosteric modulation of the presynaptic nicotinic receptor.

Data indicating that rivastigmine is particularly effective in patients with rapidly progressive illness is consistent with the possible advantage of inhibiting both butyrylcholinesterase and acetylcholinesterase. It has been argued that galantamine’s binding to nicotinic receptors modulates their function, which may enhance acetylcholine release.

Among the three agents, only rivastigmine shows a consistent, linear dose-response relationship. It is rapidly and extensively metabolized, primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite (autohydrolysis). Minimal metabolism occurs via the major cytochrome P (CYP)-450 isoenzymes. Donepezil and galantamine are metabolized by isoenzymes 2D6 and 3A4 and undergo glucuronidation.⁷

Drug interactions. Because rivastigmine avoids hepatic metabolism, interactions with drugs metabolized by CYP-450 isoenzymes have not been reported.⁸

Donepezil interacts with ketoconazole and quinidine, which inhibit donepezil metabolism and increase mean donepezil concentrations. Galantamine interacts with ketoconazole, paroxetine, and erythromycin, which increase mean galantamine concentrations.⁹

Administration. Donepezil and extended-release galantamine are given once daily because of their long half-lives, whereas regular galantamine and rivastigmine are taken twice daily with meals to minimize GI effects (Table 2). Nausea and vomiting can occur with any of the ChEIs but are more common and troublesome with rivastigmine and galantamine.

Table 2

How to use cholinesterase inhibitors for patients with dementia

Efficacy In Early AD

In controlled clinical trials, all four ChEIs have significantly improved cognition, behavior, and activities of daily living in patients with mild-to-moderate AD.^10-12 Tacrine—the first FDA-approved ChEI—is rarely used because its associated hepatoxicity requires ongoing liver enzyme monitoring.¹³ Among the other three:

Donepezil. A review of 16 trials involving 4,365 participants¹⁰ found significant benefits in cognitive functioning, activities of daily living, and behavior in persons with mild, moderate, or severe AD who were treated with donepezil for 12, 24, or 52 weeks.

Rivastigmine improved or maintained cognitive function, activities of daily living, and behavior for up to 52 weeks in patients with mild to moderate AD, according to a review of studies from 1995 to 2002.¹¹ GI irritation was the most common adverse effect. Giving rivastigmine for up to 2 years may reduce the cost of caring for patients with AD, mostly by delaying nursing home placement.

Galantamine has beneficial effects on cognition, global function, activities of daily living, and behavior in patients with AD, vascular dementia, and AD with cerebrovascular components, according to a review of clinical studies.¹² Adverse events are generally mild to moderate, transient, and gastrointestinal.

Efficacy In Other Dementias

In addition to their FDA-approved use for mildto-moderate AD, ChEIs also have been studied in persons with other types of dementia and mild cognitive impairment (MCI).

Dementia with Lewy bodies. Rivastigmine given with flexible titration from 6 to 12 mg/d improved behavior in 120 patients with Lewy body dementia.¹⁴ In the double-blind, multicenter study, patients taking rivastigmine, mean 9.7 mg/d for 20 weeks, were less apathetic and anxious and had fewer delusions and hallucinations than did those taking placebo. The drug was judged to be safe and well tolerated.

Vascular dementia. Patients with vascular dementia showed improved cognition and global function when treated with donepezil, 5 or 10 mg/d, for up to 24 weeks. Donepezil was well tolerated in this combined analysis of two randomized, placebo-controlled trials.¹⁵

Kumar et al¹⁶ compared two rivastigmine dosages in patients with mild-to-moderate AD, some of whom also had vascular dementia risk factors. Patients were randomly assigned to placebo, low-dose rivastigmine (1 to 4 mg/d), or high-dose rivastigmine (6 to 12 mg/d) for 26 weeks. Cognition, activities of daily living, and disease severity improved with rivastigmine in patients with or without vascular risk factors. Greater benefit was seen with high-dose than low-dose rivastigmine and in patients with AD plus vascular risk factors than in those with AD alone.

In a multicenter, double-blind trial,¹⁷ patients with vascular dementia or AD with vascular risk factors received galantamine, up to 24 mg/d, or placebo for 6 months. Compared with controls, those taking galantamine showed improved cognition, behavior, and function. The drug overall was well tolerated, with nausea and vomiting the most common side effects.

Parkinson’s dementia. Emre et al¹⁸ evaluated rivastigmine’s efficacy and safety in patients whose mild-to-moderate dementia developed at least 2 years after a clinical diagnosis of Parkinson’s disease (PD). Patients were randomly assigned to placebo or rivastigmine, 3 to 12 mg/d, for 24 weeks, and 410 of 541 enrollees completed the study. Compared with placebo, rivastigmine was associated with statistically significant improvements in cognition and global measures in dementia associated with PD but also with higher rates of nausea, vomiting, and tremor. PD’s motor symptoms did not change significantly in either group.

Mixed dementia states. As mentioned, galantamine improved cognitive and noncognitive abilities in patients with vascular dementia or AD with vascular risk factors in a 6-month, double-blind trial.¹⁷ Patients who received galantamine or placebo could then continue open-label galantamine, 24 mg/d, for another 6 months. In patients treated the full 12 months, galantamine continued to improve or maintain:

• cognition, based on Alzheimer’s Disease Assessment Scale-cognitive subscale scores
  
• functional ability, measured by the 40-item Disability Assessment for Dementia
  
• behavior, measured by the Neuro-psychiatric Inventory.¹⁹
  

After 12 months, the rivastigmine-treated patients were less behaviorally impaired than the matched patients, and their caregivers reported reduced stress. Rivastigmine did not prevent cognitive deterioration, as assessed with the Mini-Mental State Examination (MMSE).

Mild cognitive impairment. Persons with MCI have objective psychometric evidence of memory loss compared with their peers, but they are not significantly impaired in activities of daily living or other cognitive functions (language, abstract thinking, or problem-solving).

At this time, we do not recommend using ChEIs to treat MCI. These agents have shown little benefit and potential risk in patients who do not meet diagnostic criteria for dementia:

• Salloway et al²¹ tested donepezil’s efficacy and safety in 270 patients with MCI in a 24-week, double-blind, placebo-controlled trial. Donepezil was started at 5 mg/d for 42 days, then escalated to 10 mg/d. Compared with placebo, donepezil showed no significant effects on recall, but some improvements were seen in attention and psychomotor speed.
  
• In two unpublished placebo-controlled trials, galantamine did not improve memory when given for 2 years to elderly patients with MCI. A precaution was added to the drug’s prescribing information because 13 of the 1,026 patients taking galantamine died, compared with 1 of 1,022 taking placebo. Vascular disease caused one-half of the galantamine group deaths. No evidence of increased mortality risk has been seen in studies of galantamine in patients with mild-to-moderate AD, for which it is indicated.
  

Getting The Greatest Response

To gauge response to ChEI therapy, family reports about the patient are helpful—such as that cognition has improved or cognitive decline has not progressed as rapidly as before. Assessment tools such as the MMSE can document improvement or stabilization.

We recommend trying an initial ChEI for at least 6 months to determine its efficacy. If your patient cannot tolerate one ChEI or fails to respond to initial treatment, two consensus panels^22,23 recommend that you consider changing ChEIs:

• If switching because of intolerable side effects, wait at least 2 to 3 days after stopping the first ChEI before starting another.
  
• If switching because of poor response, you can start a different ChEI immediately after the first one is stopped.
  

Box 3

• Alzheimer’s Association. Information for health care professionals:
  • • Diagnosing Alzheimer’s www.alz.org/Health/Diagnose/overview.asp
    
  • • Treating cognitive symptoms www.alz.org/Health/Treating/symptoms.asp
    
  
  
• American Association for Geriatric Psychiatry. Information for older patients and their families on Alzheimer’s disease, other dementias. www.gmhfonline.org/gmhf/consumer/alzheimers.html.
  

• Tacrine • Cognex
  
• Donepezil • Aricept
  
• Rivastigmine • Exelon
  
• Galantamine • Razadyne (was Reminyl)
  

Drs. Kamat and LeFevre report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Grossberg receives grant/research support from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Cyberonics, Eli Lilly and Co., Eunoe, Forest Pharmaceuticals, Novartis Pharmaceuticals Corp., Pfizer, and Wyeth Pharmaceuticals. He is a consultant to AstraZeneca Pharmaceuticals, Forest Pharmaceuticals, Janssen Pharmaceutica, KV Pharma, Novartis Pharmaceuticals Corp., Organon International, and Sanofi-Synthelabo.

Acknowledgment

The authors thank Anjali Baliga, MD, for her contribution and help in preparing this article

Mrs. E, age 74, has been distraught for 6 months since the death of her husband of 45 years. She is brought for evaluation by her daughter, who is exasperated and worried about her mother’s sad mood, frequent tearfulness, weight loss (11 pounds), and social isolation.

Mrs. E says she feels lost and paralyzed, that she “sticks out like a sore thumb” when among couples “that still have each other.” She refuses to go to church, though she attended regularly in the past.

Unresolved grief appears to be linked to the onset and persistence of Mrs. E’s depressive symptoms. After a thorough evaluation confirms major depression, the psychiatrist explains the diagnosis to Mrs. E. She agrees to begin an antidepressant and interpersonal psychotherapy (IPT).

IPT is easy to use and well-suited to address abnormal grieving, role transitions, and role disputes in depressed older patients. In controlled trials, IPT has been shown effective as acute¹ and maintenance treatment^2,3 of depression. This article describes how IPT can work effectively for depressed older adults and their clinicians.

IPT and elder depression

New-onset or recurrent depression is common in older patients experiencing retirement, relocation, disabilities, or loss of important persons in their lives (Box 1) ⁴ IPT recognizes that depression, regardless of psychosocial stress or biologic vulnerability, is expressed in an interpersonal environment (Box 2).^5,6 The environment may have contributed to the depression, but it also can be a platform for intervention.

Depressed older adults who are verbal, nondemented, and engageable are candidates for IPT, with or without adjunctive antidepressant therapy. Psychotherapy is not indicated for patients with severe dementia, but this article will describe how IPT is being adapted for those with early dementia or mild cognitive impairment.

Box 1

Case continued: ‘he made all the decisions’

At Mrs. E’s first IPT session, the therapist assigns her the “sick role.” They contract to meet 12 to 16 weeks, and Mrs. E’s daughter agrees to drive her to sessions.

In the next few weeks, the therapist explains depression’s biopsychosocial model and explores dual strategies with Mrs. E: to ease her mourning and explore new interests or relationships. The therapist encourages her to express her feelings and seeks to understand the dynamics of her marriage.

Mrs. E said she was raised by nurturing parents and married soon after high school. She depended on her husband for almost every decision, including their social calendar. She describes their relationship as mutually loving. As part of an interpersonal inventory, her therapist encourages her to describe in detail all the ways she misses him.

The ‘sick role.’ The therapist assigned Mrs. E the “sick role” to emphasize that major depression can be a severe illness. A therapist might say: “If you had pneumonia, you wouldn’t think of trying to rake leaves. You would rest and take care of yourself to speed the healing. Persons with major depression should do the same.”

The contract. The therapist also explained to Mrs. E that contracting to meet weekly for 12 to 16 weeks is part of the treatment. A contract:

• encourages patients to commit to an IPT trial for a reasonable time
  
• presses patients to achieve adequate progress by the deadline
  
• discourages digression, avoidance of painful subjects, and dependence on the therapist.
  

IPT begins with a complete psychiatric evaluation, including the patient’s past, family, and social histories; alcohol and drug use; medical comorbidities; mental status exam; and sometimes blood screening to rule out metabolic abnormalities. Antidepressants are prescribed as needed to relieve vegetative symptoms and are used during IPT when indicated.

Interpersonal inventory. Each of the patient’s interpersonal relationships is then systematically reviewed. This inventory sets the stage for exploring relationships that may be linked to the depressive symptoms or offer opportunities for trying alternate coping trategies, such as learning to seek social support (Table 2).

Table 1

IPT’s understanding of depression comprises 3 component processes

‘How-to’ checklist of IPT procedures

IPT’S FOUR FOCI

IPT’s goal is to relieve depressive symptoms by identifying and focusing on problems that may have caused or are perpetuating those symptoms. Most of the reasons depressed patients give for seeking help fall into four foci: unresolved grief, role transition, role dispute, and interpersonal deficit (Table 3).^5,6 The therapist uses clarification, interpretation, confrontation, and testing of perceptions and performance to address each focus, as detailed in the IPT manual.⁶

The therapist acts as the patient’s advocate, and focuses treatment on interpersonal relationships in the “here and now,” not past traumas, childhood conflicts, cognitive-behavioral interventions, or intrapsychic themes. No attempt is made to restructure personality.

Progress in relieving depressive symptoms is reviewed regularly, and treatment ends within the contract’s time limits in many cases. Older patients may need additional sessions because they often take longer to respond to antidepressant trials (6 to 8 weeks, compared with 3 to 4 weeks for younger adults). We allow older patients to “catch up” with additional sessions if illness, lack of transportation, or other problems prevent them from receiving the “full dose” of IPT.

IPT does not work for all patients. Consider other types of treatment if a patient shows no discernable benefit.

Table 3

IPT’s 4 foci, specific to late-life depression

Case continued: stalled in grief

As the weeks pass, Mrs. E improves but remains hypoactive and reclusive. She seems afraid to take any action without her late husband’s approval. Thinking about making independent decisions overwhelms her, and she withdraws to her couch to hide.

Her therapist discerns that Mrs. E needs more-active confrontation to accept that her new life requires her to make choices, even though decision-making is difficult for her. They develop a game, hronicling all decisions Mrs. E has made for the first time, such as calling a repairman and planting the summer vegetable garden by herself.

The therapist applauds these “firsts” and points out that Mrs. E’s depressive symptoms have improved as her list of completed decisions has grown. Mrs. E holds the power to make decisions, the therapist stresses, and bears the consequences of not taking action.

Applying ipt to late-life depression

Our group has used IPT in research protocols for 15 years. We and others^7-11 have found that IPT is well-suited for treating late-life depression because:

• Older patients without psychotherapy experience or psychological sophistication can easily participate.
  
• Persons with limited education can understand IPT’s informal explanations of depression.
  
• Two foci of IPT—grief and role transition—address common themes of aging, such as spousal role disputes after retirement or caregiver stress when one partner becomes ill or shows signs of dementia.
  

Only minor IPT adaptations were required for older patients, such as:

• shorter sessions for those who reported physical discomfort
  
• accommodating for hearing loss, arranging transportation, and conducting sessions by telephone when patients were ill or shut in by inclement weather.
  

Case continued: more ‘firsts’ build confidence

Mrs. E makes slow, sometimes painful, but steady progress. Her therapist encourages her to keep trying more “firsts,”such as going back to church and attending her first social event alone, and to review her emotional reactions.

Mrs. E’s depressive symptoms wane as her confidence builds, and she readjusts her self-image to that of a widow who enjoyed a good marriage with a benevolent but overprotective husband. Her therapist links her progress to her string of successful “firsts” and to the contributing benefit of anti-depressant medication.

IPT As maintenance therapy

In the Maintenance Therapies for Late Life Depression (MTLLD) study—a randomized, double-blind, placebo-controlled trial¹²—we showed IPT to be effective as maintenance therapy for recurrent depression in patients age 60 and older. The 187 patients (mean age 67, one-third age ≥70) with nonpsychotic unipolar major depression were first treated to remission with IPT plus nortriptyline (80 to 120 ng/mL).

We then randomly assigned the 107 who achieved recovery to one of four maintenance therapies. After 3 years of monthly follow-up, relapse rates were:

• 20% with nortriptyline plus maintenance IPT
  
• 43% with nortriptyline plus medication clinic visits
  
• 64% with maintenance IPT plus placebo
  
• 90% with medication clinic plus placebo.
  

Further analysis showed that patients age ≥70 required combined treatment with nortriptyline and IPT to stay well, whereas those ages 60 to 69 stayed well with drug therapy alone. Patients age ≥70 also had a higher and more rapid relapse rate.

Recurrence by therapy focus. In patients who received placebo instead of nortriptyline:

• Time without a new depressive episode was similar for patients with a focus on grief or role transition, whether they received IPT or medication checkups.
  
• Recurrence rates were clearly lower in patients whose initial focus was role dispute if they received monthly maintenance IPT sessions instead of medication check visits.
  

Case continued: looking ahead

As the 12- to 16-week contracted period winds down, Mrs. E admits she still longs for her husband’s protection. She said she would gladly give up her independence to have that “safe” feeling back.

The therapist acknowledges that feeling but gently reminds her that she has the tools to face her new life realistically. During therapy, Mrs. E has shown she can assess life’s many decisions, make rational choices, and live with the consequences.

Their final discussion touches on the notion that Mrs. E could imagine having some kind of friendship with another man in the future.

Wrapping up. The last IPT sessions focus on reviewing any decline in depressive symptoms that may be linked to having learned new coping skills. With successful IPT, patients learn to appraise their strengths and remaining vulnerabilities and gain skills, self-confidence, and understanding to confront remaining obstacles after therapy ends.

Adapting ipt for special populations

Resistant depression. Researchers at the University of Pittsburgh are investigating whether adding IPT can achieve remission in depressed older patients who show partial response to a 6-week trial of escitalopram, 10 mg/d. In this ongoing trial, patients with Hamilton Depression Rating Scale scores of 11 to 14 after 6 weeks receive an increased escitalopram dosage (20 mg/d) and are randomly assigned to medication alone or medication plus 16 weeks of IPT.

Cognitive impairment. An unpublished follow-up to the MTLLD study enrolled 116 patients aged ≥70 and used a similar design, except that:

• patients were not required to have had recurrent depressive episodes
  
• paroxetine was used instead of nortriptyline
  
• patients with cognitive impairment (Mini-Mental Status Examination scores ?18/30) were included.
  

Cognitive impairment may have interfered with patients’ ability to benefit from traditional IPT. Thus, to improve the quality of life of depressed, cognitively-impaired elders, researchers are involving caregivers (usually a spouse or adult child) in modified forms of IPT couples therapy.^6,13-18 A team at the University of Pittsburgh is developing a flexible approach that includes meetings with the patient, the caregiver, or both. Two papers on IPT-CI (for cognitive impairment) are under review.

Related resources

• International Society for Interpersonal Psychotherapy. Accreditation, training, and research information. www.interpersonalpsychotherapy.org.
  
• Stuart S, Robertson M. Interpersonal psychotherapy: a clinician’s guide. London: Edward Arnold Ltd.; 2002.
  
• Miller MD, Reynolds CF. Interpersonal psychotherapy. In: Hepple J, Pierce J, Wilkinson P (eds). Psychological therapies with older people. East Sussex, UK: Brunner-Routledge; 2002:103-27.
  
• Miller MD, Reynolds CF. Living longer depression-free: a family guide to the recognition, treatment and prevention of depression in later life. Baltimore: Johns Hopkins University Press; 2002.
  

• Escitalopram • Lexapro
  
• Nortriptyline • Pamelor
  
• Paroxetine • Paxil
  

Dr. Miller is a consultant to Forest Laboratories and GlaxoSmithKline and is a speaker for Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

Mrs. E, age 74, has been distraught for 6 months since the death of her husband of 45 years. She is brought for evaluation by her daughter, who is exasperated and worried about her mother’s sad mood, frequent tearfulness, weight loss (11 pounds), and social isolation.

Mrs. E says she feels lost and paralyzed, that she “sticks out like a sore thumb” when among couples “that still have each other.” She refuses to go to church, though she attended regularly in the past.

Unresolved grief appears to be linked to the onset and persistence of Mrs. E’s depressive symptoms. After a thorough evaluation confirms major depression, the psychiatrist explains the diagnosis to Mrs. E. She agrees to begin an antidepressant and interpersonal psychotherapy (IPT).

IPT is easy to use and well-suited to address abnormal grieving, role transitions, and role disputes in depressed older patients. In controlled trials, IPT has been shown effective as acute¹ and maintenance treatment^2,3 of depression. This article describes how IPT can work effectively for depressed older adults and their clinicians.

IPT and elder depression

New-onset or recurrent depression is common in older patients experiencing retirement, relocation, disabilities, or loss of important persons in their lives (Box 1) ⁴ IPT recognizes that depression, regardless of psychosocial stress or biologic vulnerability, is expressed in an interpersonal environment (Box 2).^5,6 The environment may have contributed to the depression, but it also can be a platform for intervention.

Depressed older adults who are verbal, nondemented, and engageable are candidates for IPT, with or without adjunctive antidepressant therapy. Psychotherapy is not indicated for patients with severe dementia, but this article will describe how IPT is being adapted for those with early dementia or mild cognitive impairment.

Box 1

Case continued: ‘he made all the decisions’

At Mrs. E’s first IPT session, the therapist assigns her the “sick role.” They contract to meet 12 to 16 weeks, and Mrs. E’s daughter agrees to drive her to sessions.

In the next few weeks, the therapist explains depression’s biopsychosocial model and explores dual strategies with Mrs. E: to ease her mourning and explore new interests or relationships. The therapist encourages her to express her feelings and seeks to understand the dynamics of her marriage.

Mrs. E said she was raised by nurturing parents and married soon after high school. She depended on her husband for almost every decision, including their social calendar. She describes their relationship as mutually loving. As part of an interpersonal inventory, her therapist encourages her to describe in detail all the ways she misses him.

The ‘sick role.’ The therapist assigned Mrs. E the “sick role” to emphasize that major depression can be a severe illness. A therapist might say: “If you had pneumonia, you wouldn’t think of trying to rake leaves. You would rest and take care of yourself to speed the healing. Persons with major depression should do the same.”

The contract. The therapist also explained to Mrs. E that contracting to meet weekly for 12 to 16 weeks is part of the treatment. A contract:

• encourages patients to commit to an IPT trial for a reasonable time
  
• presses patients to achieve adequate progress by the deadline
  
• discourages digression, avoidance of painful subjects, and dependence on the therapist.
  

IPT begins with a complete psychiatric evaluation, including the patient’s past, family, and social histories; alcohol and drug use; medical comorbidities; mental status exam; and sometimes blood screening to rule out metabolic abnormalities. Antidepressants are prescribed as needed to relieve vegetative symptoms and are used during IPT when indicated.

Interpersonal inventory. Each of the patient’s interpersonal relationships is then systematically reviewed. This inventory sets the stage for exploring relationships that may be linked to the depressive symptoms or offer opportunities for trying alternate coping trategies, such as learning to seek social support (Table 2).

Table 1

IPT’s understanding of depression comprises 3 component processes

‘How-to’ checklist of IPT procedures

IPT’S FOUR FOCI

IPT’s goal is to relieve depressive symptoms by identifying and focusing on problems that may have caused or are perpetuating those symptoms. Most of the reasons depressed patients give for seeking help fall into four foci: unresolved grief, role transition, role dispute, and interpersonal deficit (Table 3).^5,6 The therapist uses clarification, interpretation, confrontation, and testing of perceptions and performance to address each focus, as detailed in the IPT manual.⁶

The therapist acts as the patient’s advocate, and focuses treatment on interpersonal relationships in the “here and now,” not past traumas, childhood conflicts, cognitive-behavioral interventions, or intrapsychic themes. No attempt is made to restructure personality.

Progress in relieving depressive symptoms is reviewed regularly, and treatment ends within the contract’s time limits in many cases. Older patients may need additional sessions because they often take longer to respond to antidepressant trials (6 to 8 weeks, compared with 3 to 4 weeks for younger adults). We allow older patients to “catch up” with additional sessions if illness, lack of transportation, or other problems prevent them from receiving the “full dose” of IPT.

IPT does not work for all patients. Consider other types of treatment if a patient shows no discernable benefit.

Table 3

IPT’s 4 foci, specific to late-life depression

Case continued: stalled in grief

As the weeks pass, Mrs. E improves but remains hypoactive and reclusive. She seems afraid to take any action without her late husband’s approval. Thinking about making independent decisions overwhelms her, and she withdraws to her couch to hide.

Her therapist discerns that Mrs. E needs more-active confrontation to accept that her new life requires her to make choices, even though decision-making is difficult for her. They develop a game, hronicling all decisions Mrs. E has made for the first time, such as calling a repairman and planting the summer vegetable garden by herself.

The therapist applauds these “firsts” and points out that Mrs. E’s depressive symptoms have improved as her list of completed decisions has grown. Mrs. E holds the power to make decisions, the therapist stresses, and bears the consequences of not taking action.

Applying ipt to late-life depression

Our group has used IPT in research protocols for 15 years. We and others^7-11 have found that IPT is well-suited for treating late-life depression because:

• Older patients without psychotherapy experience or psychological sophistication can easily participate.
  
• Persons with limited education can understand IPT’s informal explanations of depression.
  
• Two foci of IPT—grief and role transition—address common themes of aging, such as spousal role disputes after retirement or caregiver stress when one partner becomes ill or shows signs of dementia.
  

Only minor IPT adaptations were required for older patients, such as:

• shorter sessions for those who reported physical discomfort
  
• accommodating for hearing loss, arranging transportation, and conducting sessions by telephone when patients were ill or shut in by inclement weather.
  

Case continued: more ‘firsts’ build confidence

Mrs. E makes slow, sometimes painful, but steady progress. Her therapist encourages her to keep trying more “firsts,”such as going back to church and attending her first social event alone, and to review her emotional reactions.

Mrs. E’s depressive symptoms wane as her confidence builds, and she readjusts her self-image to that of a widow who enjoyed a good marriage with a benevolent but overprotective husband. Her therapist links her progress to her string of successful “firsts” and to the contributing benefit of anti-depressant medication.

IPT As maintenance therapy

In the Maintenance Therapies for Late Life Depression (MTLLD) study—a randomized, double-blind, placebo-controlled trial¹²—we showed IPT to be effective as maintenance therapy for recurrent depression in patients age 60 and older. The 187 patients (mean age 67, one-third age ≥70) with nonpsychotic unipolar major depression were first treated to remission with IPT plus nortriptyline (80 to 120 ng/mL).

We then randomly assigned the 107 who achieved recovery to one of four maintenance therapies. After 3 years of monthly follow-up, relapse rates were:

• 20% with nortriptyline plus maintenance IPT
  
• 43% with nortriptyline plus medication clinic visits
  
• 64% with maintenance IPT plus placebo
  
• 90% with medication clinic plus placebo.
  

Further analysis showed that patients age ≥70 required combined treatment with nortriptyline and IPT to stay well, whereas those ages 60 to 69 stayed well with drug therapy alone. Patients age ≥70 also had a higher and more rapid relapse rate.

Recurrence by therapy focus. In patients who received placebo instead of nortriptyline:

• Time without a new depressive episode was similar for patients with a focus on grief or role transition, whether they received IPT or medication checkups.
  
• Recurrence rates were clearly lower in patients whose initial focus was role dispute if they received monthly maintenance IPT sessions instead of medication check visits.
  

Case continued: looking ahead

As the 12- to 16-week contracted period winds down, Mrs. E admits she still longs for her husband’s protection. She said she would gladly give up her independence to have that “safe” feeling back.

The therapist acknowledges that feeling but gently reminds her that she has the tools to face her new life realistically. During therapy, Mrs. E has shown she can assess life’s many decisions, make rational choices, and live with the consequences.

Their final discussion touches on the notion that Mrs. E could imagine having some kind of friendship with another man in the future.

Wrapping up. The last IPT sessions focus on reviewing any decline in depressive symptoms that may be linked to having learned new coping skills. With successful IPT, patients learn to appraise their strengths and remaining vulnerabilities and gain skills, self-confidence, and understanding to confront remaining obstacles after therapy ends.

Adapting ipt for special populations

Resistant depression. Researchers at the University of Pittsburgh are investigating whether adding IPT can achieve remission in depressed older patients who show partial response to a 6-week trial of escitalopram, 10 mg/d. In this ongoing trial, patients with Hamilton Depression Rating Scale scores of 11 to 14 after 6 weeks receive an increased escitalopram dosage (20 mg/d) and are randomly assigned to medication alone or medication plus 16 weeks of IPT.

Cognitive impairment. An unpublished follow-up to the MTLLD study enrolled 116 patients aged ≥70 and used a similar design, except that:

• patients were not required to have had recurrent depressive episodes
  
• paroxetine was used instead of nortriptyline
  
• patients with cognitive impairment (Mini-Mental Status Examination scores ?18/30) were included.
  

Cognitive impairment may have interfered with patients’ ability to benefit from traditional IPT. Thus, to improve the quality of life of depressed, cognitively-impaired elders, researchers are involving caregivers (usually a spouse or adult child) in modified forms of IPT couples therapy.^6,13-18 A team at the University of Pittsburgh is developing a flexible approach that includes meetings with the patient, the caregiver, or both. Two papers on IPT-CI (for cognitive impairment) are under review.

Related resources

• International Society for Interpersonal Psychotherapy. Accreditation, training, and research information. www.interpersonalpsychotherapy.org.
  
• Stuart S, Robertson M. Interpersonal psychotherapy: a clinician’s guide. London: Edward Arnold Ltd.; 2002.
  
• Miller MD, Reynolds CF. Interpersonal psychotherapy. In: Hepple J, Pierce J, Wilkinson P (eds). Psychological therapies with older people. East Sussex, UK: Brunner-Routledge; 2002:103-27.
  
• Miller MD, Reynolds CF. Living longer depression-free: a family guide to the recognition, treatment and prevention of depression in later life. Baltimore: Johns Hopkins University Press; 2002.
  

• Escitalopram • Lexapro
  
• Nortriptyline • Pamelor
  
• Paroxetine • Paxil
  

Dr. Miller is a consultant to Forest Laboratories and GlaxoSmithKline and is a speaker for Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

Mrs. E, age 74, has been distraught for 6 months since the death of her husband of 45 years. She is brought for evaluation by her daughter, who is exasperated and worried about her mother’s sad mood, frequent tearfulness, weight loss (11 pounds), and social isolation.

Mrs. E says she feels lost and paralyzed, that she “sticks out like a sore thumb” when among couples “that still have each other.” She refuses to go to church, though she attended regularly in the past.

Unresolved grief appears to be linked to the onset and persistence of Mrs. E’s depressive symptoms. After a thorough evaluation confirms major depression, the psychiatrist explains the diagnosis to Mrs. E. She agrees to begin an antidepressant and interpersonal psychotherapy (IPT).

IPT is easy to use and well-suited to address abnormal grieving, role transitions, and role disputes in depressed older patients. In controlled trials, IPT has been shown effective as acute¹ and maintenance treatment^2,3 of depression. This article describes how IPT can work effectively for depressed older adults and their clinicians.

IPT and elder depression

New-onset or recurrent depression is common in older patients experiencing retirement, relocation, disabilities, or loss of important persons in their lives (Box 1) ⁴ IPT recognizes that depression, regardless of psychosocial stress or biologic vulnerability, is expressed in an interpersonal environment (Box 2).^5,6 The environment may have contributed to the depression, but it also can be a platform for intervention.

Depressed older adults who are verbal, nondemented, and engageable are candidates for IPT, with or without adjunctive antidepressant therapy. Psychotherapy is not indicated for patients with severe dementia, but this article will describe how IPT is being adapted for those with early dementia or mild cognitive impairment.

Box 1

Case continued: ‘he made all the decisions’

At Mrs. E’s first IPT session, the therapist assigns her the “sick role.” They contract to meet 12 to 16 weeks, and Mrs. E’s daughter agrees to drive her to sessions.

In the next few weeks, the therapist explains depression’s biopsychosocial model and explores dual strategies with Mrs. E: to ease her mourning and explore new interests or relationships. The therapist encourages her to express her feelings and seeks to understand the dynamics of her marriage.

Mrs. E said she was raised by nurturing parents and married soon after high school. She depended on her husband for almost every decision, including their social calendar. She describes their relationship as mutually loving. As part of an interpersonal inventory, her therapist encourages her to describe in detail all the ways she misses him.

The ‘sick role.’ The therapist assigned Mrs. E the “sick role” to emphasize that major depression can be a severe illness. A therapist might say: “If you had pneumonia, you wouldn’t think of trying to rake leaves. You would rest and take care of yourself to speed the healing. Persons with major depression should do the same.”

The contract. The therapist also explained to Mrs. E that contracting to meet weekly for 12 to 16 weeks is part of the treatment. A contract:

• encourages patients to commit to an IPT trial for a reasonable time
  
• presses patients to achieve adequate progress by the deadline
  
• discourages digression, avoidance of painful subjects, and dependence on the therapist.
  

IPT begins with a complete psychiatric evaluation, including the patient’s past, family, and social histories; alcohol and drug use; medical comorbidities; mental status exam; and sometimes blood screening to rule out metabolic abnormalities. Antidepressants are prescribed as needed to relieve vegetative symptoms and are used during IPT when indicated.

Interpersonal inventory. Each of the patient’s interpersonal relationships is then systematically reviewed. This inventory sets the stage for exploring relationships that may be linked to the depressive symptoms or offer opportunities for trying alternate coping trategies, such as learning to seek social support (Table 2).

Table 1

IPT’s understanding of depression comprises 3 component processes

‘How-to’ checklist of IPT procedures

IPT’S FOUR FOCI

IPT’s goal is to relieve depressive symptoms by identifying and focusing on problems that may have caused or are perpetuating those symptoms. Most of the reasons depressed patients give for seeking help fall into four foci: unresolved grief, role transition, role dispute, and interpersonal deficit (Table 3).^5,6 The therapist uses clarification, interpretation, confrontation, and testing of perceptions and performance to address each focus, as detailed in the IPT manual.⁶

The therapist acts as the patient’s advocate, and focuses treatment on interpersonal relationships in the “here and now,” not past traumas, childhood conflicts, cognitive-behavioral interventions, or intrapsychic themes. No attempt is made to restructure personality.

Progress in relieving depressive symptoms is reviewed regularly, and treatment ends within the contract’s time limits in many cases. Older patients may need additional sessions because they often take longer to respond to antidepressant trials (6 to 8 weeks, compared with 3 to 4 weeks for younger adults). We allow older patients to “catch up” with additional sessions if illness, lack of transportation, or other problems prevent them from receiving the “full dose” of IPT.

IPT does not work for all patients. Consider other types of treatment if a patient shows no discernable benefit.

Table 3

IPT’s 4 foci, specific to late-life depression

Case continued: stalled in grief

As the weeks pass, Mrs. E improves but remains hypoactive and reclusive. She seems afraid to take any action without her late husband’s approval. Thinking about making independent decisions overwhelms her, and she withdraws to her couch to hide.

Her therapist discerns that Mrs. E needs more-active confrontation to accept that her new life requires her to make choices, even though decision-making is difficult for her. They develop a game, hronicling all decisions Mrs. E has made for the first time, such as calling a repairman and planting the summer vegetable garden by herself.

The therapist applauds these “firsts” and points out that Mrs. E’s depressive symptoms have improved as her list of completed decisions has grown. Mrs. E holds the power to make decisions, the therapist stresses, and bears the consequences of not taking action.

Applying ipt to late-life depression

Our group has used IPT in research protocols for 15 years. We and others^7-11 have found that IPT is well-suited for treating late-life depression because:

• Older patients without psychotherapy experience or psychological sophistication can easily participate.
  
• Persons with limited education can understand IPT’s informal explanations of depression.
  
• Two foci of IPT—grief and role transition—address common themes of aging, such as spousal role disputes after retirement or caregiver stress when one partner becomes ill or shows signs of dementia.
  

Only minor IPT adaptations were required for older patients, such as:

• shorter sessions for those who reported physical discomfort
  
• accommodating for hearing loss, arranging transportation, and conducting sessions by telephone when patients were ill or shut in by inclement weather.
  

Case continued: more ‘firsts’ build confidence

Mrs. E makes slow, sometimes painful, but steady progress. Her therapist encourages her to keep trying more “firsts,”such as going back to church and attending her first social event alone, and to review her emotional reactions.

Mrs. E’s depressive symptoms wane as her confidence builds, and she readjusts her self-image to that of a widow who enjoyed a good marriage with a benevolent but overprotective husband. Her therapist links her progress to her string of successful “firsts” and to the contributing benefit of anti-depressant medication.

IPT As maintenance therapy

In the Maintenance Therapies for Late Life Depression (MTLLD) study—a randomized, double-blind, placebo-controlled trial¹²—we showed IPT to be effective as maintenance therapy for recurrent depression in patients age 60 and older. The 187 patients (mean age 67, one-third age ≥70) with nonpsychotic unipolar major depression were first treated to remission with IPT plus nortriptyline (80 to 120 ng/mL).

We then randomly assigned the 107 who achieved recovery to one of four maintenance therapies. After 3 years of monthly follow-up, relapse rates were:

• 20% with nortriptyline plus maintenance IPT
  
• 43% with nortriptyline plus medication clinic visits
  
• 64% with maintenance IPT plus placebo
  
• 90% with medication clinic plus placebo.
  

Further analysis showed that patients age ≥70 required combined treatment with nortriptyline and IPT to stay well, whereas those ages 60 to 69 stayed well with drug therapy alone. Patients age ≥70 also had a higher and more rapid relapse rate.

Recurrence by therapy focus. In patients who received placebo instead of nortriptyline:

• Time without a new depressive episode was similar for patients with a focus on grief or role transition, whether they received IPT or medication checkups.
  
• Recurrence rates were clearly lower in patients whose initial focus was role dispute if they received monthly maintenance IPT sessions instead of medication check visits.
  

Case continued: looking ahead

As the 12- to 16-week contracted period winds down, Mrs. E admits she still longs for her husband’s protection. She said she would gladly give up her independence to have that “safe” feeling back.

The therapist acknowledges that feeling but gently reminds her that she has the tools to face her new life realistically. During therapy, Mrs. E has shown she can assess life’s many decisions, make rational choices, and live with the consequences.

Their final discussion touches on the notion that Mrs. E could imagine having some kind of friendship with another man in the future.

Wrapping up. The last IPT sessions focus on reviewing any decline in depressive symptoms that may be linked to having learned new coping skills. With successful IPT, patients learn to appraise their strengths and remaining vulnerabilities and gain skills, self-confidence, and understanding to confront remaining obstacles after therapy ends.

Adapting ipt for special populations

Resistant depression. Researchers at the University of Pittsburgh are investigating whether adding IPT can achieve remission in depressed older patients who show partial response to a 6-week trial of escitalopram, 10 mg/d. In this ongoing trial, patients with Hamilton Depression Rating Scale scores of 11 to 14 after 6 weeks receive an increased escitalopram dosage (20 mg/d) and are randomly assigned to medication alone or medication plus 16 weeks of IPT.

Cognitive impairment. An unpublished follow-up to the MTLLD study enrolled 116 patients aged ≥70 and used a similar design, except that:

• patients were not required to have had recurrent depressive episodes
  
• paroxetine was used instead of nortriptyline
  
• patients with cognitive impairment (Mini-Mental Status Examination scores ?18/30) were included.
  

Cognitive impairment may have interfered with patients’ ability to benefit from traditional IPT. Thus, to improve the quality of life of depressed, cognitively-impaired elders, researchers are involving caregivers (usually a spouse or adult child) in modified forms of IPT couples therapy.^6,13-18 A team at the University of Pittsburgh is developing a flexible approach that includes meetings with the patient, the caregiver, or both. Two papers on IPT-CI (for cognitive impairment) are under review.

Related resources

• International Society for Interpersonal Psychotherapy. Accreditation, training, and research information. www.interpersonalpsychotherapy.org.
  
• Stuart S, Robertson M. Interpersonal psychotherapy: a clinician’s guide. London: Edward Arnold Ltd.; 2002.
  
• Miller MD, Reynolds CF. Interpersonal psychotherapy. In: Hepple J, Pierce J, Wilkinson P (eds). Psychological therapies with older people. East Sussex, UK: Brunner-Routledge; 2002:103-27.
  
• Miller MD, Reynolds CF. Living longer depression-free: a family guide to the recognition, treatment and prevention of depression in later life. Baltimore: Johns Hopkins University Press; 2002.
  

• Escitalopram • Lexapro
  
• Nortriptyline • Pamelor
  
• Paroxetine • Paxil
  

Dr. Miller is a consultant to Forest Laboratories and GlaxoSmithKline and is a speaker for Forest Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals.

Reputed Cosa Nostra boss Vincent “The Chin” Gigante deceived “the most respected minds in forensic psychiatry” for years by malingering schizophrenia.¹ Ultimately, he admitted to maintaining his charade from 1990 to 1997 during evaluations of his competency to stand trial for racketeering.

A lesson from this case—said a psychiatrist who concluded Gigante was malingering—is, “When feigning is a consideration, we must be more critical and less accepting of our impressions when we conduct and interpret a psychiatric examination…than might be the case in a typical clinical situation.”²

Even in typical clinical situations, however, psychiatrists may be reluctant to diagnose malingering³ for fear of being sued, assaulted—or wrong. An inaccurate diagnosis of malingering may unjustly stigmatize a patient and deny him needed care.⁴

Because psychiatrists need a systematized approach to detect malingering,⁵ we offer specific clinical factors and approaches to help you recognize malingered psychosis.

What is Malingering?

No other syndrome is as easy to define yet so difficult to diagnose as malingering. Reliably diagnosing malingered mental illness is complex, requiring the psychiatrist to consider collateral data beyond the patient interview.

Malingering is the intentional production of false or grossly exaggerated physical or psychological symptoms, motivated by external incentives.⁶ In practice, malingering commonly must be differentiated from factitious disorder, which also involves intentional production of symptoms. In factitious disorders, the patient’s motivation is to assume the sick role, which can be thought of as an internal or psychological incentive.

Three categories of malingering include:

• pure malingering (feigning a nonexistent disorder)
• partial malingering (consciously exaggerating real symptoms)
• false imputation (ascribing real symptoms to a cause the individual knows is unrelated to the symptoms).⁷

Motivations. Individuals usually malinger to avoid pain (such as difficult situations or punishment) or to seek pleasure (such as to obtain compensation or medications) (Table 1). In correctional settings, for example, inmates may malinger mental illness to do “easier time” or to obtain drugs. On the other hand, malingering in prison also may be an adaptive response by a mentally ill inmate to relatively sparse and difficult-to-obtain mental health resources.⁸

Table 1

Common motives of malingerers

Interview Style

When you suspect a patient is malingering, keep your suspicions to yourself and conduct an objective evaluation. Patients are likely to become defensive if you show annoyance or incredulity, and putting them on guard decreases your ability to uncover evidence of malingering.⁹

Begin by asking open-ended questions, which allow patients to report symptoms in their own words. To avoid hinting at correct responses, carefully phrase initial inquiries about symptoms. Later in the interview, you can proceed to more-detailed questions of specific symptoms, as discussed below.

If possible, review collateral data before the interview, when it is most helpful. Consider information that would support or refute the alleged symptoms, such as treatment and insurance records, police reports, and interviews of close friends or family.

The patient interview may be prolonged because fatigue may diminish a malingerer’s ability to maintain fake symptoms. In very difficult cases, consider monitoring during inpatient assessment because feigned psychosis is extremely difficult to maintain 24 hours a day.

Watch for individuals who endorse rare or improbable symptoms. Rare symptoms—by definition—occur very infrequently, and even severely disturbed patients almost never report improbable symptoms.¹⁰ Consider asking malingerers about improbable symptoms to see if they will endorse them. For example:

• “When people talk to you, do you see the words they speak spelled out?”¹¹
• “Have you ever believed that automobiles are members of an organized religion?”¹²

Watch closely for internal or external inconsistency in the suspected malingerer’s presentation (Table 2).

Table 2

Clues to identify malingering during patient evaluation

Malingered Psychotic Symptoms

Detecting malingered mental illness is considered an advanced psychiatric skill, partly because you must understand thoroughly how genuine psychotic symptoms manifest.

Hallucinations. If a patient alleges atypical hallucinations, ask about them in detail. Hallucinations are usually (88%) associated with delusions.¹³ Genuine hallucinations are typically intermittent rather than continuous.

Continue to: Auditory hallucinations

Auditory hallucinations are usually clear, not vague (7%) or inaudible. Both male and female voices are commonly heard (75%), and voices are usually perceived as originating outside the head (88%).¹⁴ In schizophrenia, the major themes are persecutory or instructive.¹⁵

Command auditory hallucinations are easy to fabricate. Persons experiencing genuine command hallucinations:

• do not always obey the voices, especially if doing so would be dangerous¹⁶
• usually present with noncommand hallucinations (85%) and delusions (75%) as well¹⁷

Thus, view with suspicion someone who alleges an isolated command hallucination without other psychotic symptoms.

Genuine schizophrenic hallucinations tend to diminish when patients are involved in activities. Thus, to deal with their hallucinations, persons with schizophrenia typically cope by:

• engaging in activities (working, listening to a radio, watching TV)
• changing posture (lying down, walking)
• seeking interpersonal contact
• taking medications.

If you suspect a person of malingered auditory hallucinations, ask what he or she does to make the voices go away or diminish in intensity. Patients with genuine schizophrenia often can stop their auditory hallucinations while in remission but not during acute illness.

Malingerers may report auditory hallucinations of stilted or implausible language. For example, we have evaluated:

• an individual charged with attempted rape who alleged that voices said, “Go commit a sex offense.”
• a bank robber who alleged that voices kept screaming, “Stick up, stick up, stick up!”

Both examples contain language that is very questionable for genuine hallucinations, while providing the patient with “psychotic justification” for an illegal act that has a rational alternative motive.

Visual hallucinations are experienced by an estimated 24% to 30% of psychotic individuals but are reported much more often by malingerers (46%) than by persons with genuine psychosis (4%).¹⁸

Genuine visual hallucinations are usually of normalsized people and are seen in color.¹⁴ On rare occasions, genuine visual hallucinations of small people (Lilliputian hallucinations) may be associated with alcohol use, organic disease, or toxic psychosis (such as anticholinergic toxicity) but are rarely seen by persons with schizophrenia.

Psychotic visual hallucinations do not typically change if the eyes are closed or open, whereas drug-induced hallucinations are more readily seen with eyes closed or in the dark. Unformed hallucinations—such as flashes of light, shadows, or moving objects—are typically associated with neurologic disease and substance use.¹⁹

Suspect malingering if the patient reports dramatic or atypical visual hallucinations. For example, one defendant charged with bank robbery calmly reported seeing “a 30-foot tall, red giant smashing down the walls” of the interview room. When he was asked detailed questions, he frequently replied, “I don’t know.” He eventually admitted to malingering.

Delusions. Genuine delusions vary in content, theme, degree of systemization, and relevance to the person’s life. The complexity and sophistication of delusional systems usually reflect the individual’s intelligence. Persecutory delusions are more likely to be acted upon than are other types of delusions.²⁰

Malingerers may claim that a delusion began or disappeared suddenly. In reality, systematized delusions usually take weeks to develop and much longer to disappear. Typically, the delusion will become somewhat less relevant, and the individual will gradually relinquish its importance over time after adequate treatment. In general, the more bizarre the delusion’s content, the more disorganized the individual’s thinking is likely to be (Table 3).

With genuine delusions, the individual’s behavior usually conforms to the delusions’ content. For example, Russell Weston—who suffered from schizophrenia—made a deadly assault on the U.S. Capitol in 1998 because he held a delusional belief that cannibalism was destroying Washington, DC. Before he shot and killed two U.S. Capitol security officers, he had gone to the Central Intelligence Agency several years before and voiced the same delusional concerns.

Suspect malingering if a patient alleges persecutory delusions without engaging in corresponding paranoid behaviors. One exception is the person with long-standing schizophrenia who has grown accustomed to the delusion and whose behavior is no longer consistent with it.

Table 3

Uncommon psychosis presentations that suggest malingering

Where Malingerers Trip Up

Malingerers may have inadequate or incomplete knowledge of the mental illness they are faking. Indeed, malingerers are like actors who can portray a role only as well as they understand it. They often overact their part or mistakenly believe the more bizarre their behavior, the more convincing they will be. Conversely, “successful” malingerers are more likely to endorse fewer symptoms and avoid endorsing overly bizarre or unusual symptoms.²¹

Continue to: Numerous clinical factors suggest malingering...

Numerous clinical factors suggest malingering (Table 4). Malingerers are more likely to eagerly “thrust forward” their illness, whereas patients with genuine schizophrenia are often reluctant to discuss their symptoms.²²

Malingerers may attempt to take control of the interview and behave in an intimidating or hostile manner. They may accuse the psychiatrist of inferring that they are faking. Such behavior is rare in genuinely psychotic individuals. Although DSM-IV-TR states that antisocial personality disorder should arouse suspicions of malingering, some studies have failed to show a relationship. One study has associated psychopathic traits with malingering.²³

Malingerers often believe that faking intellectual deficits, in addition to psychotic symptoms, will make them more believable. For example, a man who had completed several years of college alleged that he did not know the colors of the American flag.

Malingerers are more likely to give vague or hedging answers to straightforward questions. For example, when asked whether an alleged voice was male or female, one malingerer replied, “It was probably a man’s voice.” Malingerers may also answer, “I don’t know” to detailed questions about psychotic symptoms. Whereas a person with genuine psychotic symptoms could easily give an answer, the malingerer may have never experienced the symptoms and consequently “doesn’t know” the correct answer.

Psychotic symptoms such as derailment, neologisms, loose associations, and word salad are rarely simulated. This is because it is much more difficult for a malingerer to successfully imitate psychotic thought processes than psychotic thought content. Similarly, it is unusual for a malingerer to fake schizophrenia’s subtle signs, such as negative symptoms.

Table 4

Clinical factors that suggest malingering

Psychological Testing

Although many psychometric tests are available for detecting malingered psychosis, few have been validated. Among the more reliable are:

• Structured Interview of Reported Symptoms (SIRS)
• Minnesota Multiphasic Personality Inventory, Revised (MMPI-2)
• Miller Forensic Assessment of Symptoms Test (M-FAST).¹¹

SIRS includes questions about rare symptoms, uncommon symptom pairing, atypical symptoms, and other indices involving excessive symptom reporting. It takes 30 to 60 minutes to administer. Tested in inpatient, forensic, and correctional populations, the SIRS has shown consistently high accuracy in detecting malingered psychiatric illness.²⁴

Two MMPI-2 scales—F-scale and F-K Index—are the most frequently used test for evaluating suspected malingering. When using the MMPI-2 in this manner, consult the literature for appropriate cutoff scores (see Related resources). Although the MMPI-2 is the most validated psychometric method to detect malingering, a malingerer with high intelligence and previous knowledge of the test could evade detection.²⁵

M-FAST was developed to provide a brief, reliable screen for malingered mental illness. This test takes 10 to 15 minutes to administer and measures rare symptom combinations, excessive reporting, and atypical symptoms.¹¹ It has shown good validity and high correlation with the SIRS and MMPI-2.^26,27

Confronting the Malingerer

If a thorough investigation indicates that a patient is malingering psychosis, you may decide to confront the evaluee. Avoid direct accusations of lying,¹⁰ and give the suspected malingerer every opportunity to save face. For example, it is preferable to say, “You haven’t told me the whole truth.”

A thoughtful approach that asks the evaluee to clarify inconsistencies is more likely to be productive and safer for the examiner. When confronting individuals with a history of violence and aggression, have adequate security personnel with you.

Related resources

• Structured Interview of Reported Symptoms (SIRS). Available for purchase from Psychological Assessment Resources at www3.parinc.com (enter “SIRS” in search field).
• Graham JR. MMPI-2: Assessing personality and psychopathology. New York: Oxford Press; 2000. (Source of cutoff scores to use MMPI-2 scales [F-scale and F-K Index] to evaluate suspected malingering).
• Psychological Assessment Resources, Inc. Miller Forensic Assessment of Symptoms Test (M-FAST). Available at: www3.parinc.com (enter “M-FAST” in search field).

Reputed Cosa Nostra boss Vincent “The Chin” Gigante deceived “the most respected minds in forensic psychiatry” for years by malingering schizophrenia.¹ Ultimately, he admitted to maintaining his charade from 1990 to 1997 during evaluations of his competency to stand trial for racketeering.

A lesson from this case—said a psychiatrist who concluded Gigante was malingering—is, “When feigning is a consideration, we must be more critical and less accepting of our impressions when we conduct and interpret a psychiatric examination…than might be the case in a typical clinical situation.”²

Even in typical clinical situations, however, psychiatrists may be reluctant to diagnose malingering³ for fear of being sued, assaulted—or wrong. An inaccurate diagnosis of malingering may unjustly stigmatize a patient and deny him needed care.⁴

Because psychiatrists need a systematized approach to detect malingering,⁵ we offer specific clinical factors and approaches to help you recognize malingered psychosis.

What is Malingering?

No other syndrome is as easy to define yet so difficult to diagnose as malingering. Reliably diagnosing malingered mental illness is complex, requiring the psychiatrist to consider collateral data beyond the patient interview.

Malingering is the intentional production of false or grossly exaggerated physical or psychological symptoms, motivated by external incentives.⁶ In practice, malingering commonly must be differentiated from factitious disorder, which also involves intentional production of symptoms. In factitious disorders, the patient’s motivation is to assume the sick role, which can be thought of as an internal or psychological incentive.

Three categories of malingering include:

• pure malingering (feigning a nonexistent disorder)
• partial malingering (consciously exaggerating real symptoms)
• false imputation (ascribing real symptoms to a cause the individual knows is unrelated to the symptoms).⁷

Motivations. Individuals usually malinger to avoid pain (such as difficult situations or punishment) or to seek pleasure (such as to obtain compensation or medications) (Table 1). In correctional settings, for example, inmates may malinger mental illness to do “easier time” or to obtain drugs. On the other hand, malingering in prison also may be an adaptive response by a mentally ill inmate to relatively sparse and difficult-to-obtain mental health resources.⁸

Table 1

Common motives of malingerers

Interview Style

When you suspect a patient is malingering, keep your suspicions to yourself and conduct an objective evaluation. Patients are likely to become defensive if you show annoyance or incredulity, and putting them on guard decreases your ability to uncover evidence of malingering.⁹

Begin by asking open-ended questions, which allow patients to report symptoms in their own words. To avoid hinting at correct responses, carefully phrase initial inquiries about symptoms. Later in the interview, you can proceed to more-detailed questions of specific symptoms, as discussed below.

If possible, review collateral data before the interview, when it is most helpful. Consider information that would support or refute the alleged symptoms, such as treatment and insurance records, police reports, and interviews of close friends or family.

The patient interview may be prolonged because fatigue may diminish a malingerer’s ability to maintain fake symptoms. In very difficult cases, consider monitoring during inpatient assessment because feigned psychosis is extremely difficult to maintain 24 hours a day.

Watch for individuals who endorse rare or improbable symptoms. Rare symptoms—by definition—occur very infrequently, and even severely disturbed patients almost never report improbable symptoms.¹⁰ Consider asking malingerers about improbable symptoms to see if they will endorse them. For example:

• “When people talk to you, do you see the words they speak spelled out?”¹¹
• “Have you ever believed that automobiles are members of an organized religion?”¹²

Watch closely for internal or external inconsistency in the suspected malingerer’s presentation (Table 2).

Table 2

Clues to identify malingering during patient evaluation

Malingered Psychotic Symptoms

Detecting malingered mental illness is considered an advanced psychiatric skill, partly because you must understand thoroughly how genuine psychotic symptoms manifest.

Hallucinations. If a patient alleges atypical hallucinations, ask about them in detail. Hallucinations are usually (88%) associated with delusions.¹³ Genuine hallucinations are typically intermittent rather than continuous.

Continue to: Auditory hallucinations

Auditory hallucinations are usually clear, not vague (7%) or inaudible. Both male and female voices are commonly heard (75%), and voices are usually perceived as originating outside the head (88%).¹⁴ In schizophrenia, the major themes are persecutory or instructive.¹⁵

Command auditory hallucinations are easy to fabricate. Persons experiencing genuine command hallucinations:

• do not always obey the voices, especially if doing so would be dangerous¹⁶
• usually present with noncommand hallucinations (85%) and delusions (75%) as well¹⁷

Thus, view with suspicion someone who alleges an isolated command hallucination without other psychotic symptoms.

Genuine schizophrenic hallucinations tend to diminish when patients are involved in activities. Thus, to deal with their hallucinations, persons with schizophrenia typically cope by:

• engaging in activities (working, listening to a radio, watching TV)
• changing posture (lying down, walking)
• seeking interpersonal contact
• taking medications.

If you suspect a person of malingered auditory hallucinations, ask what he or she does to make the voices go away or diminish in intensity. Patients with genuine schizophrenia often can stop their auditory hallucinations while in remission but not during acute illness.

Malingerers may report auditory hallucinations of stilted or implausible language. For example, we have evaluated:

• an individual charged with attempted rape who alleged that voices said, “Go commit a sex offense.”
• a bank robber who alleged that voices kept screaming, “Stick up, stick up, stick up!”

Both examples contain language that is very questionable for genuine hallucinations, while providing the patient with “psychotic justification” for an illegal act that has a rational alternative motive.

Visual hallucinations are experienced by an estimated 24% to 30% of psychotic individuals but are reported much more often by malingerers (46%) than by persons with genuine psychosis (4%).¹⁸

Genuine visual hallucinations are usually of normalsized people and are seen in color.¹⁴ On rare occasions, genuine visual hallucinations of small people (Lilliputian hallucinations) may be associated with alcohol use, organic disease, or toxic psychosis (such as anticholinergic toxicity) but are rarely seen by persons with schizophrenia.

Psychotic visual hallucinations do not typically change if the eyes are closed or open, whereas drug-induced hallucinations are more readily seen with eyes closed or in the dark. Unformed hallucinations—such as flashes of light, shadows, or moving objects—are typically associated with neurologic disease and substance use.¹⁹

Suspect malingering if the patient reports dramatic or atypical visual hallucinations. For example, one defendant charged with bank robbery calmly reported seeing “a 30-foot tall, red giant smashing down the walls” of the interview room. When he was asked detailed questions, he frequently replied, “I don’t know.” He eventually admitted to malingering.

Delusions. Genuine delusions vary in content, theme, degree of systemization, and relevance to the person’s life. The complexity and sophistication of delusional systems usually reflect the individual’s intelligence. Persecutory delusions are more likely to be acted upon than are other types of delusions.²⁰

Malingerers may claim that a delusion began or disappeared suddenly. In reality, systematized delusions usually take weeks to develop and much longer to disappear. Typically, the delusion will become somewhat less relevant, and the individual will gradually relinquish its importance over time after adequate treatment. In general, the more bizarre the delusion’s content, the more disorganized the individual’s thinking is likely to be (Table 3).

With genuine delusions, the individual’s behavior usually conforms to the delusions’ content. For example, Russell Weston—who suffered from schizophrenia—made a deadly assault on the U.S. Capitol in 1998 because he held a delusional belief that cannibalism was destroying Washington, DC. Before he shot and killed two U.S. Capitol security officers, he had gone to the Central Intelligence Agency several years before and voiced the same delusional concerns.

Suspect malingering if a patient alleges persecutory delusions without engaging in corresponding paranoid behaviors. One exception is the person with long-standing schizophrenia who has grown accustomed to the delusion and whose behavior is no longer consistent with it.

Table 3

Uncommon psychosis presentations that suggest malingering