Current Psychiatry

Mrs. M, age 34, was referred for psychiatric evaluation by her primary care physician. She reluctantly agreed to the referral and tells the psychiatrist she “really should be seeing a cardiologist.” Numerous evaluations for chest pain and palpitations—including seven emergency room visits, ECGs and cardiac catheterization—have revealed no medical pathology.

A divorced mother of two children, she says she feels anxious about her “heart condition.” Her father died of a heart attack at age 51. She experiences chest pains at home and at work, particularly when under stress. Sometimes she feels her heart racing and numbness or tingling in her arms.

Although her primary care physician has seen her frequently during the past 6 months, she says the doctor is not taking her complaints seriously. “These chest pains are real,” she says, “so don’t try to tell me they’re all in my head.”

Psychiatrists may be the last doctors patients such as Mrs. M wish to see but the ones best equipped to relieve their suffering. Our experience in treating somatizing patients and the available evidence suggest that cognitive-behavioral therapy (CBT) combined with psychoeducation, reassurance, and sometimes drug therapy is the most effective approach.

Box

Mrs. M’s persistent chest pain of noncardiac origin is a familiar health anxiety, along with functional GI complaints, headaches, chronic fatigue, and lower back pain. Frustrating to their doctors and frustrated themselves, patients with medically unexplained complaints consume an inordinate amount of physicians’ time.¹

Without a clear definition of somatization (Box)^2-9 or useful clinical guidelines, psychiatrists must rely on the literature for guidance in managing somatization disorders. This article summarizes the evidence and describes how we apply these findings to practice. And when all else fails, we offer last-ditch advice for managing patients who resist your treatment efforts.

IDENTIFYING COMORBIDITIES

Identifying psychiatric comorbidities is the first step in successfully treating patients with somatoform complaints. In an epidemiologic study, 60% of patients with somatoform complaints also had a mood disorder and 48% had an anxiety disorder.¹⁰ In a similar study of patients with hypochondriasis, 88% also had one or more Axis I diagnosis.¹¹

If a patient meets criteria for a comorbid psychiatric disorder and is willing to be treated for it, the somatic complaints may resolve along with the underlying disorder. In fact, the presence of an identifiable Axis I disorder order may predict a more positive prognosis.¹²

Personality disorders. Somatization in patients with a personality disorder poses unique challenges.¹³ Granted, when making a diagnosis it is difficult to tease apart somatization from personality disorders because somatization itself may be considered a chronic, maladaptive coping style. However, symptoms such as deception, impulsivity, mood lability, and self-injurious behavior introduce treatment complications that exceed the scope of this article.

Posttraumatic stress disorder (PTSD)—particularly childhood sexual and physical abuse—also predisposes some patients to somatization disorders.^14,15 Patients with comorbid PTSD and somatization disorder require highly specialized treatment that is beyond the scope of this review.

COGNITIVE-BEHAVIORAL TREATMENT

Cognitive-behavioral therapy (CBT) is the best-studied and most effective treatment for somatoform disorders.¹⁶ CBT for somatization relies on both physiologic and cognitive explanations to account for the patient’s experience, without committing to an “either/or” dichotomy. It offers patients an alternate explanation of what is wrong with them—illness anxiety instead of severe physical illness.

By making patients aware of their automatic thoughts, feelings, behaviors, and underlying beliefs, CBT helps them normalize and cope with their illness anxiety. CBT techniques can be applied in a predetermined course of therapy (such as 12 sessions with a mental health clinician), in a group setting, or piecemeal by any health care provider.

Effective strategies. In a review of 30 controlled trials of CBT for somatoform disorders, Looper¹⁷ showed overall effect ranging from 0.38 to 2.5, where 0.2 was defined as a small effect, 0.5 as medium, and 0.8 as large. Hypochondriasis, somatization disorder, body dysmorphic disorder, chronic pain, chronic fatigue, and noncardiac chest pain were included in this review. The most effective strategies:

• included 6 to 16 treatment sessions
• were symptom-focused as opposed to providing general relaxation training
• included maintenance sessions after the initial series.

Four factors of health anxiety. CBT primarily targets the patient’s false beliefs that he or she is physically ill. These beliefs are based on how the patient misinterprets innocuous physical symptoms and responds to them.¹⁸ The cognitive theory of health anxiety holds that health anxiety severity is affected by four factors:

• perceived likelihood of illness
• perceived burden of illness
• perceived ability to cope with illness
• perception of the extent to which external factors will help.¹⁹

Table 1

Common dysfunctional beliefs of somatizing patients

The first two factors worsen and the latter two mitigate health anxiety. An individual patient’s presenting fears often suggest which factors to address. For example, Mrs. M may describe the burden of illness as the focus of her fears (“If I have a heart attack, who will care for my children?”). This information cues you to shift the focus of therapy to helping her cope with child care needs despite her recurring symptoms.

If she focuses on her likelihood of illness, then uncoupling the symptoms from the diagnosis could be more productive. When she reports palpitations, diaphoresis, and dizziness, have her do breathing exercises that induce those symptoms without producing a heart attack.

Table 2

Journaling homework: 5 questions for patients to answer about one symptom each day

She might describe feeling unable to cope when she feels symptoms or when cardiologists tell her nothing is wrong with her heart. In that case, focus on relaxation techniques, global stress reduction, and reducing cardiac risk factors to bolster her ability to cope with her illness.

Journaling is a critical component of CBT in treating somatization disorders. Regular journaling by the patient can reveal dysfunctional beliefs that may be driving his or her health anxieties, such as those listed in Table 1. We find it useful to assign patients to answer five questions about one symptom experience each day (Table 2). This self-monitoring provides material to work on with the patient during each session.

Cognitive restructuring. During therapy sessions, we ask patients to suggest alternate explanations for the symptoms recorded in their journals. We then ask them to determine which explanations are more feasible.

For example, if Mrs. M develops palpitations during emotionally charged arguments, we would ask her to develop explanations other than, “I was having a heart attack.” Reality testing includes rhetorical questions such as, “Would you be alive today if you were having a heart attack every time you had palpitations?” Automatic thoughts are successively identified and then tested aloud with the patient:

• “Has every unexplained symptom led to the discovery of a serious illness?”
• “Does every instance of hurt equal harm?”

Eventually, patterns of automatic thoughts emerge, and these reveal the underlying dysfunctional beliefs.

Dysfunctional beliefs are maintained when patients selectively attend to and amplify somatic sensations. Behavioral experiments during sessions can demonstrate to the patient in vivo the process by which they misattribute illness to physical symptoms. For example, overbreathing with a patient during a session may elicit light-headedness, paresthesias, or tachycardia, which can then be linked to overbreathing rather than a chronic or catastrophic illness.

Furthermore, patients can be taught to control the experience. Some patients with headaches or GI pain may be made aware of symptoms by simply asking them to focus their attention on the respective organs. Simply explaining the cycle of misattribution, autonomic activation, and further symptom development with an in vivo demonstration can be illuminating.

Response prevention. Another behavioral technique is to cut back in small increments on actions the patient takes in response to physical symptoms and automatic thoughts. For example, a patient could take medicine and seek reassurance less frequently and avoid rubbing the affected area.

PSYCHOEDUCATION

Two psychoeducation programs for somatization behavior have been formally studied.

The Personal Health Improvement Program²⁰—led by trained facilitators—includes classroom videos, cognitive-behavioral exercises, and home study assignments. After completing the 6-week course, 171 patients with somatization disorders reported reduced physical and psychological distress and increased function. They also visited their primary care physicians less often.

Table 3

How to effectively reassure somatizing patients

Coping with Illness Anxiety²¹ relies on mini-lectures, demonstrations, videos, and focused group discussions. After six 2-hour sessions, 33 of 43 study patients (78%) used medical services less often and reported reduced disease conviction, consequences of bodily complaints, health anxiety, and checking and avoidance behaviors. Two psychology graduate students taught the course from a manual, with 6 to 9 patients per group.

Psychoeducation in this context relies on didactic presentations, readings, role playing, and videotaped material. The goal is to teach patients to recognize thoughts, emotions, and behaviors that lead to and result from somatic preoccupation. Patients can improve when they recognize dysfunctional behavioral patterns and learn alternate coping strategies.

Somatizing patients—with their aversion to the stigma of mental illness—may find psychoeducation particularly attractive. They can be treated as students who are being educated, rather than as patients who are being treated. Classrooms in both studies cited above were located in medical outpatient offices, not in mental health facilities.

REASSURANCE

Reassurance is a common therapeutic technique in medicine, although it is poorly understood, poorly taught, and not methodically applied. Reassurance alleviates anxiety, enables patients to endure dysphoria, encourages hope, gives insight, and enhances the doctor-patient relationship.²²

Table 4

How to avoid becoming frustrated with persistent somatization

Whereas CBT seeks to challenge patients’ underlying beliefs and restructure their thought processes,²³ reassurance can help them tolerate their dysfunctional beliefs and dissuade them from believing their health is dangerously impaired. Reassurance offers a substitute explanation of patients’ dysfunction, although this explanation is not as central or detailed as it is in CBT.

How to reassure. Patients may consider reassurance offered prematurely or by a stranger to be patronizing or dismissive. Reassurance is most effective when:

• given by a trusted person who is reliable, consistent, firm, and empathic
• the patient’s condition has been established as unresponsive to conventional diagnostics or biological therapies.

Patients are most receptive to reassurance when they express distress or frustration with their unexplained symptoms. Affirming that their suffering is legitimate opens the door to further treatment.

Reassurance is least effective when a patient is expressing anger or mistrust, although this is when the physician may feel most pressured to reassure. To successfully reassure a patient, the psychiatrist needs to:

• credibly identify with the patient’s distress
• and listen empathically (such as using body language and facial expressions that convey concern and consideration to the patient).²⁴

Starcevic suggests useful techniques for providing reassurance (Table 3).²²

DRUG THERAPIES

Psychotropics are considered a first-line treatment for patients with somatization disorders when:

• the patient spontaneously identifies any discrete, vegetative, or psychological complaints that may respond to drug therapy, such as insomnia, weight loss, sadness, or preoccupation
• the patient meets diagnostic criteria for comorbid anxiety or depressive disorders
• the therapeutic alliance is strong enough to weather the inevitable struggle with side effects and incomplete response to treatment. We do not recommend medication in the first encounter, when it may threaten a nascent alliance.

A common obstacle to prescribing psychotropics to somatizing patients is their sensitivity to suggestions that their complaints are “all in their heads.” To sidestep this resistance, describe the medication as treating the stress caused. by—not causing.—their chronic physical complaints. Proposing antidepressant therapy after—rather than instead of—physical exams and other diagnostics may elicit a more positive response.

Antidepressants. In clinical trials, somatoform complaints show moderate improvement after antidepressant treatment. In a meta-analysis of 6,595 patients with unexplained symptoms treated only with antidepressants, the number needed to treat was 3 to yield a positive response.²⁵ This report of 94 medication trials included patients with headache, fibromyalgia, functional GI syndromes, idiopathic pain, tinnitus, or chronic fatigue.

In other trials:

• Amitriptyline has reduced somatic symptoms in patients labeled as having “masked depression.”²⁶
• Sertraline has reduced disease fear, disease conviction, and bodily preoccupation in patients with hypochondriasis and panic disorder.²⁷

Consider side effects when choosing medication for patients with somatoform disorders. Selective serotonin reuptake inhibitors (SSRIs) in general—and sertraline, citalopram, and escitalopram specifically—have fewer side effects than tricyclics. The adage of “start low, go slow” is appropriate for somatizing patients; we usually start with one-half the dosages recommended for treating depression.

Antipsychotics. In case reports, patients with “atypical psychosis,” “monosymptomatic hypochondriacal psychosis,” or “delusional disorder, somatic type” have responded to antipsychotics. These patients’ somatic beliefs are of delusional intensity, such as the rare fear of being eaten alive by an intestinal parasite (delusional parasitosis). Reported behaviors associated with the delusion include starvation, excessive laxative abuse, ingestion of sharp objects, and self-inflicted stab wounds. Treatments described in the literature include the typical agents pimozide and haloperidol and the atypicals olanzapine and risperidone.

TREATMENT-RESISTANT PATIENTS

Some patients with somatoform disorders will not accept CBT, psychotropics, reassurance, or referrals to group psychoeducation. Despite your best efforts, they may persist in focusing on somatic complaints. If you are willing to maintain a therapeutic relationship with them, be prepared to tolerate several ongoing paradoxes (Table 4).

Behaviorally, you must “listen more and do less.” Emotionally, you must be willing to enter into a long-term relationship with an inherently frustrating patient whose pathologies make you feel therapeutically hopeless and helpless. Understand that their physical symptoms function as a metaphor for psychological distress. You are not required to explore the source, content, or meaning of the metaphor in detail but simply listen to their somatic complaints through that psychological filter.

Related resources

• Starcevic V, Lipsitt D (eds). Hypochondriasis: modern perspectives on an ancient malady. New York: Oxford University Press, 2001.
• Information and support Web site for persons with health anxiety or hypochondria. www.healthanxiety.com
• Anxiety Disorders Association of America. www.adaa.org

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Sertraline • Zoloft

Disclosure

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

Dr. Wise receives grant support from Eli Lilly & Co. and is a consultant or speaker for Eli Lilly & Co., Pfizer Inc., Bristol-Myers Squibb Co., and GlaxoSmithKline.

Mrs. M, age 34, was referred for psychiatric evaluation by her primary care physician. She reluctantly agreed to the referral and tells the psychiatrist she “really should be seeing a cardiologist.” Numerous evaluations for chest pain and palpitations—including seven emergency room visits, ECGs and cardiac catheterization—have revealed no medical pathology.

A divorced mother of two children, she says she feels anxious about her “heart condition.” Her father died of a heart attack at age 51. She experiences chest pains at home and at work, particularly when under stress. Sometimes she feels her heart racing and numbness or tingling in her arms.

Although her primary care physician has seen her frequently during the past 6 months, she says the doctor is not taking her complaints seriously. “These chest pains are real,” she says, “so don’t try to tell me they’re all in my head.”

Psychiatrists may be the last doctors patients such as Mrs. M wish to see but the ones best equipped to relieve their suffering. Our experience in treating somatizing patients and the available evidence suggest that cognitive-behavioral therapy (CBT) combined with psychoeducation, reassurance, and sometimes drug therapy is the most effective approach.

Box

Mrs. M’s persistent chest pain of noncardiac origin is a familiar health anxiety, along with functional GI complaints, headaches, chronic fatigue, and lower back pain. Frustrating to their doctors and frustrated themselves, patients with medically unexplained complaints consume an inordinate amount of physicians’ time.¹

Without a clear definition of somatization (Box)^2-9 or useful clinical guidelines, psychiatrists must rely on the literature for guidance in managing somatization disorders. This article summarizes the evidence and describes how we apply these findings to practice. And when all else fails, we offer last-ditch advice for managing patients who resist your treatment efforts.

IDENTIFYING COMORBIDITIES

Identifying psychiatric comorbidities is the first step in successfully treating patients with somatoform complaints. In an epidemiologic study, 60% of patients with somatoform complaints also had a mood disorder and 48% had an anxiety disorder.¹⁰ In a similar study of patients with hypochondriasis, 88% also had one or more Axis I diagnosis.¹¹

If a patient meets criteria for a comorbid psychiatric disorder and is willing to be treated for it, the somatic complaints may resolve along with the underlying disorder. In fact, the presence of an identifiable Axis I disorder order may predict a more positive prognosis.¹²

Personality disorders. Somatization in patients with a personality disorder poses unique challenges.¹³ Granted, when making a diagnosis it is difficult to tease apart somatization from personality disorders because somatization itself may be considered a chronic, maladaptive coping style. However, symptoms such as deception, impulsivity, mood lability, and self-injurious behavior introduce treatment complications that exceed the scope of this article.

Posttraumatic stress disorder (PTSD)—particularly childhood sexual and physical abuse—also predisposes some patients to somatization disorders.^14,15 Patients with comorbid PTSD and somatization disorder require highly specialized treatment that is beyond the scope of this review.

COGNITIVE-BEHAVIORAL TREATMENT

Cognitive-behavioral therapy (CBT) is the best-studied and most effective treatment for somatoform disorders.¹⁶ CBT for somatization relies on both physiologic and cognitive explanations to account for the patient’s experience, without committing to an “either/or” dichotomy. It offers patients an alternate explanation of what is wrong with them—illness anxiety instead of severe physical illness.

By making patients aware of their automatic thoughts, feelings, behaviors, and underlying beliefs, CBT helps them normalize and cope with their illness anxiety. CBT techniques can be applied in a predetermined course of therapy (such as 12 sessions with a mental health clinician), in a group setting, or piecemeal by any health care provider.

Effective strategies. In a review of 30 controlled trials of CBT for somatoform disorders, Looper¹⁷ showed overall effect ranging from 0.38 to 2.5, where 0.2 was defined as a small effect, 0.5 as medium, and 0.8 as large. Hypochondriasis, somatization disorder, body dysmorphic disorder, chronic pain, chronic fatigue, and noncardiac chest pain were included in this review. The most effective strategies:

• included 6 to 16 treatment sessions
• were symptom-focused as opposed to providing general relaxation training
• included maintenance sessions after the initial series.

Four factors of health anxiety. CBT primarily targets the patient’s false beliefs that he or she is physically ill. These beliefs are based on how the patient misinterprets innocuous physical symptoms and responds to them.¹⁸ The cognitive theory of health anxiety holds that health anxiety severity is affected by four factors:

• perceived likelihood of illness
• perceived burden of illness
• perceived ability to cope with illness
• perception of the extent to which external factors will help.¹⁹

Table 1

Common dysfunctional beliefs of somatizing patients

The first two factors worsen and the latter two mitigate health anxiety. An individual patient’s presenting fears often suggest which factors to address. For example, Mrs. M may describe the burden of illness as the focus of her fears (“If I have a heart attack, who will care for my children?”). This information cues you to shift the focus of therapy to helping her cope with child care needs despite her recurring symptoms.

If she focuses on her likelihood of illness, then uncoupling the symptoms from the diagnosis could be more productive. When she reports palpitations, diaphoresis, and dizziness, have her do breathing exercises that induce those symptoms without producing a heart attack.

Table 2

Journaling homework: 5 questions for patients to answer about one symptom each day

She might describe feeling unable to cope when she feels symptoms or when cardiologists tell her nothing is wrong with her heart. In that case, focus on relaxation techniques, global stress reduction, and reducing cardiac risk factors to bolster her ability to cope with her illness.

Journaling is a critical component of CBT in treating somatization disorders. Regular journaling by the patient can reveal dysfunctional beliefs that may be driving his or her health anxieties, such as those listed in Table 1. We find it useful to assign patients to answer five questions about one symptom experience each day (Table 2). This self-monitoring provides material to work on with the patient during each session.

Cognitive restructuring. During therapy sessions, we ask patients to suggest alternate explanations for the symptoms recorded in their journals. We then ask them to determine which explanations are more feasible.

For example, if Mrs. M develops palpitations during emotionally charged arguments, we would ask her to develop explanations other than, “I was having a heart attack.” Reality testing includes rhetorical questions such as, “Would you be alive today if you were having a heart attack every time you had palpitations?” Automatic thoughts are successively identified and then tested aloud with the patient:

• “Has every unexplained symptom led to the discovery of a serious illness?”
• “Does every instance of hurt equal harm?”

Eventually, patterns of automatic thoughts emerge, and these reveal the underlying dysfunctional beliefs.

Dysfunctional beliefs are maintained when patients selectively attend to and amplify somatic sensations. Behavioral experiments during sessions can demonstrate to the patient in vivo the process by which they misattribute illness to physical symptoms. For example, overbreathing with a patient during a session may elicit light-headedness, paresthesias, or tachycardia, which can then be linked to overbreathing rather than a chronic or catastrophic illness.

Furthermore, patients can be taught to control the experience. Some patients with headaches or GI pain may be made aware of symptoms by simply asking them to focus their attention on the respective organs. Simply explaining the cycle of misattribution, autonomic activation, and further symptom development with an in vivo demonstration can be illuminating.

Response prevention. Another behavioral technique is to cut back in small increments on actions the patient takes in response to physical symptoms and automatic thoughts. For example, a patient could take medicine and seek reassurance less frequently and avoid rubbing the affected area.

PSYCHOEDUCATION

Two psychoeducation programs for somatization behavior have been formally studied.

The Personal Health Improvement Program²⁰—led by trained facilitators—includes classroom videos, cognitive-behavioral exercises, and home study assignments. After completing the 6-week course, 171 patients with somatization disorders reported reduced physical and psychological distress and increased function. They also visited their primary care physicians less often.

Table 3

How to effectively reassure somatizing patients

Coping with Illness Anxiety²¹ relies on mini-lectures, demonstrations, videos, and focused group discussions. After six 2-hour sessions, 33 of 43 study patients (78%) used medical services less often and reported reduced disease conviction, consequences of bodily complaints, health anxiety, and checking and avoidance behaviors. Two psychology graduate students taught the course from a manual, with 6 to 9 patients per group.

Psychoeducation in this context relies on didactic presentations, readings, role playing, and videotaped material. The goal is to teach patients to recognize thoughts, emotions, and behaviors that lead to and result from somatic preoccupation. Patients can improve when they recognize dysfunctional behavioral patterns and learn alternate coping strategies.

Somatizing patients—with their aversion to the stigma of mental illness—may find psychoeducation particularly attractive. They can be treated as students who are being educated, rather than as patients who are being treated. Classrooms in both studies cited above were located in medical outpatient offices, not in mental health facilities.

REASSURANCE

Reassurance is a common therapeutic technique in medicine, although it is poorly understood, poorly taught, and not methodically applied. Reassurance alleviates anxiety, enables patients to endure dysphoria, encourages hope, gives insight, and enhances the doctor-patient relationship.²²

Table 4

How to avoid becoming frustrated with persistent somatization

Whereas CBT seeks to challenge patients’ underlying beliefs and restructure their thought processes,²³ reassurance can help them tolerate their dysfunctional beliefs and dissuade them from believing their health is dangerously impaired. Reassurance offers a substitute explanation of patients’ dysfunction, although this explanation is not as central or detailed as it is in CBT.

How to reassure. Patients may consider reassurance offered prematurely or by a stranger to be patronizing or dismissive. Reassurance is most effective when:

• given by a trusted person who is reliable, consistent, firm, and empathic
• the patient’s condition has been established as unresponsive to conventional diagnostics or biological therapies.

Patients are most receptive to reassurance when they express distress or frustration with their unexplained symptoms. Affirming that their suffering is legitimate opens the door to further treatment.

Reassurance is least effective when a patient is expressing anger or mistrust, although this is when the physician may feel most pressured to reassure. To successfully reassure a patient, the psychiatrist needs to:

• credibly identify with the patient’s distress
• and listen empathically (such as using body language and facial expressions that convey concern and consideration to the patient).²⁴

Starcevic suggests useful techniques for providing reassurance (Table 3).²²

DRUG THERAPIES

Psychotropics are considered a first-line treatment for patients with somatization disorders when:

• the patient spontaneously identifies any discrete, vegetative, or psychological complaints that may respond to drug therapy, such as insomnia, weight loss, sadness, or preoccupation
• the patient meets diagnostic criteria for comorbid anxiety or depressive disorders
• the therapeutic alliance is strong enough to weather the inevitable struggle with side effects and incomplete response to treatment. We do not recommend medication in the first encounter, when it may threaten a nascent alliance.

A common obstacle to prescribing psychotropics to somatizing patients is their sensitivity to suggestions that their complaints are “all in their heads.” To sidestep this resistance, describe the medication as treating the stress caused. by—not causing.—their chronic physical complaints. Proposing antidepressant therapy after—rather than instead of—physical exams and other diagnostics may elicit a more positive response.

Antidepressants. In clinical trials, somatoform complaints show moderate improvement after antidepressant treatment. In a meta-analysis of 6,595 patients with unexplained symptoms treated only with antidepressants, the number needed to treat was 3 to yield a positive response.²⁵ This report of 94 medication trials included patients with headache, fibromyalgia, functional GI syndromes, idiopathic pain, tinnitus, or chronic fatigue.

In other trials:

• Amitriptyline has reduced somatic symptoms in patients labeled as having “masked depression.”²⁶
• Sertraline has reduced disease fear, disease conviction, and bodily preoccupation in patients with hypochondriasis and panic disorder.²⁷

Consider side effects when choosing medication for patients with somatoform disorders. Selective serotonin reuptake inhibitors (SSRIs) in general—and sertraline, citalopram, and escitalopram specifically—have fewer side effects than tricyclics. The adage of “start low, go slow” is appropriate for somatizing patients; we usually start with one-half the dosages recommended for treating depression.

Antipsychotics. In case reports, patients with “atypical psychosis,” “monosymptomatic hypochondriacal psychosis,” or “delusional disorder, somatic type” have responded to antipsychotics. These patients’ somatic beliefs are of delusional intensity, such as the rare fear of being eaten alive by an intestinal parasite (delusional parasitosis). Reported behaviors associated with the delusion include starvation, excessive laxative abuse, ingestion of sharp objects, and self-inflicted stab wounds. Treatments described in the literature include the typical agents pimozide and haloperidol and the atypicals olanzapine and risperidone.

TREATMENT-RESISTANT PATIENTS

Some patients with somatoform disorders will not accept CBT, psychotropics, reassurance, or referrals to group psychoeducation. Despite your best efforts, they may persist in focusing on somatic complaints. If you are willing to maintain a therapeutic relationship with them, be prepared to tolerate several ongoing paradoxes (Table 4).

Behaviorally, you must “listen more and do less.” Emotionally, you must be willing to enter into a long-term relationship with an inherently frustrating patient whose pathologies make you feel therapeutically hopeless and helpless. Understand that their physical symptoms function as a metaphor for psychological distress. You are not required to explore the source, content, or meaning of the metaphor in detail but simply listen to their somatic complaints through that psychological filter.

Related resources

• Starcevic V, Lipsitt D (eds). Hypochondriasis: modern perspectives on an ancient malady. New York: Oxford University Press, 2001.
• Information and support Web site for persons with health anxiety or hypochondria. www.healthanxiety.com
• Anxiety Disorders Association of America. www.adaa.org

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Sertraline • Zoloft

Disclosure

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

Dr. Wise receives grant support from Eli Lilly & Co. and is a consultant or speaker for Eli Lilly & Co., Pfizer Inc., Bristol-Myers Squibb Co., and GlaxoSmithKline.

Mrs. M, age 34, was referred for psychiatric evaluation by her primary care physician. She reluctantly agreed to the referral and tells the psychiatrist she “really should be seeing a cardiologist.” Numerous evaluations for chest pain and palpitations—including seven emergency room visits, ECGs and cardiac catheterization—have revealed no medical pathology.

A divorced mother of two children, she says she feels anxious about her “heart condition.” Her father died of a heart attack at age 51. She experiences chest pains at home and at work, particularly when under stress. Sometimes she feels her heart racing and numbness or tingling in her arms.

Although her primary care physician has seen her frequently during the past 6 months, she says the doctor is not taking her complaints seriously. “These chest pains are real,” she says, “so don’t try to tell me they’re all in my head.”

Psychiatrists may be the last doctors patients such as Mrs. M wish to see but the ones best equipped to relieve their suffering. Our experience in treating somatizing patients and the available evidence suggest that cognitive-behavioral therapy (CBT) combined with psychoeducation, reassurance, and sometimes drug therapy is the most effective approach.

Box

Mrs. M’s persistent chest pain of noncardiac origin is a familiar health anxiety, along with functional GI complaints, headaches, chronic fatigue, and lower back pain. Frustrating to their doctors and frustrated themselves, patients with medically unexplained complaints consume an inordinate amount of physicians’ time.¹

Without a clear definition of somatization (Box)^2-9 or useful clinical guidelines, psychiatrists must rely on the literature for guidance in managing somatization disorders. This article summarizes the evidence and describes how we apply these findings to practice. And when all else fails, we offer last-ditch advice for managing patients who resist your treatment efforts.

IDENTIFYING COMORBIDITIES

Identifying psychiatric comorbidities is the first step in successfully treating patients with somatoform complaints. In an epidemiologic study, 60% of patients with somatoform complaints also had a mood disorder and 48% had an anxiety disorder.¹⁰ In a similar study of patients with hypochondriasis, 88% also had one or more Axis I diagnosis.¹¹

If a patient meets criteria for a comorbid psychiatric disorder and is willing to be treated for it, the somatic complaints may resolve along with the underlying disorder. In fact, the presence of an identifiable Axis I disorder order may predict a more positive prognosis.¹²

Personality disorders. Somatization in patients with a personality disorder poses unique challenges.¹³ Granted, when making a diagnosis it is difficult to tease apart somatization from personality disorders because somatization itself may be considered a chronic, maladaptive coping style. However, symptoms such as deception, impulsivity, mood lability, and self-injurious behavior introduce treatment complications that exceed the scope of this article.

Posttraumatic stress disorder (PTSD)—particularly childhood sexual and physical abuse—also predisposes some patients to somatization disorders.^14,15 Patients with comorbid PTSD and somatization disorder require highly specialized treatment that is beyond the scope of this review.

COGNITIVE-BEHAVIORAL TREATMENT

Cognitive-behavioral therapy (CBT) is the best-studied and most effective treatment for somatoform disorders.¹⁶ CBT for somatization relies on both physiologic and cognitive explanations to account for the patient’s experience, without committing to an “either/or” dichotomy. It offers patients an alternate explanation of what is wrong with them—illness anxiety instead of severe physical illness.

By making patients aware of their automatic thoughts, feelings, behaviors, and underlying beliefs, CBT helps them normalize and cope with their illness anxiety. CBT techniques can be applied in a predetermined course of therapy (such as 12 sessions with a mental health clinician), in a group setting, or piecemeal by any health care provider.

Effective strategies. In a review of 30 controlled trials of CBT for somatoform disorders, Looper¹⁷ showed overall effect ranging from 0.38 to 2.5, where 0.2 was defined as a small effect, 0.5 as medium, and 0.8 as large. Hypochondriasis, somatization disorder, body dysmorphic disorder, chronic pain, chronic fatigue, and noncardiac chest pain were included in this review. The most effective strategies:

• included 6 to 16 treatment sessions
• were symptom-focused as opposed to providing general relaxation training
• included maintenance sessions after the initial series.

Four factors of health anxiety. CBT primarily targets the patient’s false beliefs that he or she is physically ill. These beliefs are based on how the patient misinterprets innocuous physical symptoms and responds to them.¹⁸ The cognitive theory of health anxiety holds that health anxiety severity is affected by four factors:

• perceived likelihood of illness
• perceived burden of illness
• perceived ability to cope with illness
• perception of the extent to which external factors will help.¹⁹

Table 1

Common dysfunctional beliefs of somatizing patients

The first two factors worsen and the latter two mitigate health anxiety. An individual patient’s presenting fears often suggest which factors to address. For example, Mrs. M may describe the burden of illness as the focus of her fears (“If I have a heart attack, who will care for my children?”). This information cues you to shift the focus of therapy to helping her cope with child care needs despite her recurring symptoms.

If she focuses on her likelihood of illness, then uncoupling the symptoms from the diagnosis could be more productive. When she reports palpitations, diaphoresis, and dizziness, have her do breathing exercises that induce those symptoms without producing a heart attack.

Table 2

Journaling homework: 5 questions for patients to answer about one symptom each day

She might describe feeling unable to cope when she feels symptoms or when cardiologists tell her nothing is wrong with her heart. In that case, focus on relaxation techniques, global stress reduction, and reducing cardiac risk factors to bolster her ability to cope with her illness.

Journaling is a critical component of CBT in treating somatization disorders. Regular journaling by the patient can reveal dysfunctional beliefs that may be driving his or her health anxieties, such as those listed in Table 1. We find it useful to assign patients to answer five questions about one symptom experience each day (Table 2). This self-monitoring provides material to work on with the patient during each session.

Cognitive restructuring. During therapy sessions, we ask patients to suggest alternate explanations for the symptoms recorded in their journals. We then ask them to determine which explanations are more feasible.

For example, if Mrs. M develops palpitations during emotionally charged arguments, we would ask her to develop explanations other than, “I was having a heart attack.” Reality testing includes rhetorical questions such as, “Would you be alive today if you were having a heart attack every time you had palpitations?” Automatic thoughts are successively identified and then tested aloud with the patient:

• “Has every unexplained symptom led to the discovery of a serious illness?”
• “Does every instance of hurt equal harm?”

Eventually, patterns of automatic thoughts emerge, and these reveal the underlying dysfunctional beliefs.

Dysfunctional beliefs are maintained when patients selectively attend to and amplify somatic sensations. Behavioral experiments during sessions can demonstrate to the patient in vivo the process by which they misattribute illness to physical symptoms. For example, overbreathing with a patient during a session may elicit light-headedness, paresthesias, or tachycardia, which can then be linked to overbreathing rather than a chronic or catastrophic illness.

Furthermore, patients can be taught to control the experience. Some patients with headaches or GI pain may be made aware of symptoms by simply asking them to focus their attention on the respective organs. Simply explaining the cycle of misattribution, autonomic activation, and further symptom development with an in vivo demonstration can be illuminating.

Response prevention. Another behavioral technique is to cut back in small increments on actions the patient takes in response to physical symptoms and automatic thoughts. For example, a patient could take medicine and seek reassurance less frequently and avoid rubbing the affected area.

PSYCHOEDUCATION

Two psychoeducation programs for somatization behavior have been formally studied.

The Personal Health Improvement Program²⁰—led by trained facilitators—includes classroom videos, cognitive-behavioral exercises, and home study assignments. After completing the 6-week course, 171 patients with somatization disorders reported reduced physical and psychological distress and increased function. They also visited their primary care physicians less often.

Table 3

How to effectively reassure somatizing patients

Coping with Illness Anxiety²¹ relies on mini-lectures, demonstrations, videos, and focused group discussions. After six 2-hour sessions, 33 of 43 study patients (78%) used medical services less often and reported reduced disease conviction, consequences of bodily complaints, health anxiety, and checking and avoidance behaviors. Two psychology graduate students taught the course from a manual, with 6 to 9 patients per group.

Psychoeducation in this context relies on didactic presentations, readings, role playing, and videotaped material. The goal is to teach patients to recognize thoughts, emotions, and behaviors that lead to and result from somatic preoccupation. Patients can improve when they recognize dysfunctional behavioral patterns and learn alternate coping strategies.

Somatizing patients—with their aversion to the stigma of mental illness—may find psychoeducation particularly attractive. They can be treated as students who are being educated, rather than as patients who are being treated. Classrooms in both studies cited above were located in medical outpatient offices, not in mental health facilities.

REASSURANCE

Reassurance is a common therapeutic technique in medicine, although it is poorly understood, poorly taught, and not methodically applied. Reassurance alleviates anxiety, enables patients to endure dysphoria, encourages hope, gives insight, and enhances the doctor-patient relationship.²²

Table 4

How to avoid becoming frustrated with persistent somatization

Whereas CBT seeks to challenge patients’ underlying beliefs and restructure their thought processes,²³ reassurance can help them tolerate their dysfunctional beliefs and dissuade them from believing their health is dangerously impaired. Reassurance offers a substitute explanation of patients’ dysfunction, although this explanation is not as central or detailed as it is in CBT.

How to reassure. Patients may consider reassurance offered prematurely or by a stranger to be patronizing or dismissive. Reassurance is most effective when:

• given by a trusted person who is reliable, consistent, firm, and empathic
• the patient’s condition has been established as unresponsive to conventional diagnostics or biological therapies.

Patients are most receptive to reassurance when they express distress or frustration with their unexplained symptoms. Affirming that their suffering is legitimate opens the door to further treatment.

Reassurance is least effective when a patient is expressing anger or mistrust, although this is when the physician may feel most pressured to reassure. To successfully reassure a patient, the psychiatrist needs to:

• credibly identify with the patient’s distress
• and listen empathically (such as using body language and facial expressions that convey concern and consideration to the patient).²⁴

Starcevic suggests useful techniques for providing reassurance (Table 3).²²

DRUG THERAPIES

Psychotropics are considered a first-line treatment for patients with somatization disorders when:

• the patient spontaneously identifies any discrete, vegetative, or psychological complaints that may respond to drug therapy, such as insomnia, weight loss, sadness, or preoccupation
• the patient meets diagnostic criteria for comorbid anxiety or depressive disorders
• the therapeutic alliance is strong enough to weather the inevitable struggle with side effects and incomplete response to treatment. We do not recommend medication in the first encounter, when it may threaten a nascent alliance.

A common obstacle to prescribing psychotropics to somatizing patients is their sensitivity to suggestions that their complaints are “all in their heads.” To sidestep this resistance, describe the medication as treating the stress caused. by—not causing.—their chronic physical complaints. Proposing antidepressant therapy after—rather than instead of—physical exams and other diagnostics may elicit a more positive response.

Antidepressants. In clinical trials, somatoform complaints show moderate improvement after antidepressant treatment. In a meta-analysis of 6,595 patients with unexplained symptoms treated only with antidepressants, the number needed to treat was 3 to yield a positive response.²⁵ This report of 94 medication trials included patients with headache, fibromyalgia, functional GI syndromes, idiopathic pain, tinnitus, or chronic fatigue.

In other trials:

• Amitriptyline has reduced somatic symptoms in patients labeled as having “masked depression.”²⁶
• Sertraline has reduced disease fear, disease conviction, and bodily preoccupation in patients with hypochondriasis and panic disorder.²⁷

Consider side effects when choosing medication for patients with somatoform disorders. Selective serotonin reuptake inhibitors (SSRIs) in general—and sertraline, citalopram, and escitalopram specifically—have fewer side effects than tricyclics. The adage of “start low, go slow” is appropriate for somatizing patients; we usually start with one-half the dosages recommended for treating depression.

Antipsychotics. In case reports, patients with “atypical psychosis,” “monosymptomatic hypochondriacal psychosis,” or “delusional disorder, somatic type” have responded to antipsychotics. These patients’ somatic beliefs are of delusional intensity, such as the rare fear of being eaten alive by an intestinal parasite (delusional parasitosis). Reported behaviors associated with the delusion include starvation, excessive laxative abuse, ingestion of sharp objects, and self-inflicted stab wounds. Treatments described in the literature include the typical agents pimozide and haloperidol and the atypicals olanzapine and risperidone.

TREATMENT-RESISTANT PATIENTS

Some patients with somatoform disorders will not accept CBT, psychotropics, reassurance, or referrals to group psychoeducation. Despite your best efforts, they may persist in focusing on somatic complaints. If you are willing to maintain a therapeutic relationship with them, be prepared to tolerate several ongoing paradoxes (Table 4).

Behaviorally, you must “listen more and do less.” Emotionally, you must be willing to enter into a long-term relationship with an inherently frustrating patient whose pathologies make you feel therapeutically hopeless and helpless. Understand that their physical symptoms function as a metaphor for psychological distress. You are not required to explore the source, content, or meaning of the metaphor in detail but simply listen to their somatic complaints through that psychological filter.

Related resources

• Starcevic V, Lipsitt D (eds). Hypochondriasis: modern perspectives on an ancient malady. New York: Oxford University Press, 2001.
• Information and support Web site for persons with health anxiety or hypochondria. www.healthanxiety.com
• Anxiety Disorders Association of America. www.adaa.org

Drug brand names

• Amitriptyline • Elavil
• Citalopram • Celexa
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Pimozide • Orap
• Risperidone • Risperdal
• Sertraline • Zoloft

Disclosure

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

Dr. Wise receives grant support from Eli Lilly & Co. and is a consultant or speaker for Eli Lilly & Co., Pfizer Inc., Bristol-Myers Squibb Co., and GlaxoSmithKline.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When switching antipsychotics for patients with schizophrenia, you can ease this potentially perilous passage by choosing the right time to switch and preventing psychotic relapse. This article describes four keys to a smooth transition:

• assess response and side effects with the existing medication
• weigh the pros and cons of switching, with input from the patient or caregiver
• select a replacement with characteristics that could improve patient function
• choose a switching strategy while considering safety and efficacy data.

RISKS AND BENEFITS OF SWITCHING

The two most compelling reasons to switch antipsychotics are enhanced clinical response and improved tolerability. Others may include lower medication cost, less-frequent monitoring, fewer drug interactions, or easier administration (such as once-daily versus twice-daily dosing).

Table 1

Sample response criteria to evaluate an antipsychotic switch

The greatest risk in a relatively stable patient is for psychotic symptoms to re-emerge. Be very careful when switching patients who:

• might harm themselves or others if their psychosis re-emerges during the switch
• were recently stabilized after an acute psychotic episode and have been maintained for less than 6 months on the medication that controlled their symptoms
• cannot adhere to oral medications and are being maintained on long-acting depot formulations.¹

Other factors to consider include:

• the need for more-frequent patient visits during the transition to monitor for adverse effects
• the patient’s willingness to switch
• influence of external stressors—such as recent bereavement—or aspects of the patient’s workplace or living environment that may interfere with adherence to a new regimen
• medication cost and coverage by third-party payers.

Establishing specific response criteria for each patient (Table 1) will help you know when to continue or terminate a switch.

INADEQUATE RESPONSE

Because antipsychotics do not eliminate all positive and negative symptoms, an adequate response is considered a reasonable therapeutic goal. Many patients with schizophrenia respond adequately to traditional or atypical antipsychotics, but approximately one-third do not.²

What is an “adequate” response? No advisory groups or consensus panels have defined this term or set standards for when to switch. Therefore, psychiatrists must evaluate a patient’s response to an antipsychotic by using clinical judgment and patient/caregiver input. To gather the information you need, it is important to:

• identify target symptoms at baseline
• regularly monitor symptom severity, frequency, and intrusion on activities of daily living and quality of life.

Quantitative measures. In research, response is measured as a percent reduction in scores on standard assessments such as the Positive and Negative Syndrome Scales (PANSS). Using the PANSS, however, is too time-consuming for clinical practice.

The Brief Psychiatric Rating Scale (BPRS) is simpler than PANSS and can be administered more quickly but is less specific for negative symptoms. Even so, using the BPRS can help quantify baseline symptoms and monitor clinical response. It is useful to complete a BPRS rating prior to a switch and at subsequent visits during the transition. A >20% reduction in the total score is considered an adequate response.

Qualitative measures. Rating scales do not measure patients’ and sfamilies’ subjective feelings. One patient may view a 50% decrease in psychotic symptoms as extremely favorable and another as unacceptable. Switching therefore may be reasonable for one patient but not for another with a similar clinical response.

Table 2

Treatment-limiting antipsychotic side effects and options for switching

Underdosing contributes to inadequate response, so assess whether an antipsychotic has been given a sufficient trial. For example, 400 to 800 mg/d of quetiapine is considered a therapeutic dosage, assuming adequate tolerability, but some clinicians stop increasing the dosage below that range. Similarly, the usual antipsychotic trial continues at least 3 to 4 weeks at a therapeutic dosage.

TREATMENT-LIMITING EFFECTS

Antipsychotic side effects that justify switching may be treatment-limiting or simply bothersome. For example, switching is necessary for antipsychotic-induced QTc prolongation in a patient with a history of cardiac dysrhythmias and reasonable for excessive daytime sedation in a patient who is working or attending school.

Extrapyramidal symptoms (EPS) and hyperprolactinemia may limit a patient’s tolerance of an antipsychotic. Patients who are especially sensitive to EPS may not tolerate high-potency agents such an haloperidol or even low to moderate dosages of risperidone. Others may not develop EPS while receiving haloperidol or higher dosages of risperidone.

Switching to an antipsychotic with relatively less histamine or alpha-adrenergic blockade may reduce problematic side effects such as sedation and orthostatic hypotension, respectively (Table 2).

Patients vary in how well they tolerate other side effects, such as weight gain. For example, a 10-lb weight gain may be acceptable to one patient and unacceptable to another. The decision to switch may be more obvious in a patient with diabetes, for whom substantial weight gain is unacceptable.

SWITCHING STRATEGIES

No method is universally accepted for switching from one antipsychotic to another. In clinical practice and research, three common methods (Figure) are used:

• immediately discontinuing drug A while starting drug B at full dosage
• slowly tapering drug A while starting drug B at full dosage
• slowly tapering drug A while slowly increasing drug B to full dosage.

Each method has advantages and disadvantages. Gradual cross-titration and tapering may reduce the risk of relapse but increase the risk of side effects. Elaborate regimens may confuse some patients—especially those with cognitive impairment—and increase the risk for adverse events and nonadherence.

Abruptly discontinuing an agent is less confusing and more convenient than gradual tapering, but patients may experience acute withdrawal (as with clozapine). Finally, no guidelines exist on how quickly to make the transition when one or both medications are cross-titrated and tapered. For inpatients receiving intense monitoring, a transition may be completed in 3 to 7 days, whereas outpatients may require 1 to 3 weeks.

Recommendation. The evidence cited in the next section of this article suggests that any of the three methods can be used when switching antipsychotics, except clozapine. When switching from clozapine, extend the cross-taper period to help minimize or eliminate rebound psychosis and cholinergic symptoms.

SWITCHING FROM DEPOT TO ORAL AGENTS

For patients switching from depot to oral antipsychotics, a 1-month cross-titration taper has been shown to be efficient and safe.

Godleski et al³ randomized 26 patients who had received IM depot antipsychotics (haloperidol or fluphenazine decanoate) for at least 3 years to either continue the IM depot antipsychotic or switch to olanzapine. Although the study was designed to assess the safety and efficacy of the switch, it also provided data on the transition method.

Figure 3 common antipsychotic switching strategies

Patients receiving olanzapine improved on several efficacy measures, although the clinical relevance was minimal. For example, their mean PANSS total score decreased 3.23 points. One patient—in the control group—was hospitalized. Those who received olanzapine preferred this agent to the IM depot formulations and chose to continue daily olanzapine therapy. Adverse events did not increase significantly while patients received IM depot injections plus olanzapine.

SWITCHING ORAL AGENTS

Clozapine. When risperidone entered the U.S. market in the 1990s, a number of patients who had been treated with clozapine were abruptly switched to risperidone. Many experienced acute symptom exacerbation,^4,5 including some whose rebound psychosis was more severe than their original symptoms. Other adverse effects—including nausea, diarrhea, vomiting, headache, restlessness, and sweating— have been attributed to cholinergic rebound caused by abruptly discontinuing clozapine.

To minimize the potential for rebound psychosis and cholinergic symptoms, taper clozapine across a minimum of 1 to 2 weeks. When you need to discontinue clozapine immediately—such as for patients experiencing serious hematologic effects—adding an anticholinergic such as benztropine may minimize the cholinergic rebound.

Risperidone. No studies have formally assessed methods for switching patients to risperidone.

Olanzapine. When switching to olanzapine, a direct switch or cross-titration tapering appear to be viable options.

In one multicenter, open-label study,² 108 patients were randomly assigned to olanzapine, 10 mg/d, after abruptly discontinuing a previous antipsychotic (direct switch) or by cross-titration tapering in a 1:1 fashion. Patients in the crosstitration group started olanzapine and discontinued their original antipsychotics across 2 weeks. Olanzapine dosages were adjusted as needed from 5 to 20 mg/d.

At study entry, approximately 95% of subjects in the direct-switch group and 85% in the crosstitration taper group were taking at least one typical antipsychotic—usually haloperidol. A switch was considered successful if a patient completed the 6-week trial without psychotic symptom worsening or EPS.

The 92 (85%) subjects who completed the study comprised similar percentages from both groups. Their scores on the PANSS total and subscales and Clinical Global Impression (CGI) scale also were similar.

The most common adverse events were somnolence, insomnia, and headache in the directs-witch group (all 11%), and somnolence (15%), headache (9%), insomnia (7%), and increased appetite (7%) in the cross-titration group. Differences in these percentages were not statistically significant.

EPS and akathisia improved significantly in both groups (p< 0.01) after switching to olanzapine. Thirteen (24%) patients in the direct-switch group and 17 (32%) in the cross-titration taper group required at least one dose of benztropine. Use of concomitant medications was similar.

Quetiapine can be abruptly discontinued with minimal risk of adverse events when initiating another antipsychotic.

Cutler et al⁶ switched 50 stable patients who had been treated with risperidone, thioridazine, haloperidol, or haloperidol plus benztropine. The original antipsychotics were abruptly discontinued, and quetiapine was initiated in a doseescalating fashion and then maintained at 300 mg/d for 12 days. After that, quetiapine was abruptly discontinued and patients were assessed for side effects, including EPS.

Most patients’ BPRS or CGI-Severity of Illness scores did not change significantly. Two patients (4%) experienced psychotic relapse during the switch. The authors speculated that these relapses might have been related to subtherapeutic quetiapine dosing. Transient nausea and vomiting were reported after quetiapine was discontinued.

Ziprasidone. When switching from another antipsychotic to ziprasidone, all three strategies appear well tolerated and maintain symptom control.

Using randomized, open-label trials, Weiden et al⁷ investigated strategies for switching patients to ziprasidone from olanzapine, risperidone, and traditional antipsychotics. All participants were diagnosed with schizophrenia or schizoaffective disorder and had experienced partial or inadequate response or side effects with their original antipsychotics.

Patients were assigned to one of three switching strategies:

• abruptly discontinue the initial antipsychotic
• decrease the initial antipsychotic’s dosage by 50% for 1 week, then discontinue it
• gradually taper the initial antipsychotic, so that subjects received 100% for 3 days of ziprasidone treatment, 50% for the next 4 days, and none thereafter.

For all three strategies, ziprasidone was started at 80 mg/d for 2 days, with dosing adjusted as needed to 40 to 160 mg/d.

All patients’ total score and positive and negative PANSS subscale scores improved significantly (p<0.01) across 6 weeks, although these data represent symptom changes after switching to ziprasidone. No efficacy or safety data were reported during switching. The authors concluded that patients could switch successfully to ziprasidone over a relatively short period using a variety of methods.

In another study, Stip⁸ switched 54 patients to ziprasidone from haloperidol. All received ziprasidone, 40 mg bid for 2 days and then 80 mg bid. Haloperidol was discontinued:

• immediately on day 1
• after the dosage was decreased by 50% for 7 days
• or after continuing the full dosage for 2 days, then taking 50% of the initial dosage for 5 days.

All patients maintained symptom control while switching, and 40 of 54 completed the trial. Among responders, BPRS and CGI scores improved significantly across 6 weeks, and EPS improved as expected.

Aripiprazole. Direct-switch and cross-titration tapering methods appear to be effective and welltolerated when switching stable patients to aripiprazole.

In an 8-week, randomized, open-label trial, Casey et al⁹ switched 311 outpatients with schizophrenia or schizoaffective disorder to aripiprazole. The patients—who had been taking stable dosages of haloperidol, chlorpromazine, risperidone, or olanzapine for at least 1 month—were randomly assigned to three groups:

• group 1 immediately discontinued the previous antipsychotic and started aripiprazole, 30 mg/d
• group 2 started aripiprazole, 30 mg/d, and discontinued the previous antipsychotic across 2 weeks
• group 3 started aripiprazole (10 mg/d in week 1, 20 mg/d in week 2, and 30 mg/d in week 3) and tapered the previous antipsychotic (50% less in week 1, another 50% less in week 2, then discontinued).

Investigators assessed treatment efficacy using the PANSS and CGI at baseline and weeks 4 and 8. They questioned patients about adverse events at each follow-up visit.

Nearly three-fourths (72%) of patients completed the trial. Discontinuation rates were 31% in group 1, 34% in group 2, and 19% in group 3. Efficacy, safety, tolerability, and incidence of discontinuation because of worsening psychosis were comparable across groups.

Similar percentages of patients in each group reported one or more adverse event (89%, 89%, and 81% for groups 1, 2, and 3, respectively). Most adverse events were described as mild to moderate. Insomnia was reported most frequently. Other adverse effects that occurred in >10% of subjects included nausea, akathisia, anxiety, psychosis, headache (groups 2 and 3), somnolence, lightheadedness (groups 1 and 2) vomiting (group 2 only), agitation (group 3 only), and diarrhea (group 2 only).

Seven patients were hospitalized for serious adverse events—usually worsening psychosis. Hospitalization rates were comparable among the three groups.

All groups improved slightly on the Barnes Akathisia Scale, Simpson Angus Rating Scale, and Abnormal Involuntary Movement Scale. Few patients in each group required benztropine (2%, 4%, and 7% for groups 1, 2 and 3, respectively).

Related resources

• Borison RL. Changing antipsychotic medication: guidelines on the transition to treatment with risperidone. The Consensus Study Group on Risperidone Dosing. Clin Ther 1996;18(4):592-607.

Drug brand names

• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Winans is a consultant for Bristol-Myers Squibb Co. and is a speaker for Pfizer Inc., Abbott Laboratories, and Bristol-Myers Squibb Co.

When switching antipsychotics for patients with schizophrenia, you can ease this potentially perilous passage by choosing the right time to switch and preventing psychotic relapse. This article describes four keys to a smooth transition:

• assess response and side effects with the existing medication
• weigh the pros and cons of switching, with input from the patient or caregiver
• select a replacement with characteristics that could improve patient function
• choose a switching strategy while considering safety and efficacy data.

RISKS AND BENEFITS OF SWITCHING

The two most compelling reasons to switch antipsychotics are enhanced clinical response and improved tolerability. Others may include lower medication cost, less-frequent monitoring, fewer drug interactions, or easier administration (such as once-daily versus twice-daily dosing).

Table 1

Sample response criteria to evaluate an antipsychotic switch

The greatest risk in a relatively stable patient is for psychotic symptoms to re-emerge. Be very careful when switching patients who:

• might harm themselves or others if their psychosis re-emerges during the switch
• were recently stabilized after an acute psychotic episode and have been maintained for less than 6 months on the medication that controlled their symptoms
• cannot adhere to oral medications and are being maintained on long-acting depot formulations.¹

Other factors to consider include:

• the need for more-frequent patient visits during the transition to monitor for adverse effects
• the patient’s willingness to switch
• influence of external stressors—such as recent bereavement—or aspects of the patient’s workplace or living environment that may interfere with adherence to a new regimen
• medication cost and coverage by third-party payers.

Establishing specific response criteria for each patient (Table 1) will help you know when to continue or terminate a switch.

INADEQUATE RESPONSE

Because antipsychotics do not eliminate all positive and negative symptoms, an adequate response is considered a reasonable therapeutic goal. Many patients with schizophrenia respond adequately to traditional or atypical antipsychotics, but approximately one-third do not.²

What is an “adequate” response? No advisory groups or consensus panels have defined this term or set standards for when to switch. Therefore, psychiatrists must evaluate a patient’s response to an antipsychotic by using clinical judgment and patient/caregiver input. To gather the information you need, it is important to:

• identify target symptoms at baseline
• regularly monitor symptom severity, frequency, and intrusion on activities of daily living and quality of life.

Quantitative measures. In research, response is measured as a percent reduction in scores on standard assessments such as the Positive and Negative Syndrome Scales (PANSS). Using the PANSS, however, is too time-consuming for clinical practice.

The Brief Psychiatric Rating Scale (BPRS) is simpler than PANSS and can be administered more quickly but is less specific for negative symptoms. Even so, using the BPRS can help quantify baseline symptoms and monitor clinical response. It is useful to complete a BPRS rating prior to a switch and at subsequent visits during the transition. A >20% reduction in the total score is considered an adequate response.

Qualitative measures. Rating scales do not measure patients’ and sfamilies’ subjective feelings. One patient may view a 50% decrease in psychotic symptoms as extremely favorable and another as unacceptable. Switching therefore may be reasonable for one patient but not for another with a similar clinical response.

Table 2

Treatment-limiting antipsychotic side effects and options for switching

Underdosing contributes to inadequate response, so assess whether an antipsychotic has been given a sufficient trial. For example, 400 to 800 mg/d of quetiapine is considered a therapeutic dosage, assuming adequate tolerability, but some clinicians stop increasing the dosage below that range. Similarly, the usual antipsychotic trial continues at least 3 to 4 weeks at a therapeutic dosage.

TREATMENT-LIMITING EFFECTS

Antipsychotic side effects that justify switching may be treatment-limiting or simply bothersome. For example, switching is necessary for antipsychotic-induced QTc prolongation in a patient with a history of cardiac dysrhythmias and reasonable for excessive daytime sedation in a patient who is working or attending school.

Extrapyramidal symptoms (EPS) and hyperprolactinemia may limit a patient’s tolerance of an antipsychotic. Patients who are especially sensitive to EPS may not tolerate high-potency agents such an haloperidol or even low to moderate dosages of risperidone. Others may not develop EPS while receiving haloperidol or higher dosages of risperidone.

Switching to an antipsychotic with relatively less histamine or alpha-adrenergic blockade may reduce problematic side effects such as sedation and orthostatic hypotension, respectively (Table 2).

Patients vary in how well they tolerate other side effects, such as weight gain. For example, a 10-lb weight gain may be acceptable to one patient and unacceptable to another. The decision to switch may be more obvious in a patient with diabetes, for whom substantial weight gain is unacceptable.

SWITCHING STRATEGIES

No method is universally accepted for switching from one antipsychotic to another. In clinical practice and research, three common methods (Figure) are used:

• immediately discontinuing drug A while starting drug B at full dosage
• slowly tapering drug A while starting drug B at full dosage
• slowly tapering drug A while slowly increasing drug B to full dosage.

Each method has advantages and disadvantages. Gradual cross-titration and tapering may reduce the risk of relapse but increase the risk of side effects. Elaborate regimens may confuse some patients—especially those with cognitive impairment—and increase the risk for adverse events and nonadherence.

Abruptly discontinuing an agent is less confusing and more convenient than gradual tapering, but patients may experience acute withdrawal (as with clozapine). Finally, no guidelines exist on how quickly to make the transition when one or both medications are cross-titrated and tapered. For inpatients receiving intense monitoring, a transition may be completed in 3 to 7 days, whereas outpatients may require 1 to 3 weeks.

Recommendation. The evidence cited in the next section of this article suggests that any of the three methods can be used when switching antipsychotics, except clozapine. When switching from clozapine, extend the cross-taper period to help minimize or eliminate rebound psychosis and cholinergic symptoms.

SWITCHING FROM DEPOT TO ORAL AGENTS

For patients switching from depot to oral antipsychotics, a 1-month cross-titration taper has been shown to be efficient and safe.

Godleski et al³ randomized 26 patients who had received IM depot antipsychotics (haloperidol or fluphenazine decanoate) for at least 3 years to either continue the IM depot antipsychotic or switch to olanzapine. Although the study was designed to assess the safety and efficacy of the switch, it also provided data on the transition method.

Figure 3 common antipsychotic switching strategies

Patients receiving olanzapine improved on several efficacy measures, although the clinical relevance was minimal. For example, their mean PANSS total score decreased 3.23 points. One patient—in the control group—was hospitalized. Those who received olanzapine preferred this agent to the IM depot formulations and chose to continue daily olanzapine therapy. Adverse events did not increase significantly while patients received IM depot injections plus olanzapine.

SWITCHING ORAL AGENTS

Clozapine. When risperidone entered the U.S. market in the 1990s, a number of patients who had been treated with clozapine were abruptly switched to risperidone. Many experienced acute symptom exacerbation,^4,5 including some whose rebound psychosis was more severe than their original symptoms. Other adverse effects—including nausea, diarrhea, vomiting, headache, restlessness, and sweating— have been attributed to cholinergic rebound caused by abruptly discontinuing clozapine.

To minimize the potential for rebound psychosis and cholinergic symptoms, taper clozapine across a minimum of 1 to 2 weeks. When you need to discontinue clozapine immediately—such as for patients experiencing serious hematologic effects—adding an anticholinergic such as benztropine may minimize the cholinergic rebound.

Risperidone. No studies have formally assessed methods for switching patients to risperidone.

Olanzapine. When switching to olanzapine, a direct switch or cross-titration tapering appear to be viable options.

In one multicenter, open-label study,² 108 patients were randomly assigned to olanzapine, 10 mg/d, after abruptly discontinuing a previous antipsychotic (direct switch) or by cross-titration tapering in a 1:1 fashion. Patients in the crosstitration group started olanzapine and discontinued their original antipsychotics across 2 weeks. Olanzapine dosages were adjusted as needed from 5 to 20 mg/d.

At study entry, approximately 95% of subjects in the direct-switch group and 85% in the crosstitration taper group were taking at least one typical antipsychotic—usually haloperidol. A switch was considered successful if a patient completed the 6-week trial without psychotic symptom worsening or EPS.

The 92 (85%) subjects who completed the study comprised similar percentages from both groups. Their scores on the PANSS total and subscales and Clinical Global Impression (CGI) scale also were similar.

The most common adverse events were somnolence, insomnia, and headache in the directs-witch group (all 11%), and somnolence (15%), headache (9%), insomnia (7%), and increased appetite (7%) in the cross-titration group. Differences in these percentages were not statistically significant.

EPS and akathisia improved significantly in both groups (p< 0.01) after switching to olanzapine. Thirteen (24%) patients in the direct-switch group and 17 (32%) in the cross-titration taper group required at least one dose of benztropine. Use of concomitant medications was similar.

Quetiapine can be abruptly discontinued with minimal risk of adverse events when initiating another antipsychotic.

Cutler et al⁶ switched 50 stable patients who had been treated with risperidone, thioridazine, haloperidol, or haloperidol plus benztropine. The original antipsychotics were abruptly discontinued, and quetiapine was initiated in a doseescalating fashion and then maintained at 300 mg/d for 12 days. After that, quetiapine was abruptly discontinued and patients were assessed for side effects, including EPS.

Most patients’ BPRS or CGI-Severity of Illness scores did not change significantly. Two patients (4%) experienced psychotic relapse during the switch. The authors speculated that these relapses might have been related to subtherapeutic quetiapine dosing. Transient nausea and vomiting were reported after quetiapine was discontinued.

Ziprasidone. When switching from another antipsychotic to ziprasidone, all three strategies appear well tolerated and maintain symptom control.

Using randomized, open-label trials, Weiden et al⁷ investigated strategies for switching patients to ziprasidone from olanzapine, risperidone, and traditional antipsychotics. All participants were diagnosed with schizophrenia or schizoaffective disorder and had experienced partial or inadequate response or side effects with their original antipsychotics.

Patients were assigned to one of three switching strategies:

• abruptly discontinue the initial antipsychotic
• decrease the initial antipsychotic’s dosage by 50% for 1 week, then discontinue it
• gradually taper the initial antipsychotic, so that subjects received 100% for 3 days of ziprasidone treatment, 50% for the next 4 days, and none thereafter.

For all three strategies, ziprasidone was started at 80 mg/d for 2 days, with dosing adjusted as needed to 40 to 160 mg/d.

All patients’ total score and positive and negative PANSS subscale scores improved significantly (p<0.01) across 6 weeks, although these data represent symptom changes after switching to ziprasidone. No efficacy or safety data were reported during switching. The authors concluded that patients could switch successfully to ziprasidone over a relatively short period using a variety of methods.

In another study, Stip⁸ switched 54 patients to ziprasidone from haloperidol. All received ziprasidone, 40 mg bid for 2 days and then 80 mg bid. Haloperidol was discontinued:

• immediately on day 1
• after the dosage was decreased by 50% for 7 days
• or after continuing the full dosage for 2 days, then taking 50% of the initial dosage for 5 days.

All patients maintained symptom control while switching, and 40 of 54 completed the trial. Among responders, BPRS and CGI scores improved significantly across 6 weeks, and EPS improved as expected.

Aripiprazole. Direct-switch and cross-titration tapering methods appear to be effective and welltolerated when switching stable patients to aripiprazole.

In an 8-week, randomized, open-label trial, Casey et al⁹ switched 311 outpatients with schizophrenia or schizoaffective disorder to aripiprazole. The patients—who had been taking stable dosages of haloperidol, chlorpromazine, risperidone, or olanzapine for at least 1 month—were randomly assigned to three groups:

• group 1 immediately discontinued the previous antipsychotic and started aripiprazole, 30 mg/d
• group 2 started aripiprazole, 30 mg/d, and discontinued the previous antipsychotic across 2 weeks
• group 3 started aripiprazole (10 mg/d in week 1, 20 mg/d in week 2, and 30 mg/d in week 3) and tapered the previous antipsychotic (50% less in week 1, another 50% less in week 2, then discontinued).

Investigators assessed treatment efficacy using the PANSS and CGI at baseline and weeks 4 and 8. They questioned patients about adverse events at each follow-up visit.

Nearly three-fourths (72%) of patients completed the trial. Discontinuation rates were 31% in group 1, 34% in group 2, and 19% in group 3. Efficacy, safety, tolerability, and incidence of discontinuation because of worsening psychosis were comparable across groups.

Similar percentages of patients in each group reported one or more adverse event (89%, 89%, and 81% for groups 1, 2, and 3, respectively). Most adverse events were described as mild to moderate. Insomnia was reported most frequently. Other adverse effects that occurred in >10% of subjects included nausea, akathisia, anxiety, psychosis, headache (groups 2 and 3), somnolence, lightheadedness (groups 1 and 2) vomiting (group 2 only), agitation (group 3 only), and diarrhea (group 2 only).

Seven patients were hospitalized for serious adverse events—usually worsening psychosis. Hospitalization rates were comparable among the three groups.

All groups improved slightly on the Barnes Akathisia Scale, Simpson Angus Rating Scale, and Abnormal Involuntary Movement Scale. Few patients in each group required benztropine (2%, 4%, and 7% for groups 1, 2 and 3, respectively).

Related resources

• Borison RL. Changing antipsychotic medication: guidelines on the transition to treatment with risperidone. The Consensus Study Group on Risperidone Dosing. Clin Ther 1996;18(4):592-607.

Drug brand names

• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Winans is a consultant for Bristol-Myers Squibb Co. and is a speaker for Pfizer Inc., Abbott Laboratories, and Bristol-Myers Squibb Co.

When switching antipsychotics for patients with schizophrenia, you can ease this potentially perilous passage by choosing the right time to switch and preventing psychotic relapse. This article describes four keys to a smooth transition:

• assess response and side effects with the existing medication
• weigh the pros and cons of switching, with input from the patient or caregiver
• select a replacement with characteristics that could improve patient function
• choose a switching strategy while considering safety and efficacy data.

RISKS AND BENEFITS OF SWITCHING

The two most compelling reasons to switch antipsychotics are enhanced clinical response and improved tolerability. Others may include lower medication cost, less-frequent monitoring, fewer drug interactions, or easier administration (such as once-daily versus twice-daily dosing).

Table 1

Sample response criteria to evaluate an antipsychotic switch

The greatest risk in a relatively stable patient is for psychotic symptoms to re-emerge. Be very careful when switching patients who:

• might harm themselves or others if their psychosis re-emerges during the switch
• were recently stabilized after an acute psychotic episode and have been maintained for less than 6 months on the medication that controlled their symptoms
• cannot adhere to oral medications and are being maintained on long-acting depot formulations.¹

Other factors to consider include:

• the need for more-frequent patient visits during the transition to monitor for adverse effects
• the patient’s willingness to switch
• influence of external stressors—such as recent bereavement—or aspects of the patient’s workplace or living environment that may interfere with adherence to a new regimen
• medication cost and coverage by third-party payers.

Establishing specific response criteria for each patient (Table 1) will help you know when to continue or terminate a switch.

INADEQUATE RESPONSE

Because antipsychotics do not eliminate all positive and negative symptoms, an adequate response is considered a reasonable therapeutic goal. Many patients with schizophrenia respond adequately to traditional or atypical antipsychotics, but approximately one-third do not.²

What is an “adequate” response? No advisory groups or consensus panels have defined this term or set standards for when to switch. Therefore, psychiatrists must evaluate a patient’s response to an antipsychotic by using clinical judgment and patient/caregiver input. To gather the information you need, it is important to:

• identify target symptoms at baseline
• regularly monitor symptom severity, frequency, and intrusion on activities of daily living and quality of life.

Quantitative measures. In research, response is measured as a percent reduction in scores on standard assessments such as the Positive and Negative Syndrome Scales (PANSS). Using the PANSS, however, is too time-consuming for clinical practice.

The Brief Psychiatric Rating Scale (BPRS) is simpler than PANSS and can be administered more quickly but is less specific for negative symptoms. Even so, using the BPRS can help quantify baseline symptoms and monitor clinical response. It is useful to complete a BPRS rating prior to a switch and at subsequent visits during the transition. A >20% reduction in the total score is considered an adequate response.

Qualitative measures. Rating scales do not measure patients’ and sfamilies’ subjective feelings. One patient may view a 50% decrease in psychotic symptoms as extremely favorable and another as unacceptable. Switching therefore may be reasonable for one patient but not for another with a similar clinical response.

Table 2

Treatment-limiting antipsychotic side effects and options for switching

Underdosing contributes to inadequate response, so assess whether an antipsychotic has been given a sufficient trial. For example, 400 to 800 mg/d of quetiapine is considered a therapeutic dosage, assuming adequate tolerability, but some clinicians stop increasing the dosage below that range. Similarly, the usual antipsychotic trial continues at least 3 to 4 weeks at a therapeutic dosage.

TREATMENT-LIMITING EFFECTS

Antipsychotic side effects that justify switching may be treatment-limiting or simply bothersome. For example, switching is necessary for antipsychotic-induced QTc prolongation in a patient with a history of cardiac dysrhythmias and reasonable for excessive daytime sedation in a patient who is working or attending school.

Extrapyramidal symptoms (EPS) and hyperprolactinemia may limit a patient’s tolerance of an antipsychotic. Patients who are especially sensitive to EPS may not tolerate high-potency agents such an haloperidol or even low to moderate dosages of risperidone. Others may not develop EPS while receiving haloperidol or higher dosages of risperidone.

Switching to an antipsychotic with relatively less histamine or alpha-adrenergic blockade may reduce problematic side effects such as sedation and orthostatic hypotension, respectively (Table 2).

Patients vary in how well they tolerate other side effects, such as weight gain. For example, a 10-lb weight gain may be acceptable to one patient and unacceptable to another. The decision to switch may be more obvious in a patient with diabetes, for whom substantial weight gain is unacceptable.

SWITCHING STRATEGIES

No method is universally accepted for switching from one antipsychotic to another. In clinical practice and research, three common methods (Figure) are used:

• immediately discontinuing drug A while starting drug B at full dosage
• slowly tapering drug A while starting drug B at full dosage
• slowly tapering drug A while slowly increasing drug B to full dosage.

Each method has advantages and disadvantages. Gradual cross-titration and tapering may reduce the risk of relapse but increase the risk of side effects. Elaborate regimens may confuse some patients—especially those with cognitive impairment—and increase the risk for adverse events and nonadherence.

Abruptly discontinuing an agent is less confusing and more convenient than gradual tapering, but patients may experience acute withdrawal (as with clozapine). Finally, no guidelines exist on how quickly to make the transition when one or both medications are cross-titrated and tapered. For inpatients receiving intense monitoring, a transition may be completed in 3 to 7 days, whereas outpatients may require 1 to 3 weeks.

Recommendation. The evidence cited in the next section of this article suggests that any of the three methods can be used when switching antipsychotics, except clozapine. When switching from clozapine, extend the cross-taper period to help minimize or eliminate rebound psychosis and cholinergic symptoms.

SWITCHING FROM DEPOT TO ORAL AGENTS

For patients switching from depot to oral antipsychotics, a 1-month cross-titration taper has been shown to be efficient and safe.

Godleski et al³ randomized 26 patients who had received IM depot antipsychotics (haloperidol or fluphenazine decanoate) for at least 3 years to either continue the IM depot antipsychotic or switch to olanzapine. Although the study was designed to assess the safety and efficacy of the switch, it also provided data on the transition method.

Figure 3 common antipsychotic switching strategies

Patients receiving olanzapine improved on several efficacy measures, although the clinical relevance was minimal. For example, their mean PANSS total score decreased 3.23 points. One patient—in the control group—was hospitalized. Those who received olanzapine preferred this agent to the IM depot formulations and chose to continue daily olanzapine therapy. Adverse events did not increase significantly while patients received IM depot injections plus olanzapine.

SWITCHING ORAL AGENTS

Clozapine. When risperidone entered the U.S. market in the 1990s, a number of patients who had been treated with clozapine were abruptly switched to risperidone. Many experienced acute symptom exacerbation,^4,5 including some whose rebound psychosis was more severe than their original symptoms. Other adverse effects—including nausea, diarrhea, vomiting, headache, restlessness, and sweating— have been attributed to cholinergic rebound caused by abruptly discontinuing clozapine.

To minimize the potential for rebound psychosis and cholinergic symptoms, taper clozapine across a minimum of 1 to 2 weeks. When you need to discontinue clozapine immediately—such as for patients experiencing serious hematologic effects—adding an anticholinergic such as benztropine may minimize the cholinergic rebound.

Risperidone. No studies have formally assessed methods for switching patients to risperidone.

Olanzapine. When switching to olanzapine, a direct switch or cross-titration tapering appear to be viable options.

In one multicenter, open-label study,² 108 patients were randomly assigned to olanzapine, 10 mg/d, after abruptly discontinuing a previous antipsychotic (direct switch) or by cross-titration tapering in a 1:1 fashion. Patients in the crosstitration group started olanzapine and discontinued their original antipsychotics across 2 weeks. Olanzapine dosages were adjusted as needed from 5 to 20 mg/d.

At study entry, approximately 95% of subjects in the direct-switch group and 85% in the crosstitration taper group were taking at least one typical antipsychotic—usually haloperidol. A switch was considered successful if a patient completed the 6-week trial without psychotic symptom worsening or EPS.

The 92 (85%) subjects who completed the study comprised similar percentages from both groups. Their scores on the PANSS total and subscales and Clinical Global Impression (CGI) scale also were similar.

The most common adverse events were somnolence, insomnia, and headache in the directs-witch group (all 11%), and somnolence (15%), headache (9%), insomnia (7%), and increased appetite (7%) in the cross-titration group. Differences in these percentages were not statistically significant.

EPS and akathisia improved significantly in both groups (p< 0.01) after switching to olanzapine. Thirteen (24%) patients in the direct-switch group and 17 (32%) in the cross-titration taper group required at least one dose of benztropine. Use of concomitant medications was similar.

Quetiapine can be abruptly discontinued with minimal risk of adverse events when initiating another antipsychotic.

Cutler et al⁶ switched 50 stable patients who had been treated with risperidone, thioridazine, haloperidol, or haloperidol plus benztropine. The original antipsychotics were abruptly discontinued, and quetiapine was initiated in a doseescalating fashion and then maintained at 300 mg/d for 12 days. After that, quetiapine was abruptly discontinued and patients were assessed for side effects, including EPS.

Most patients’ BPRS or CGI-Severity of Illness scores did not change significantly. Two patients (4%) experienced psychotic relapse during the switch. The authors speculated that these relapses might have been related to subtherapeutic quetiapine dosing. Transient nausea and vomiting were reported after quetiapine was discontinued.

Ziprasidone. When switching from another antipsychotic to ziprasidone, all three strategies appear well tolerated and maintain symptom control.

Using randomized, open-label trials, Weiden et al⁷ investigated strategies for switching patients to ziprasidone from olanzapine, risperidone, and traditional antipsychotics. All participants were diagnosed with schizophrenia or schizoaffective disorder and had experienced partial or inadequate response or side effects with their original antipsychotics.

Patients were assigned to one of three switching strategies:

• abruptly discontinue the initial antipsychotic
• decrease the initial antipsychotic’s dosage by 50% for 1 week, then discontinue it
• gradually taper the initial antipsychotic, so that subjects received 100% for 3 days of ziprasidone treatment, 50% for the next 4 days, and none thereafter.

For all three strategies, ziprasidone was started at 80 mg/d for 2 days, with dosing adjusted as needed to 40 to 160 mg/d.

All patients’ total score and positive and negative PANSS subscale scores improved significantly (p<0.01) across 6 weeks, although these data represent symptom changes after switching to ziprasidone. No efficacy or safety data were reported during switching. The authors concluded that patients could switch successfully to ziprasidone over a relatively short period using a variety of methods.

In another study, Stip⁸ switched 54 patients to ziprasidone from haloperidol. All received ziprasidone, 40 mg bid for 2 days and then 80 mg bid. Haloperidol was discontinued:

• immediately on day 1
• after the dosage was decreased by 50% for 7 days
• or after continuing the full dosage for 2 days, then taking 50% of the initial dosage for 5 days.

All patients maintained symptom control while switching, and 40 of 54 completed the trial. Among responders, BPRS and CGI scores improved significantly across 6 weeks, and EPS improved as expected.

Aripiprazole. Direct-switch and cross-titration tapering methods appear to be effective and welltolerated when switching stable patients to aripiprazole.

In an 8-week, randomized, open-label trial, Casey et al⁹ switched 311 outpatients with schizophrenia or schizoaffective disorder to aripiprazole. The patients—who had been taking stable dosages of haloperidol, chlorpromazine, risperidone, or olanzapine for at least 1 month—were randomly assigned to three groups:

• group 1 immediately discontinued the previous antipsychotic and started aripiprazole, 30 mg/d
• group 2 started aripiprazole, 30 mg/d, and discontinued the previous antipsychotic across 2 weeks
• group 3 started aripiprazole (10 mg/d in week 1, 20 mg/d in week 2, and 30 mg/d in week 3) and tapered the previous antipsychotic (50% less in week 1, another 50% less in week 2, then discontinued).

Investigators assessed treatment efficacy using the PANSS and CGI at baseline and weeks 4 and 8. They questioned patients about adverse events at each follow-up visit.

Nearly three-fourths (72%) of patients completed the trial. Discontinuation rates were 31% in group 1, 34% in group 2, and 19% in group 3. Efficacy, safety, tolerability, and incidence of discontinuation because of worsening psychosis were comparable across groups.

Similar percentages of patients in each group reported one or more adverse event (89%, 89%, and 81% for groups 1, 2, and 3, respectively). Most adverse events were described as mild to moderate. Insomnia was reported most frequently. Other adverse effects that occurred in >10% of subjects included nausea, akathisia, anxiety, psychosis, headache (groups 2 and 3), somnolence, lightheadedness (groups 1 and 2) vomiting (group 2 only), agitation (group 3 only), and diarrhea (group 2 only).

Seven patients were hospitalized for serious adverse events—usually worsening psychosis. Hospitalization rates were comparable among the three groups.

All groups improved slightly on the Barnes Akathisia Scale, Simpson Angus Rating Scale, and Abnormal Involuntary Movement Scale. Few patients in each group required benztropine (2%, 4%, and 7% for groups 1, 2 and 3, respectively).

Related resources

• Borison RL. Changing antipsychotic medication: guidelines on the transition to treatment with risperidone. The Consensus Study Group on Risperidone Dosing. Clin Ther 1996;18(4):592-607.

Drug brand names

• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Winans is a consultant for Bristol-Myers Squibb Co. and is a speaker for Pfizer Inc., Abbott Laboratories, and Bristol-Myers Squibb Co.

Today’s physician needs to stay abreast of ever-changing prescribing information. Print and CD-ROM drug guides, long regarded as the gold standard in clinical reference, are constrained by press deadlines and start becoming outdated upon publication.

Electronic drug guides, available online or via handheld computers, are updated regularly and provide real-time developments about drug alerts, safety recalls, and changes in prescribing information.

Online drug guides

Benefits. Drug-drug interactions can be checked with a couple of clicks. By contrast, scanning printed lists of interactions for each medication could cost you valuable time.

Some electronic guides list the medication’s cost and formulary availability in addition to dosing, indication(s), drug mechanism, precautions, and adverse reactions.

Drawbacks. Depending on the type of subscription, access to an online drug reference may be restricted. Many institutions purchase access to online references, which are readily available at any terminal or computer in the hospital network. When attempting to access the resource from an outside computer, however, access is denied.

Some facilities circumvent this problem by providing a proxy server to relay access or use a virtual private network to connect to the hospital network. Individual subscriptions, which provide access via password, do not have this limitation.

The table lists benefits and drawbacks of individual programs.

Drug guides for handhelds

Drug guides for personal digital assistants are more accessible, but many handhelds lack sufficient memory for the guides’ databases and programs.

Some programs, such as the American Hospital Formulary Service guide and Physicians’ Desk Reference, can operate from external memory-such as secure digital or compact flash-thus preserving the limited main memory of most handhelds. In working this way, however, these programs’ databases often cannot be updated automatically and require user intervention.

The handheld’s small screen size is another potential drawback. The better handheld drug guides are designed to maximize limited screen space and promote easy navigation by utilizing hyperlinks to jump to related information or pop up windows to provide additional information. Ideally, content should be succinct yet offer sufficient detail.

How to choose a drug reference guide

Electronic drug reference guides vary greatly in their detail, organization of content, and ease of navigation and downloading. To decide which drug reference guide is right for you, try several demonstration versions:

• Compare different features. Look for sufficient content and intuitive navigation.
• Find out if pre-made patient education brochures are available for printing.
• For handheld guides, determine how much memory is required by the program and databases, how often they must be updated, and whether they can be stored on external memory.
• Ask if discounts are offered for purchases during trade shows or for a combination purchase of the guide’s online and handheld versions.

The following table, which lists quick reviews of reference guide demonstration products, can help you explore the options.

If you have any questions about these products or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to: [email protected].

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

Today’s physician needs to stay abreast of ever-changing prescribing information. Print and CD-ROM drug guides, long regarded as the gold standard in clinical reference, are constrained by press deadlines and start becoming outdated upon publication.

Electronic drug guides, available online or via handheld computers, are updated regularly and provide real-time developments about drug alerts, safety recalls, and changes in prescribing information.

Online drug guides

Benefits. Drug-drug interactions can be checked with a couple of clicks. By contrast, scanning printed lists of interactions for each medication could cost you valuable time.

Some electronic guides list the medication’s cost and formulary availability in addition to dosing, indication(s), drug mechanism, precautions, and adverse reactions.

Drawbacks. Depending on the type of subscription, access to an online drug reference may be restricted. Many institutions purchase access to online references, which are readily available at any terminal or computer in the hospital network. When attempting to access the resource from an outside computer, however, access is denied.

Some facilities circumvent this problem by providing a proxy server to relay access or use a virtual private network to connect to the hospital network. Individual subscriptions, which provide access via password, do not have this limitation.

The table lists benefits and drawbacks of individual programs.

Drug guides for handhelds

Drug guides for personal digital assistants are more accessible, but many handhelds lack sufficient memory for the guides’ databases and programs.

Some programs, such as the American Hospital Formulary Service guide and Physicians’ Desk Reference, can operate from external memory-such as secure digital or compact flash-thus preserving the limited main memory of most handhelds. In working this way, however, these programs’ databases often cannot be updated automatically and require user intervention.

The handheld’s small screen size is another potential drawback. The better handheld drug guides are designed to maximize limited screen space and promote easy navigation by utilizing hyperlinks to jump to related information or pop up windows to provide additional information. Ideally, content should be succinct yet offer sufficient detail.

How to choose a drug reference guide

Electronic drug reference guides vary greatly in their detail, organization of content, and ease of navigation and downloading. To decide which drug reference guide is right for you, try several demonstration versions:

• Compare different features. Look for sufficient content and intuitive navigation.
• Find out if pre-made patient education brochures are available for printing.
• For handheld guides, determine how much memory is required by the program and databases, how often they must be updated, and whether they can be stored on external memory.
• Ask if discounts are offered for purchases during trade shows or for a combination purchase of the guide’s online and handheld versions.

The following table, which lists quick reviews of reference guide demonstration products, can help you explore the options.

If you have any questions about these products or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to: [email protected].

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

Today’s physician needs to stay abreast of ever-changing prescribing information. Print and CD-ROM drug guides, long regarded as the gold standard in clinical reference, are constrained by press deadlines and start becoming outdated upon publication.

Electronic drug guides, available online or via handheld computers, are updated regularly and provide real-time developments about drug alerts, safety recalls, and changes in prescribing information.

Online drug guides

Benefits. Drug-drug interactions can be checked with a couple of clicks. By contrast, scanning printed lists of interactions for each medication could cost you valuable time.

Some electronic guides list the medication’s cost and formulary availability in addition to dosing, indication(s), drug mechanism, precautions, and adverse reactions.

Drawbacks. Depending on the type of subscription, access to an online drug reference may be restricted. Many institutions purchase access to online references, which are readily available at any terminal or computer in the hospital network. When attempting to access the resource from an outside computer, however, access is denied.

Some facilities circumvent this problem by providing a proxy server to relay access or use a virtual private network to connect to the hospital network. Individual subscriptions, which provide access via password, do not have this limitation.

The table lists benefits and drawbacks of individual programs.

Drug guides for handhelds

Drug guides for personal digital assistants are more accessible, but many handhelds lack sufficient memory for the guides’ databases and programs.

Some programs, such as the American Hospital Formulary Service guide and Physicians’ Desk Reference, can operate from external memory-such as secure digital or compact flash-thus preserving the limited main memory of most handhelds. In working this way, however, these programs’ databases often cannot be updated automatically and require user intervention.

The handheld’s small screen size is another potential drawback. The better handheld drug guides are designed to maximize limited screen space and promote easy navigation by utilizing hyperlinks to jump to related information or pop up windows to provide additional information. Ideally, content should be succinct yet offer sufficient detail.

How to choose a drug reference guide

Electronic drug reference guides vary greatly in their detail, organization of content, and ease of navigation and downloading. To decide which drug reference guide is right for you, try several demonstration versions:

• Compare different features. Look for sufficient content and intuitive navigation.
• Find out if pre-made patient education brochures are available for printing.
• For handheld guides, determine how much memory is required by the program and databases, how often they must be updated, and whether they can be stored on external memory.
• Ask if discounts are offered for purchases during trade shows or for a combination purchase of the guide’s online and handheld versions.

The following table, which lists quick reviews of reference guide demonstration products, can help you explore the options.

If you have any questions about these products or comments about Psyber Psychiatry, click here to contact Dr. Luo or send an e-mail to: [email protected].

Disclosure

Dr. Luo reports no financial relationship with any company whose products are mentioned in this article. The opinions expressed by Dr. Luo in this column are his own and do not necessarily reflect those of Current Psychiatry.

Severely mentally ill patients often do not get the care they need for chronic medical conditions such as diabetes, hypertension, or hepatitis C. They may lack insurance, forget follow-up appointments, or fail to provide adequate or accurate history because of cognitive deficits. Some fear blood work or other tests, and many adhere poorly to treatment.

12 ways to expedite care

The following tips can help remove some of these roadblocks to proper care:

1. Review the patient’s records—psychiatric and medical—to obtain information the patient might not have provided.
   
2. Explain the medical problem in terms the patient understands. Describe why an evaluation or treatment is necessary.
   
3. Ask the patient’s case manager or program nurse to follow up with the patient.
   
4. Refer the patient to a family doctor or internist who participates in the patient’s insurance plan and with whom he or she is comfortable.
   
5. Remind the patient of his or her appointment, preferably that morning. If possible, have the case manager arrange transportation.
   
6. Have a family member or staff member accompany the patient on the visit if the patient expresses fear beforehand. Consider offering an anxiolytic to be taken the day of the visit as needed. Above all, be encouraging.
   
7. Write a note to the doctor about the reason for the referral. Include some history because the patient may not be able to give it, especially within a 15-minute office visit.
   
8. Order specific blood work to be drawn before the visit, if indicated. Have results sent to the doctor’s office.
   
9. Consider screening high-risk patients for hepatitis, including those with a history of IV drug use or multiple sexual partners. Do not automatically attribute liver enzyme elevations to divalproex.
   
10. Review your patient’s diet and exercise habits. Politely discourage excessive sugar and caffeine intake. I always keep some bottled water and raw vegetables on hand to model recommended habits. Many patients have limited incomes, so recommend affordable, healthy foods.
    
11. Monitor for side effects of psychotropics, such as white blood counts for patients on clozapine, liver function and platelet counts with valproate, renal and thyroid function with lithium, etc.
    
12. Don’t give up. If your patient has missed multiple doctors’ appointments, keeps insisting he or she is not sick, or repeatedly fails to comply with diet or medication, continue to be encouraging and advocate the need for proper care.
    

• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Lithium • Eskalith, Lithobid, others
  
• Valproate • Depacon
  

Severely mentally ill patients often do not get the care they need for chronic medical conditions such as diabetes, hypertension, or hepatitis C. They may lack insurance, forget follow-up appointments, or fail to provide adequate or accurate history because of cognitive deficits. Some fear blood work or other tests, and many adhere poorly to treatment.

12 ways to expedite care

The following tips can help remove some of these roadblocks to proper care:

1. Review the patient’s records—psychiatric and medical—to obtain information the patient might not have provided.
   
2. Explain the medical problem in terms the patient understands. Describe why an evaluation or treatment is necessary.
   
3. Ask the patient’s case manager or program nurse to follow up with the patient.
   
4. Refer the patient to a family doctor or internist who participates in the patient’s insurance plan and with whom he or she is comfortable.
   
5. Remind the patient of his or her appointment, preferably that morning. If possible, have the case manager arrange transportation.
   
6. Have a family member or staff member accompany the patient on the visit if the patient expresses fear beforehand. Consider offering an anxiolytic to be taken the day of the visit as needed. Above all, be encouraging.
   
7. Write a note to the doctor about the reason for the referral. Include some history because the patient may not be able to give it, especially within a 15-minute office visit.
   
8. Order specific blood work to be drawn before the visit, if indicated. Have results sent to the doctor’s office.
   
9. Consider screening high-risk patients for hepatitis, including those with a history of IV drug use or multiple sexual partners. Do not automatically attribute liver enzyme elevations to divalproex.
   
10. Review your patient’s diet and exercise habits. Politely discourage excessive sugar and caffeine intake. I always keep some bottled water and raw vegetables on hand to model recommended habits. Many patients have limited incomes, so recommend affordable, healthy foods.
    
11. Monitor for side effects of psychotropics, such as white blood counts for patients on clozapine, liver function and platelet counts with valproate, renal and thyroid function with lithium, etc.
    
12. Don’t give up. If your patient has missed multiple doctors’ appointments, keeps insisting he or she is not sick, or repeatedly fails to comply with diet or medication, continue to be encouraging and advocate the need for proper care.
    

• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Lithium • Eskalith, Lithobid, others
  
• Valproate • Depacon
  

Severely mentally ill patients often do not get the care they need for chronic medical conditions such as diabetes, hypertension, or hepatitis C. They may lack insurance, forget follow-up appointments, or fail to provide adequate or accurate history because of cognitive deficits. Some fear blood work or other tests, and many adhere poorly to treatment.

12 ways to expedite care

The following tips can help remove some of these roadblocks to proper care:

1. Review the patient’s records—psychiatric and medical—to obtain information the patient might not have provided.
   
2. Explain the medical problem in terms the patient understands. Describe why an evaluation or treatment is necessary.
   
3. Ask the patient’s case manager or program nurse to follow up with the patient.
   
4. Refer the patient to a family doctor or internist who participates in the patient’s insurance plan and with whom he or she is comfortable.
   
5. Remind the patient of his or her appointment, preferably that morning. If possible, have the case manager arrange transportation.
   
6. Have a family member or staff member accompany the patient on the visit if the patient expresses fear beforehand. Consider offering an anxiolytic to be taken the day of the visit as needed. Above all, be encouraging.
   
7. Write a note to the doctor about the reason for the referral. Include some history because the patient may not be able to give it, especially within a 15-minute office visit.
   
8. Order specific blood work to be drawn before the visit, if indicated. Have results sent to the doctor’s office.
   
9. Consider screening high-risk patients for hepatitis, including those with a history of IV drug use or multiple sexual partners. Do not automatically attribute liver enzyme elevations to divalproex.
   
10. Review your patient’s diet and exercise habits. Politely discourage excessive sugar and caffeine intake. I always keep some bottled water and raw vegetables on hand to model recommended habits. Many patients have limited incomes, so recommend affordable, healthy foods.
    
11. Monitor for side effects of psychotropics, such as white blood counts for patients on clozapine, liver function and platelet counts with valproate, renal and thyroid function with lithium, etc.
    
12. Don’t give up. If your patient has missed multiple doctors’ appointments, keeps insisting he or she is not sick, or repeatedly fails to comply with diet or medication, continue to be encouraging and advocate the need for proper care.
    

• Clozapine • Clozaril
  
• Divalproex • Depakote
  
• Lithium • Eskalith, Lithobid, others
  
• Valproate • Depacon
  

Where do you learn about new psychotropics? One source is the drug reps who come to see us all the time, but their educational materials have a marketing objective.

Current Psychiatry’s “Out of the Pipeline” offers an alernative—a source of early, unbiased information about new medications for psychiatric practice.

This month’s “Out of the Pipeline” examines sodium oxybate (Xyrem), indicated for treating cataplexy in patients with narcolepsy. Sodium oxybate is a legally manufactured form of an illegal “date rape” drug. As an orphan drug, sodium oxybate has undergone less clinical testing than is required for conventional FDA approvals. I want to know as much as possible about this medication before I prescribe it, and the article by Lois E. Krahn, MD—one of Current Psychiatry’s associate editors—is a good start.

Frankly, it is difficult to find qualified “Out of the Pipeline” authors who don’t have apparent conflicts of interest. Almost anyone who could write knowledgeably about premarket experience with a drug has participated in its clinical trials, most of which are supported by pharmaceutical companies. To address this concern, we:

• identify and invite the authors ourselves (without input from pharmaceutical companies)
• emphasize to authors the need for balance and objectivity
• disclose authors’ financial relationships with any companies whose products are mentioned or with manufacturers of competing products
• subject each article to peer review and revision before publication.

I expect more drugs will be developed with novel mechanisms of action and very specific indications. This trend will benefit our patients but increase our need for trusted advice, as in Current Psychiatry.

Where do you learn about new psychotropics? One source is the drug reps who come to see us all the time, but their educational materials have a marketing objective.

Current Psychiatry’s “Out of the Pipeline” offers an alernative—a source of early, unbiased information about new medications for psychiatric practice.

This month’s “Out of the Pipeline” examines sodium oxybate (Xyrem), indicated for treating cataplexy in patients with narcolepsy. Sodium oxybate is a legally manufactured form of an illegal “date rape” drug. As an orphan drug, sodium oxybate has undergone less clinical testing than is required for conventional FDA approvals. I want to know as much as possible about this medication before I prescribe it, and the article by Lois E. Krahn, MD—one of Current Psychiatry’s associate editors—is a good start.

Frankly, it is difficult to find qualified “Out of the Pipeline” authors who don’t have apparent conflicts of interest. Almost anyone who could write knowledgeably about premarket experience with a drug has participated in its clinical trials, most of which are supported by pharmaceutical companies. To address this concern, we:

• identify and invite the authors ourselves (without input from pharmaceutical companies)
• emphasize to authors the need for balance and objectivity
• disclose authors’ financial relationships with any companies whose products are mentioned or with manufacturers of competing products
• subject each article to peer review and revision before publication.

I expect more drugs will be developed with novel mechanisms of action and very specific indications. This trend will benefit our patients but increase our need for trusted advice, as in Current Psychiatry.

Where do you learn about new psychotropics? One source is the drug reps who come to see us all the time, but their educational materials have a marketing objective.

Current Psychiatry’s “Out of the Pipeline” offers an alernative—a source of early, unbiased information about new medications for psychiatric practice.

This month’s “Out of the Pipeline” examines sodium oxybate (Xyrem), indicated for treating cataplexy in patients with narcolepsy. Sodium oxybate is a legally manufactured form of an illegal “date rape” drug. As an orphan drug, sodium oxybate has undergone less clinical testing than is required for conventional FDA approvals. I want to know as much as possible about this medication before I prescribe it, and the article by Lois E. Krahn, MD—one of Current Psychiatry’s associate editors—is a good start.

Frankly, it is difficult to find qualified “Out of the Pipeline” authors who don’t have apparent conflicts of interest. Almost anyone who could write knowledgeably about premarket experience with a drug has participated in its clinical trials, most of which are supported by pharmaceutical companies. To address this concern, we:

• identify and invite the authors ourselves (without input from pharmaceutical companies)
• emphasize to authors the need for balance and objectivity
• disclose authors’ financial relationships with any companies whose products are mentioned or with manufacturers of competing products
• subject each article to peer review and revision before publication.

I expect more drugs will be developed with novel mechanisms of action and very specific indications. This trend will benefit our patients but increase our need for trusted advice, as in Current Psychiatry.

Assessing an adolescent for a possible substance use disorder can be streamlined by choosing age-appropriate screening tools and asking targeted questions. Based on our experience, we offer a 4-step approach to these at-risk patients¹ (Box) that focuses on:

• quantifying alcohol or drug abuse and/or dependence
• identifying and treating psychiatric comorbidity
• evaluating and addressing social influences that contribute to substance use
• assessing negative consequences associated with substance abuse.

Box

INITIAL EVALUATION

Adolescents generally do not seek substance abuse treatment but are referred because of alcohol- or drug-related legal, school, or family problems. Thus, most present for evaluation with their parents, legal guardians, or officers of the court.

We begin by finding out from parents or guardians the reasons for the evaluation, their perspectives on the adolescent’s behavior, and their expectations of treatment. Then we interview the adolescent alone, assessing for substance use and evaluating peer relationships.

Components. A typical initial evaluation takes 90 minutes to 2 hours and includes:

• psychiatric history and symptoms
• medical history
• previous hospitalizations (medical and psychiatric)
• family history
• social history.

Specifically, the assessment focuses on the reason for the evaluation, with attention to diagnostic criteria for substance use/dependence.

STEP 1: QUANTIFYING DEPENDENCE

As with adults, clinical diagnosis of substance abuse or dependence in adolescents is based on DSM-IV diagnostic criteria (Table 1). Adolescents, however, differ from adults in diagnostic presentation, risk of dependence, and patterns of substance use.

Diagnostic ‘orphans.’ DSM-IV criteria for alcohol use disorders have limitations in adolescents.² Teens who report one or two dependence symptoms and no abuse symptoms have been described as “diagnostic orphans”³—they fall short of criteria for dependence or abuse but clearly demonstrate substance use patterns. This presentation is common; in a survey of 74,008 high school students, almost 10% of 12th graders reported one or two dependence symptoms and no abuse symptoms.⁴

Risk of dependence. Adolescents who begin using alcohol or drugs develop dependence more rapidly than adults do.⁵

Patterns of use. Adolescents are more likely than adults to binge with alcohol and drugs, which may conceal the severity of their abuse. DSM-IV diagnostic criteria for substance abuse or dependence do not consider quantity of use, such as number of drinks or percent of days drinking or using drugs.

Assessment instruments. Many assessment instruments are available to explore adolescent substance use and its associated consequences. Some are described in detail and are available on the Internet. Common screening instruments that can be used for adolescent substance use are compared in Table 2.

DUSI-A and POSIT. Two self-report instruments—Drug Use Screening Inventory-Adolescents (DUSI-A)⁶ and Problem Oriented Screening Instrument for Teenagers (POSIT)⁷—can help explore alcohol or drug use in teens who admit to substance use. Anyone who endorses at least one DSM-IV abuse or dependence criterion requires further evaluation. Either test is a good starting point, and both have a built-in “lie” scale.

T-ASI and CASI. The Teen Addiction Severity Index (T-ASI)⁸ and Comprehensive Adolescent Severity Inventory (CASI)⁹ are more labor-intensive and require training to administer. These assessments are more appropriate for adolescents with extensive alcohol or drug abuse.

A-OCDS and Deas-MOCS. Our group recently developed the Adolescent Obsessive Compulsive Drinking Scale (A-OCDS)¹⁰ and the Deas-Marijuana Obsessive Compulsive Scale (Deas-MOCS).¹¹

These self-report instruments have been validated in treatment- and nontreatment-seeking adolescents and young adults in inpatient and outpatient populations. They are sensitive and specific in identifying problem drinkers and marijuana users, respectively, and are quick, useful screens to determine need for further assessment.

Toxicology is useful for initial assessment and to monitor substance use patterns during treatment.

Urine samples are used to assess marijuana, sedative/hypnotic, amphetamine, cocaine, opiate, and phencyclidine use. Alcohol may be detected in urine, but alcohol levels detected by blood and breath testing are more accurate.

Table 1

Diagnostic criteria for substance abuse and dependence

Marijuana may be detected in the urine for 3 days to 4 weeks, depending on level of use. Cocaine can be detected for 2 to 4 days in urine and longer in hair analysis.

Random screening. Adolescents who use drugs usually know how long substances can be detected, so random urine drug screening is important to treatment progress. We inform adolescents at the beginning of treatment that random screening will be performed to corroborate self-report of substance use. To ensure a reliable urine sample, same-gender staff observe while the adolescent gives the sample.

Table 2

Common screening instruments for alcohol and drug use in adolescents

STEP 2: IDENTIFYING PSYCHIATRIC COMORBIDITY

In adolescents, substance use disorder frequently goes hand-in-hand with psychiatric disorders, particularly:

• mood and anxiety disorders
• disruptive disorders (attention-deficit/hyperactivity, oppositional defiant, and conduct disorders)¹²
• and posttraumatic stress disorder.¹³

Uncontrolled psychiatric disorders may sabotage substance abuse treatment. Therefore, assess any adolescent presenting with substance use for psychiatric illness.

Did psychiatric symptoms predate or postdate substance use? The answer may suggest self-medication or a substance-induced phenomenon. This assumption does not always apply, however, as many factors affect the relationship between substance use and psychiatric disorders.

Adolescents who meet DSM-IV criteria for conduct disorder—especially those who are highly aggressive—tend to initiate substance use much earlier than adolescents without conduct disorder, and they continue their use longer.

Most adolescents with comorbid psychiatric and substance use disorders develop the psychiatric disorder first. Some report using various substances to medicate their psychiatric symptoms. Early diagnosis and treatment of the psychiatric disorder may prevent or decrease the adolescent’s substance use.

STEPS 3 AND 4: EVALUATING SOCIAL INFLUENCES AND CONSEQUENCES

Social influences that contribute to adolescent alcohol and drug abuse include family dynamics and peer relationships. Consequences include educational and legal problems. We explore these areas with the adolescents and their parents/guardians. In most cases, adolescents are honest when reporting how their alcohol or drug use has affected their lives.

What is his family like? Assess the adolescent’s family, including its structure and history of substance abuse, psychiatric illness, or trauma (Table 3). Adolescents whose parents or siblings use alcohol or drugs are at increased risk for substance use.¹⁴ To what extent this association is genetic, environmental, or both is undetermined, but the genetic influence increases as adolescents age.¹⁵

Who are her friends? Adolescents who try alcohol or drugs and continue to use them tend to have peers who use these substances.¹⁶ Moreover, the severity of adolescents’ substance use is correlated with the number of substance-using peers. To explore peer relationships, ask about:

• peer group composition, including whether peers use alcohol or drugs
• peer interactions, including the adolescent’s ability to assert him- or herself in the peer group
• markers for risky sexual behaviors related to substance use, including infection with HIV and other sexually transmitted diseases.

How is she doing in school? Inquire about the teen’s academic performance, attendance, disciplinary problems, and motivation. Even a small decline in school performance or an increase in disciplinary problems that result in suspension or expulsion can indicate substance use or other at-risk behaviors.

Poor grades or attendance problems suggest but are not the only clues to substance use. Some adolescents with good school performance engage in substance use and may be impaired in other life domains.

Has he been arrested? Substance-abusing adolescents tend to engage in delinquent behaviors, including shoplifting, vandalism, curfew violations, disorderly conduct, and drunken driving. When assessing for delinquency, ask about behaviors that did or did not result in arrest. The teen who avoided arrest for illegal activities may perceive his/her behaviors as less severe than those involving arrest, and it may help to address this denial in individual or group therapy.

Table 3

Questions to assess family influence on an adolescent’s substance use

TREATMENT

We consider any adolescent with dependence symptoms—whether or not the presentation meets full DSM-IV diagnostic criteria—to be a candidate for further assessment and treatment. Early intervention may prevent progression to substance dependence.

Effective treatments:

• are intensive and of sufficient duration to change attitude and behaviors
• are comprehensive and target multiple domains of the adolescent’s life
• are sensitive to cultural and socioeconomic realities
• involve the family
• emphasize pro-social recreational activities, such as playing sports, attending movies, camping, having lunch or dinner with peers, etc.

Inpatient or outpatient? Managed care and insurance restrictions limit many patients’ eligibility for inpatient or residential treatment, so partial hospitalization and outpatient settings have become standard for substance abuse treatment. Partial hospitalization programs vary but may entail several hours, several days per week. Outpatient treatment may encompass individual, group, and family therapy, including after-school programs.

Inpatient treatment is usually reserved for adolescents:

• who need detoxification
• with comorbid psychiatric disorders
• or who may harm themselves or others.

PSYCHOTHERAPIES

Behavioral therapy, family-based therapy, multisystematic therapy (MST), and 12-step approaches have shown efficacy in treating adolescents with substance use disorders.

Behavioral therapy. Behavioral therapy is recommended as initial treatment because substance use plays a functional role in the adolescent’s life and is learned and reinforced in the adolescent’s environment. Homework assignments and role-play are commonly used in therapy.

Three central ingredients are:

• functional analysis (identifying internal and external triggers for starting and continuing substance use)
• skills training (targeting problems identified in the functional analysis)
• and relapse prevention.

Behavioral therapy is more effective than supportive therapy in improving family relationships and school and work attendance and in decreasing substance use, as indicated by fewer positive urine toxicology screens.¹⁷

Cognitive-behavioral therapy (CBT) approaches substance use as a maladaptive response to life problems. Its goal is to teach new skills to help the adolescent recognize and avoid high-risk situations and cope with associated problems and behaviors.

In a recent study, Kaminer et al randomly assigned 82 adolescents with psychiatric and substance use disorders to 8 weeks of CBT or psychoeducational therapy (didactic or videotaped presentations of ways to address problems associated with substance use). Substance use was reduced in both treatment groups, but:

• adolescents receiving CBT had significantly fewer positive urine toxicology tests
• adolescents with comorbid conduct disorder were least likely to complete treatment or return for follow-up
• those with depressive and anxiety disorders were most likely to complete treatment.¹⁸

Family-based therapy. Two detailed reviews^19,20 demonstrate that the adolescent’s family, community, and school relationships affect his or her perceptions and behaviors. Maladaptive relationships in any of these systems may lead to high-risk behaviors. Therefore, family therapy is core to the adolescent’s treatment, regardless of what modality is chosen.

Goals of family therapy may be:

• to help the adolescent abstain from substance use
• to engage in pro-social activities
• to decrease parental denial of the adolescent’s substance use
• to decrease resistance to treatment
• treatment maintenance
• to establish or re-establish structure in the adolescent’s environment
• to improve communication in the family.

Multisystemic therapy is comprehensive and involves all systems that relate to the adolescent’s substance use, including the family, school, community, and legal system. MST requires special training and intensive supervision, so it is usually reserved for adolescents who have not benefited from other forms of treatment.²¹

12-step approaches. For adolescents, 12-step programs usually augment other treatments and are rarely used alone. Alcoholics Anonymous, Narcotics Anonymous, and other 12-step programs have been studied more extensively in adults than in adolescents.

Adolescents, who often feel invulnerable, may have difficulty accepting the 12-step doctrine of lack of control. A modified 12-step program and workbook for adolescents are available through the American Academy of Child and Adolescent Psychiatry.²²

Referral tips. If possible, refer an adolescent to a 12-step group specifically for adolescents. Teens who attend adult groups often perceive their substance use as normal, compared with the more severe and chronic patterns of some adults. Most adolescents relate better to peers with similar problems and may benefit from reminders of the negative consequences of substance use and the benefits of abstinence.

DRUG THERAPY

Drug therapy for adolescents with substance use disorders is usually considered in the context of detoxification, treating withdrawal symptoms, and treating comorbid psychiatric disorders. The same detoxification and withdrawal treatment principles used in adults apply to adolescents.

Clinical withdrawal symptoms are less common in adolescents than adults, probably because of adolescents’ binge patterns of substance use. Even so, some adolescents do experience withdrawal and may be at risk for complications if improperly treated.

Psychiatric comorbidity. To our knowledge, only two double-blind, placebo-controlled studies of drug therapy in treating adolescent substance use disorders have been published.

Depression. Deas et al²³ randomized 10 adolescents with alcohol use disorders and depression to 12 weeks of group CBT plus sertraline or placebo. Sertraline was started at 25 mg/d and titrated to a maximum of 100 mg/d. Drinks per drinking day, percent of days drinking, and Hamilton Rating Scale for Depression scores declined similarly in both groups.

Drinking decreased significantly from baseline (by an average 4.7 drinks), and adolescents in both groups no longer met DSM-IV criteria for depression at the end of treatment. CBT’s effectiveness in treating alcohol use disorders and depression might have concealed any difference in effect between sertaline and placebo.

Bipolar disorder. Geller et al²⁴ randomly assigned 25 adolescents with bipolar disorder and substance dependence to lithium or placebo for 6 weeks. Lithium was started as an evening dose of 600 mg and titrated to achieve a lithium blood level of 0.9 to 1.3 mEq/L. Among the 21 adolescents who completed the trial, those receiving lithium had significantly fewer positive urine toxicology screens and higher clinical global assessment of function scores.

Related resources

• National Clearinghouse for Alcohol and Drug Information, Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services. www.health.org/govpubs/bkd306/31k.aspx
• National Institute on Alcohol Abuse and Alcoholism (assessment instruments). www.niaaa.nih.gov/publications/instable.htm
• Deas D, Thomas SE. An overview of controlled studies of adolescent substance abuse treatment. Am J Addict 2001;10:178-89.

Drug brand names

• Sertraline • Zoloft

Disclosure

Dr. Deas receives grant support from Pfizer, Inc. and the National Institute of Alcohol Abuse and Alcoholism.

Dr. Upadhyaya receives grant support from the National Institute of Drug Abuse and GlaxoSmithKline.

Acknowledgment

The authors wish to thank Alva Blair for assistance with preparing this manuscript and Natalie Johnson, MA, Kess Mughelli, BS, and Lakeleia Middleton-Robinson, MA, for technical support.

Assessing an adolescent for a possible substance use disorder can be streamlined by choosing age-appropriate screening tools and asking targeted questions. Based on our experience, we offer a 4-step approach to these at-risk patients¹ (Box) that focuses on:

• quantifying alcohol or drug abuse and/or dependence
• identifying and treating psychiatric comorbidity
• evaluating and addressing social influences that contribute to substance use
• assessing negative consequences associated with substance abuse.

Box

INITIAL EVALUATION

Adolescents generally do not seek substance abuse treatment but are referred because of alcohol- or drug-related legal, school, or family problems. Thus, most present for evaluation with their parents, legal guardians, or officers of the court.

We begin by finding out from parents or guardians the reasons for the evaluation, their perspectives on the adolescent’s behavior, and their expectations of treatment. Then we interview the adolescent alone, assessing for substance use and evaluating peer relationships.

Components. A typical initial evaluation takes 90 minutes to 2 hours and includes:

• psychiatric history and symptoms
• medical history
• previous hospitalizations (medical and psychiatric)
• family history
• social history.

Specifically, the assessment focuses on the reason for the evaluation, with attention to diagnostic criteria for substance use/dependence.

STEP 1: QUANTIFYING DEPENDENCE

As with adults, clinical diagnosis of substance abuse or dependence in adolescents is based on DSM-IV diagnostic criteria (Table 1). Adolescents, however, differ from adults in diagnostic presentation, risk of dependence, and patterns of substance use.

Diagnostic ‘orphans.’ DSM-IV criteria for alcohol use disorders have limitations in adolescents.² Teens who report one or two dependence symptoms and no abuse symptoms have been described as “diagnostic orphans”³—they fall short of criteria for dependence or abuse but clearly demonstrate substance use patterns. This presentation is common; in a survey of 74,008 high school students, almost 10% of 12th graders reported one or two dependence symptoms and no abuse symptoms.⁴

Risk of dependence. Adolescents who begin using alcohol or drugs develop dependence more rapidly than adults do.⁵

Patterns of use. Adolescents are more likely than adults to binge with alcohol and drugs, which may conceal the severity of their abuse. DSM-IV diagnostic criteria for substance abuse or dependence do not consider quantity of use, such as number of drinks or percent of days drinking or using drugs.

Assessment instruments. Many assessment instruments are available to explore adolescent substance use and its associated consequences. Some are described in detail and are available on the Internet. Common screening instruments that can be used for adolescent substance use are compared in Table 2.

DUSI-A and POSIT. Two self-report instruments—Drug Use Screening Inventory-Adolescents (DUSI-A)⁶ and Problem Oriented Screening Instrument for Teenagers (POSIT)⁷—can help explore alcohol or drug use in teens who admit to substance use. Anyone who endorses at least one DSM-IV abuse or dependence criterion requires further evaluation. Either test is a good starting point, and both have a built-in “lie” scale.

T-ASI and CASI. The Teen Addiction Severity Index (T-ASI)⁸ and Comprehensive Adolescent Severity Inventory (CASI)⁹ are more labor-intensive and require training to administer. These assessments are more appropriate for adolescents with extensive alcohol or drug abuse.

A-OCDS and Deas-MOCS. Our group recently developed the Adolescent Obsessive Compulsive Drinking Scale (A-OCDS)¹⁰ and the Deas-Marijuana Obsessive Compulsive Scale (Deas-MOCS).¹¹

These self-report instruments have been validated in treatment- and nontreatment-seeking adolescents and young adults in inpatient and outpatient populations. They are sensitive and specific in identifying problem drinkers and marijuana users, respectively, and are quick, useful screens to determine need for further assessment.

Toxicology is useful for initial assessment and to monitor substance use patterns during treatment.

Urine samples are used to assess marijuana, sedative/hypnotic, amphetamine, cocaine, opiate, and phencyclidine use. Alcohol may be detected in urine, but alcohol levels detected by blood and breath testing are more accurate.

Table 1

Diagnostic criteria for substance abuse and dependence

Marijuana may be detected in the urine for 3 days to 4 weeks, depending on level of use. Cocaine can be detected for 2 to 4 days in urine and longer in hair analysis.

Random screening. Adolescents who use drugs usually know how long substances can be detected, so random urine drug screening is important to treatment progress. We inform adolescents at the beginning of treatment that random screening will be performed to corroborate self-report of substance use. To ensure a reliable urine sample, same-gender staff observe while the adolescent gives the sample.

Table 2

Common screening instruments for alcohol and drug use in adolescents

STEP 2: IDENTIFYING PSYCHIATRIC COMORBIDITY

In adolescents, substance use disorder frequently goes hand-in-hand with psychiatric disorders, particularly:

• mood and anxiety disorders
• disruptive disorders (attention-deficit/hyperactivity, oppositional defiant, and conduct disorders)¹²
• and posttraumatic stress disorder.¹³

Uncontrolled psychiatric disorders may sabotage substance abuse treatment. Therefore, assess any adolescent presenting with substance use for psychiatric illness.

Did psychiatric symptoms predate or postdate substance use? The answer may suggest self-medication or a substance-induced phenomenon. This assumption does not always apply, however, as many factors affect the relationship between substance use and psychiatric disorders.

Adolescents who meet DSM-IV criteria for conduct disorder—especially those who are highly aggressive—tend to initiate substance use much earlier than adolescents without conduct disorder, and they continue their use longer.

Most adolescents with comorbid psychiatric and substance use disorders develop the psychiatric disorder first. Some report using various substances to medicate their psychiatric symptoms. Early diagnosis and treatment of the psychiatric disorder may prevent or decrease the adolescent’s substance use.

STEPS 3 AND 4: EVALUATING SOCIAL INFLUENCES AND CONSEQUENCES

Social influences that contribute to adolescent alcohol and drug abuse include family dynamics and peer relationships. Consequences include educational and legal problems. We explore these areas with the adolescents and their parents/guardians. In most cases, adolescents are honest when reporting how their alcohol or drug use has affected their lives.

What is his family like? Assess the adolescent’s family, including its structure and history of substance abuse, psychiatric illness, or trauma (Table 3). Adolescents whose parents or siblings use alcohol or drugs are at increased risk for substance use.¹⁴ To what extent this association is genetic, environmental, or both is undetermined, but the genetic influence increases as adolescents age.¹⁵

Who are her friends? Adolescents who try alcohol or drugs and continue to use them tend to have peers who use these substances.¹⁶ Moreover, the severity of adolescents’ substance use is correlated with the number of substance-using peers. To explore peer relationships, ask about:

• peer group composition, including whether peers use alcohol or drugs
• peer interactions, including the adolescent’s ability to assert him- or herself in the peer group
• markers for risky sexual behaviors related to substance use, including infection with HIV and other sexually transmitted diseases.

How is she doing in school? Inquire about the teen’s academic performance, attendance, disciplinary problems, and motivation. Even a small decline in school performance or an increase in disciplinary problems that result in suspension or expulsion can indicate substance use or other at-risk behaviors.

Poor grades or attendance problems suggest but are not the only clues to substance use. Some adolescents with good school performance engage in substance use and may be impaired in other life domains.

Has he been arrested? Substance-abusing adolescents tend to engage in delinquent behaviors, including shoplifting, vandalism, curfew violations, disorderly conduct, and drunken driving. When assessing for delinquency, ask about behaviors that did or did not result in arrest. The teen who avoided arrest for illegal activities may perceive his/her behaviors as less severe than those involving arrest, and it may help to address this denial in individual or group therapy.

Table 3

Questions to assess family influence on an adolescent’s substance use

TREATMENT

We consider any adolescent with dependence symptoms—whether or not the presentation meets full DSM-IV diagnostic criteria—to be a candidate for further assessment and treatment. Early intervention may prevent progression to substance dependence.

Effective treatments:

• are intensive and of sufficient duration to change attitude and behaviors
• are comprehensive and target multiple domains of the adolescent’s life
• are sensitive to cultural and socioeconomic realities
• involve the family
• emphasize pro-social recreational activities, such as playing sports, attending movies, camping, having lunch or dinner with peers, etc.

Inpatient or outpatient? Managed care and insurance restrictions limit many patients’ eligibility for inpatient or residential treatment, so partial hospitalization and outpatient settings have become standard for substance abuse treatment. Partial hospitalization programs vary but may entail several hours, several days per week. Outpatient treatment may encompass individual, group, and family therapy, including after-school programs.

Inpatient treatment is usually reserved for adolescents:

• who need detoxification
• with comorbid psychiatric disorders
• or who may harm themselves or others.

PSYCHOTHERAPIES

Behavioral therapy, family-based therapy, multisystematic therapy (MST), and 12-step approaches have shown efficacy in treating adolescents with substance use disorders.

Behavioral therapy. Behavioral therapy is recommended as initial treatment because substance use plays a functional role in the adolescent’s life and is learned and reinforced in the adolescent’s environment. Homework assignments and role-play are commonly used in therapy.

Three central ingredients are:

• functional analysis (identifying internal and external triggers for starting and continuing substance use)
• skills training (targeting problems identified in the functional analysis)
• and relapse prevention.

Behavioral therapy is more effective than supportive therapy in improving family relationships and school and work attendance and in decreasing substance use, as indicated by fewer positive urine toxicology screens.¹⁷

Cognitive-behavioral therapy (CBT) approaches substance use as a maladaptive response to life problems. Its goal is to teach new skills to help the adolescent recognize and avoid high-risk situations and cope with associated problems and behaviors.

In a recent study, Kaminer et al randomly assigned 82 adolescents with psychiatric and substance use disorders to 8 weeks of CBT or psychoeducational therapy (didactic or videotaped presentations of ways to address problems associated with substance use). Substance use was reduced in both treatment groups, but:

• adolescents receiving CBT had significantly fewer positive urine toxicology tests
• adolescents with comorbid conduct disorder were least likely to complete treatment or return for follow-up
• those with depressive and anxiety disorders were most likely to complete treatment.¹⁸

Family-based therapy. Two detailed reviews^19,20 demonstrate that the adolescent’s family, community, and school relationships affect his or her perceptions and behaviors. Maladaptive relationships in any of these systems may lead to high-risk behaviors. Therefore, family therapy is core to the adolescent’s treatment, regardless of what modality is chosen.

Goals of family therapy may be:

• to help the adolescent abstain from substance use
• to engage in pro-social activities
• to decrease parental denial of the adolescent’s substance use
• to decrease resistance to treatment
• treatment maintenance
• to establish or re-establish structure in the adolescent’s environment
• to improve communication in the family.

Multisystemic therapy is comprehensive and involves all systems that relate to the adolescent’s substance use, including the family, school, community, and legal system. MST requires special training and intensive supervision, so it is usually reserved for adolescents who have not benefited from other forms of treatment.²¹

12-step approaches. For adolescents, 12-step programs usually augment other treatments and are rarely used alone. Alcoholics Anonymous, Narcotics Anonymous, and other 12-step programs have been studied more extensively in adults than in adolescents.

Adolescents, who often feel invulnerable, may have difficulty accepting the 12-step doctrine of lack of control. A modified 12-step program and workbook for adolescents are available through the American Academy of Child and Adolescent Psychiatry.²²

Referral tips. If possible, refer an adolescent to a 12-step group specifically for adolescents. Teens who attend adult groups often perceive their substance use as normal, compared with the more severe and chronic patterns of some adults. Most adolescents relate better to peers with similar problems and may benefit from reminders of the negative consequences of substance use and the benefits of abstinence.

DRUG THERAPY

Drug therapy for adolescents with substance use disorders is usually considered in the context of detoxification, treating withdrawal symptoms, and treating comorbid psychiatric disorders. The same detoxification and withdrawal treatment principles used in adults apply to adolescents.

Clinical withdrawal symptoms are less common in adolescents than adults, probably because of adolescents’ binge patterns of substance use. Even so, some adolescents do experience withdrawal and may be at risk for complications if improperly treated.

Psychiatric comorbidity. To our knowledge, only two double-blind, placebo-controlled studies of drug therapy in treating adolescent substance use disorders have been published.

Depression. Deas et al²³ randomized 10 adolescents with alcohol use disorders and depression to 12 weeks of group CBT plus sertraline or placebo. Sertraline was started at 25 mg/d and titrated to a maximum of 100 mg/d. Drinks per drinking day, percent of days drinking, and Hamilton Rating Scale for Depression scores declined similarly in both groups.

Drinking decreased significantly from baseline (by an average 4.7 drinks), and adolescents in both groups no longer met DSM-IV criteria for depression at the end of treatment. CBT’s effectiveness in treating alcohol use disorders and depression might have concealed any difference in effect between sertaline and placebo.

Bipolar disorder. Geller et al²⁴ randomly assigned 25 adolescents with bipolar disorder and substance dependence to lithium or placebo for 6 weeks. Lithium was started as an evening dose of 600 mg and titrated to achieve a lithium blood level of 0.9 to 1.3 mEq/L. Among the 21 adolescents who completed the trial, those receiving lithium had significantly fewer positive urine toxicology screens and higher clinical global assessment of function scores.

Related resources

• National Clearinghouse for Alcohol and Drug Information, Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services. www.health.org/govpubs/bkd306/31k.aspx
• National Institute on Alcohol Abuse and Alcoholism (assessment instruments). www.niaaa.nih.gov/publications/instable.htm
• Deas D, Thomas SE. An overview of controlled studies of adolescent substance abuse treatment. Am J Addict 2001;10:178-89.

Drug brand names

• Sertraline • Zoloft

Disclosure

Dr. Deas receives grant support from Pfizer, Inc. and the National Institute of Alcohol Abuse and Alcoholism.

Dr. Upadhyaya receives grant support from the National Institute of Drug Abuse and GlaxoSmithKline.

Acknowledgment

The authors wish to thank Alva Blair for assistance with preparing this manuscript and Natalie Johnson, MA, Kess Mughelli, BS, and Lakeleia Middleton-Robinson, MA, for technical support.

Assessing an adolescent for a possible substance use disorder can be streamlined by choosing age-appropriate screening tools and asking targeted questions. Based on our experience, we offer a 4-step approach to these at-risk patients¹ (Box) that focuses on:

• quantifying alcohol or drug abuse and/or dependence
• identifying and treating psychiatric comorbidity
• evaluating and addressing social influences that contribute to substance use
• assessing negative consequences associated with substance abuse.

Box

INITIAL EVALUATION

Adolescents generally do not seek substance abuse treatment but are referred because of alcohol- or drug-related legal, school, or family problems. Thus, most present for evaluation with their parents, legal guardians, or officers of the court.

We begin by finding out from parents or guardians the reasons for the evaluation, their perspectives on the adolescent’s behavior, and their expectations of treatment. Then we interview the adolescent alone, assessing for substance use and evaluating peer relationships.

Components. A typical initial evaluation takes 90 minutes to 2 hours and includes:

• psychiatric history and symptoms
• medical history
• previous hospitalizations (medical and psychiatric)
• family history
• social history.

Specifically, the assessment focuses on the reason for the evaluation, with attention to diagnostic criteria for substance use/dependence.

STEP 1: QUANTIFYING DEPENDENCE

As with adults, clinical diagnosis of substance abuse or dependence in adolescents is based on DSM-IV diagnostic criteria (Table 1). Adolescents, however, differ from adults in diagnostic presentation, risk of dependence, and patterns of substance use.

Diagnostic ‘orphans.’ DSM-IV criteria for alcohol use disorders have limitations in adolescents.² Teens who report one or two dependence symptoms and no abuse symptoms have been described as “diagnostic orphans”³—they fall short of criteria for dependence or abuse but clearly demonstrate substance use patterns. This presentation is common; in a survey of 74,008 high school students, almost 10% of 12th graders reported one or two dependence symptoms and no abuse symptoms.⁴

Risk of dependence. Adolescents who begin using alcohol or drugs develop dependence more rapidly than adults do.⁵

Patterns of use. Adolescents are more likely than adults to binge with alcohol and drugs, which may conceal the severity of their abuse. DSM-IV diagnostic criteria for substance abuse or dependence do not consider quantity of use, such as number of drinks or percent of days drinking or using drugs.

Assessment instruments. Many assessment instruments are available to explore adolescent substance use and its associated consequences. Some are described in detail and are available on the Internet. Common screening instruments that can be used for adolescent substance use are compared in Table 2.

DUSI-A and POSIT. Two self-report instruments—Drug Use Screening Inventory-Adolescents (DUSI-A)⁶ and Problem Oriented Screening Instrument for Teenagers (POSIT)⁷—can help explore alcohol or drug use in teens who admit to substance use. Anyone who endorses at least one DSM-IV abuse or dependence criterion requires further evaluation. Either test is a good starting point, and both have a built-in “lie” scale.

T-ASI and CASI. The Teen Addiction Severity Index (T-ASI)⁸ and Comprehensive Adolescent Severity Inventory (CASI)⁹ are more labor-intensive and require training to administer. These assessments are more appropriate for adolescents with extensive alcohol or drug abuse.

A-OCDS and Deas-MOCS. Our group recently developed the Adolescent Obsessive Compulsive Drinking Scale (A-OCDS)¹⁰ and the Deas-Marijuana Obsessive Compulsive Scale (Deas-MOCS).¹¹

These self-report instruments have been validated in treatment- and nontreatment-seeking adolescents and young adults in inpatient and outpatient populations. They are sensitive and specific in identifying problem drinkers and marijuana users, respectively, and are quick, useful screens to determine need for further assessment.

Toxicology is useful for initial assessment and to monitor substance use patterns during treatment.

Urine samples are used to assess marijuana, sedative/hypnotic, amphetamine, cocaine, opiate, and phencyclidine use. Alcohol may be detected in urine, but alcohol levels detected by blood and breath testing are more accurate.

Table 1

Diagnostic criteria for substance abuse and dependence

Marijuana may be detected in the urine for 3 days to 4 weeks, depending on level of use. Cocaine can be detected for 2 to 4 days in urine and longer in hair analysis.

Random screening. Adolescents who use drugs usually know how long substances can be detected, so random urine drug screening is important to treatment progress. We inform adolescents at the beginning of treatment that random screening will be performed to corroborate self-report of substance use. To ensure a reliable urine sample, same-gender staff observe while the adolescent gives the sample.

Table 2

Common screening instruments for alcohol and drug use in adolescents

STEP 2: IDENTIFYING PSYCHIATRIC COMORBIDITY

In adolescents, substance use disorder frequently goes hand-in-hand with psychiatric disorders, particularly:

• mood and anxiety disorders
• disruptive disorders (attention-deficit/hyperactivity, oppositional defiant, and conduct disorders)¹²
• and posttraumatic stress disorder.¹³

Uncontrolled psychiatric disorders may sabotage substance abuse treatment. Therefore, assess any adolescent presenting with substance use for psychiatric illness.

Did psychiatric symptoms predate or postdate substance use? The answer may suggest self-medication or a substance-induced phenomenon. This assumption does not always apply, however, as many factors affect the relationship between substance use and psychiatric disorders.

Adolescents who meet DSM-IV criteria for conduct disorder—especially those who are highly aggressive—tend to initiate substance use much earlier than adolescents without conduct disorder, and they continue their use longer.

Most adolescents with comorbid psychiatric and substance use disorders develop the psychiatric disorder first. Some report using various substances to medicate their psychiatric symptoms. Early diagnosis and treatment of the psychiatric disorder may prevent or decrease the adolescent’s substance use.

STEPS 3 AND 4: EVALUATING SOCIAL INFLUENCES AND CONSEQUENCES

Social influences that contribute to adolescent alcohol and drug abuse include family dynamics and peer relationships. Consequences include educational and legal problems. We explore these areas with the adolescents and their parents/guardians. In most cases, adolescents are honest when reporting how their alcohol or drug use has affected their lives.

What is his family like? Assess the adolescent’s family, including its structure and history of substance abuse, psychiatric illness, or trauma (Table 3). Adolescents whose parents or siblings use alcohol or drugs are at increased risk for substance use.¹⁴ To what extent this association is genetic, environmental, or both is undetermined, but the genetic influence increases as adolescents age.¹⁵

Who are her friends? Adolescents who try alcohol or drugs and continue to use them tend to have peers who use these substances.¹⁶ Moreover, the severity of adolescents’ substance use is correlated with the number of substance-using peers. To explore peer relationships, ask about:

• peer group composition, including whether peers use alcohol or drugs
• peer interactions, including the adolescent’s ability to assert him- or herself in the peer group
• markers for risky sexual behaviors related to substance use, including infection with HIV and other sexually transmitted diseases.

How is she doing in school? Inquire about the teen’s academic performance, attendance, disciplinary problems, and motivation. Even a small decline in school performance or an increase in disciplinary problems that result in suspension or expulsion can indicate substance use or other at-risk behaviors.

Poor grades or attendance problems suggest but are not the only clues to substance use. Some adolescents with good school performance engage in substance use and may be impaired in other life domains.

Has he been arrested? Substance-abusing adolescents tend to engage in delinquent behaviors, including shoplifting, vandalism, curfew violations, disorderly conduct, and drunken driving. When assessing for delinquency, ask about behaviors that did or did not result in arrest. The teen who avoided arrest for illegal activities may perceive his/her behaviors as less severe than those involving arrest, and it may help to address this denial in individual or group therapy.

Table 3

Questions to assess family influence on an adolescent’s substance use

TREATMENT

We consider any adolescent with dependence symptoms—whether or not the presentation meets full DSM-IV diagnostic criteria—to be a candidate for further assessment and treatment. Early intervention may prevent progression to substance dependence.

Effective treatments:

• are intensive and of sufficient duration to change attitude and behaviors
• are comprehensive and target multiple domains of the adolescent’s life
• are sensitive to cultural and socioeconomic realities
• involve the family
• emphasize pro-social recreational activities, such as playing sports, attending movies, camping, having lunch or dinner with peers, etc.

Inpatient or outpatient? Managed care and insurance restrictions limit many patients’ eligibility for inpatient or residential treatment, so partial hospitalization and outpatient settings have become standard for substance abuse treatment. Partial hospitalization programs vary but may entail several hours, several days per week. Outpatient treatment may encompass individual, group, and family therapy, including after-school programs.

Inpatient treatment is usually reserved for adolescents:

• who need detoxification
• with comorbid psychiatric disorders
• or who may harm themselves or others.

PSYCHOTHERAPIES

Behavioral therapy, family-based therapy, multisystematic therapy (MST), and 12-step approaches have shown efficacy in treating adolescents with substance use disorders.

Behavioral therapy. Behavioral therapy is recommended as initial treatment because substance use plays a functional role in the adolescent’s life and is learned and reinforced in the adolescent’s environment. Homework assignments and role-play are commonly used in therapy.

Three central ingredients are:

• functional analysis (identifying internal and external triggers for starting and continuing substance use)
• skills training (targeting problems identified in the functional analysis)
• and relapse prevention.

Behavioral therapy is more effective than supportive therapy in improving family relationships and school and work attendance and in decreasing substance use, as indicated by fewer positive urine toxicology screens.¹⁷

Cognitive-behavioral therapy (CBT) approaches substance use as a maladaptive response to life problems. Its goal is to teach new skills to help the adolescent recognize and avoid high-risk situations and cope with associated problems and behaviors.

In a recent study, Kaminer et al randomly assigned 82 adolescents with psychiatric and substance use disorders to 8 weeks of CBT or psychoeducational therapy (didactic or videotaped presentations of ways to address problems associated with substance use). Substance use was reduced in both treatment groups, but:

• adolescents receiving CBT had significantly fewer positive urine toxicology tests
• adolescents with comorbid conduct disorder were least likely to complete treatment or return for follow-up
• those with depressive and anxiety disorders were most likely to complete treatment.¹⁸

Family-based therapy. Two detailed reviews^19,20 demonstrate that the adolescent’s family, community, and school relationships affect his or her perceptions and behaviors. Maladaptive relationships in any of these systems may lead to high-risk behaviors. Therefore, family therapy is core to the adolescent’s treatment, regardless of what modality is chosen.

Goals of family therapy may be:

• to help the adolescent abstain from substance use
• to engage in pro-social activities
• to decrease parental denial of the adolescent’s substance use
• to decrease resistance to treatment
• treatment maintenance
• to establish or re-establish structure in the adolescent’s environment
• to improve communication in the family.

Multisystemic therapy is comprehensive and involves all systems that relate to the adolescent’s substance use, including the family, school, community, and legal system. MST requires special training and intensive supervision, so it is usually reserved for adolescents who have not benefited from other forms of treatment.²¹

12-step approaches. For adolescents, 12-step programs usually augment other treatments and are rarely used alone. Alcoholics Anonymous, Narcotics Anonymous, and other 12-step programs have been studied more extensively in adults than in adolescents.

Adolescents, who often feel invulnerable, may have difficulty accepting the 12-step doctrine of lack of control. A modified 12-step program and workbook for adolescents are available through the American Academy of Child and Adolescent Psychiatry.²²

Referral tips. If possible, refer an adolescent to a 12-step group specifically for adolescents. Teens who attend adult groups often perceive their substance use as normal, compared with the more severe and chronic patterns of some adults. Most adolescents relate better to peers with similar problems and may benefit from reminders of the negative consequences of substance use and the benefits of abstinence.

DRUG THERAPY

Drug therapy for adolescents with substance use disorders is usually considered in the context of detoxification, treating withdrawal symptoms, and treating comorbid psychiatric disorders. The same detoxification and withdrawal treatment principles used in adults apply to adolescents.

Clinical withdrawal symptoms are less common in adolescents than adults, probably because of adolescents’ binge patterns of substance use. Even so, some adolescents do experience withdrawal and may be at risk for complications if improperly treated.

Psychiatric comorbidity. To our knowledge, only two double-blind, placebo-controlled studies of drug therapy in treating adolescent substance use disorders have been published.

Depression. Deas et al²³ randomized 10 adolescents with alcohol use disorders and depression to 12 weeks of group CBT plus sertraline or placebo. Sertraline was started at 25 mg/d and titrated to a maximum of 100 mg/d. Drinks per drinking day, percent of days drinking, and Hamilton Rating Scale for Depression scores declined similarly in both groups.

Drinking decreased significantly from baseline (by an average 4.7 drinks), and adolescents in both groups no longer met DSM-IV criteria for depression at the end of treatment. CBT’s effectiveness in treating alcohol use disorders and depression might have concealed any difference in effect between sertaline and placebo.

Bipolar disorder. Geller et al²⁴ randomly assigned 25 adolescents with bipolar disorder and substance dependence to lithium or placebo for 6 weeks. Lithium was started as an evening dose of 600 mg and titrated to achieve a lithium blood level of 0.9 to 1.3 mEq/L. Among the 21 adolescents who completed the trial, those receiving lithium had significantly fewer positive urine toxicology screens and higher clinical global assessment of function scores.

Related resources

• National Clearinghouse for Alcohol and Drug Information, Substance Abuse and Mental Health Services Administration, U.S. Department of Health and Human Services. www.health.org/govpubs/bkd306/31k.aspx
• National Institute on Alcohol Abuse and Alcoholism (assessment instruments). www.niaaa.nih.gov/publications/instable.htm
• Deas D, Thomas SE. An overview of controlled studies of adolescent substance abuse treatment. Am J Addict 2001;10:178-89.

Drug brand names

• Sertraline • Zoloft

Disclosure

Dr. Deas receives grant support from Pfizer, Inc. and the National Institute of Alcohol Abuse and Alcoholism.

Dr. Upadhyaya receives grant support from the National Institute of Drug Abuse and GlaxoSmithKline.

Acknowledgment

The authors wish to thank Alva Blair for assistance with preparing this manuscript and Natalie Johnson, MA, Kess Mughelli, BS, and Lakeleia Middleton-Robinson, MA, for technical support.

Prescribing drug therapy for pregnant bipolar women requires psychiatrists to balance the potential for neonatal malformations against the high risk of relapse when patients discontinue their medications.¹ To help you achieve this balance, we offer an evidence-based approach that includes:

• analysis of the FDA’s teratogenicity categories for psychotropics
• review of the safety profiles of drugs used in mood stabilization
• an algorithm for managing patients who are considering conception or are pregnant.

PSYCHOTROPIC RISKS TO OFFSPRING

All psychotropic medications diffuse across the placenta, which exposes the fetus to some degree. Risks include teratogenicity, obstetrical complications, perinatal syndromes, and long-term postnatal behavioral sequelae.

Teratogenicity. A medication is considered teratogenic when prenatal exposure significantly increases the risk of congenital deformities over the baseline risk, which is 2% in the United States.² The cause of most congenital malformations is unknown. Risk for teratogenicity occurs in the first 12 weeks of gestation, as organs are formed.

Table 1

FDA Use-in-Pregnancy ratings for medications The FDA system weighs the degree to which research findings have ruled out risk to the fetus

Obstetrical complications include preterm delivery, low birth weight, and delivery complications such as low Apgar scores or behavioral effects requiring intensive care.

Perinatal syndromes include physical and behavioral symptoms noticed shortly after birth (such as jitteriness). These consequences are putatively related to drug use at or near birth and have limited duration.

Postnatal behavioral sequelae include long-term neurobehavioral abnormalities in children who were exposed to psychotropics in utero.

BALANCING RISKS

Risks with medication. The FDA’s “use in pregnancy” rating system (Table 1) uses available data to assess the degree of teratogenic risk. These guidelines can be confusing and are one of many tools to use when considering a possible drug treatment.

Most psychotropics are category “C” or “D,” which imply a chance of harm to the exposed fetus. Category “B” drugs would appear safer, but this rating could simply indicate a lack of adequate human data or that no data have shown harm in animals.

Moreover, a category “D” drug may be chosen more often during pregnancy than a category “C” drug. This may occur when more human data exist on using the category “D” drug in patients with a particular disorder (such as using lithium versus valproate or olanzapine in pregnant bipolar women).

No psychotropics are classified as “A,” meaning either some risks are associated with every psychotropic or the risk of some agents has not been adequately explored. Furthermore, no psychotropics are FDA-approved for use during pregnancy.

Risks without medication. Teratogenicity notwithstanding, psychotropic intervention is the most effective treatment for women with bipolar disorder. Patients who discontinue mood-stabilizing medication after conception increase their risk of relapse into depression or mania,³ either of which could lead to complications and untoward effects on the fetus.

Depression during pregnancy has been linked to low birth weight and preterm delivery.^4,5 These effects may be mediated by the illness itself or by other factors that indirectly affect birth outcomes. For example, depression during pregnancy is associated with decreased appetite, substance use and abuse, and lower use of prenatal care.⁶

Untreated mania may also be associated with perinatal risks, as a pregnant patient in a manic state may engage in impulsive, high-risk behaviors that endanger her and the fetus.⁷

MOOD STABILIZERS

The FDA categorizes as “D” the three most commonly used mood stabilizers: lithium, valproate, and carbamazepine (Table 2). This rating implies that studies have demonstrated fetal risk but the drug’s potential benefit may still outweigh the risk.

Lithium. The International Registry of Lithium reported increased rates of cardiovascular malformations— such as Ebstein’s anomaly—in children whose mothers took lithium during pregnancy.

Relative risk for Ebstein’s anomaly in children with fetal exposure to lithium may be 20 times higher than the risk in unexposed children, although the absolute risk with lithium exposure remains low (1 in 1,000 births).^1,8

No significant neurobehavioral teratogenicity has been reported in infants exposed in utero to lithium, although few cases have been studied. One study reported that 22 lithium-exposed infants attained developmental milestones at a pace comparable to that of unexposed controls.⁹

“Floppy baby” syndrome, in which infants experience hypotonicity and cyanosis, is the most recognized adverse effect in infants exposed to lithium in utero.¹⁰ Its frequency is unknown, but rare. Neonatal hypothyroidism and nephrogenic diabetes insipidus have also been documented.

Anticonvulsants. To date, no studies have examined the outcomes of children whose mothers took anticonvulsants for bipolar disorder during pregnancy, though the research concerning epileptic mothers is extensive.

Neural tube defects. Data associate anticonvulsant exposure with a significantly greater risk for malformations than in the general population. Specifically, anticonvulsants may cause neural tube defects such as spina bifida, ancephaly, and encephaly in 2 to 5% of those exposed, as well as craniofacial anomalies, microcephaly, growth retardation, and heart defects.^11-14

Table 2

FDA’s teratogenicity ratings of mood stabilizers and other antimanic agents

More minor malformations—such as rotated ears, depressed nasal bridge, short nose, elongated upper lip, and fingernail hypoplasia—have been reported in infants exposed to anticonvulsants in utero.¹⁴ These malformations disappear with age.¹³ Teratogenicity increases with the use of multiple anticonvulsants and possibly with higher maternal plasma levels and toxic metabolites.¹⁵

Conclusion. The three most commonly used mood stabilizers are all teratogenic. The least risk may occur with lithium (0.1%) versus valproate (2 to 5%) or carbamazepine (1 to 3%). These risks must be weighed against the up to 50% chance of relapse with medication discontinuation.³

ANTIPSYCHOTICS

Antipsychotics are often used to treat mania because of their rapid effects and sedative properties. Most antipsychotics—specifically, haloperidol, olanzapine, and risperidone—are labeled “C,” specifying that fetal risk cannot be ruled out.

Table 3

FDA’s teratogenicity ratings of common antidepressants

Chlorpromazine and haloperidol have been most studied during pregnancy but in relation to treating hyperemesis gravidarum and psychosis, not bipolar disorder. Results regarding antipsychotics’ teratogenic and behavioral risks are mixed,^16-21 probably because the various compounds have different effects on the fetus.

The underlying illness—rather than the medications—may increase the rate of anomalies seen with exposure to antipsychotics:

• Rieder et al²² reported an increased rate of perinatal death in infants of schizophrenic mothers but no significant association between the mothers’ use of antipsychotics and perinatal death.
• Sobel²³ compared psychotic women with and without histories of chlorpromazine exposure during pregnancy. Rates of fetal damage were similar and approximately twice that of the general population.

A meta-analysis of 74,337 live births revealed that first-trimester exposure to low-potency antipsychotics increases the relative risk of fetal anomalies in nonpsychotic women. Phenothiazines may increase the 2% baseline incidence of malformations to 2.4%.¹ No specific organ malformation following fetal exposure to phenothiazines has been consistently identified.

Olanzapine was recently approved for treating mania. Very little data exist regarding its impact on fetal development when used during pregnancy, although studies on small numbers of women have not revealed teratogenicity.^24,25

Conclusion. Psychotic illness itself may increase the risk of poor fetal outcome to a greater extent than does antipsychotic use. Prenatal exposure to low-potency phenothiazines may further increase this risk, although only slightly. The effect of prenatal exposure to atypical antipsychotics requires further study.

BENZODIAZEPINES

Benzodiazepines are rarely a primary treatment for mania or depression. Thus, a comprehensive review of their effect on fetal outcome is beyond the scope of this review. A meta-analysis of exposure in the first trimester suggests a very small but significant increase in risk for cleft palate.¹ The absolute risk is <1 in 1,000 cases.

ANTIDEPRESSANTS

Whereas treatment of acute mania is considered a medical emergency, women with bipolar disorder may also relapse into depression during pregnancy. An antidepressant should not be used without a mood stabilizer when treating bipolar I disorder, although a mood stabilizer alone may be inadequate to treat depression. Using tricyclics and selective serotonin reuptake inhibitors (SSRIs) during pregnancy has not been associated with teratogenicity (Table 3),²⁶ although perinatal effects have been reported.¹

Tricyclics. In case-control studies involving more than 300,000 live births, 414 incidences of first-trimester exposure to tricyclics were followed. Information from these patients found no significant association between fetal exposure to tricyclics and increased rates of congenital malformations.¹ The few studies that have been performed suggest no long-term effects from in utero exposure.²⁶ Although these results suggest that prenatal exposure to tricyclics is relatively safe, more research is needed.

SSRIs. To date, no significant teratogenic effects of SSRIs have been identified in offspring of treated women.

The manufacturer’s register for fluoxetine contains approximately 2,000 cases of treated patients, with no excess cases of congenital anomalies or malformations following prenatal exposure. Citalopram has the next largest database of in utero exposure (n=365), again with no increased risk for teratogenicity. Several smaller systematic reports are available on in utero exposure to sertraline, paroxetine, or escitalopram.²⁶

Most studies of pregnant women taking fluoxetine in the first trimester have found no increased risk of obstetrical complications—including spontaneous pregnancy loss, preterm labor, or low birth weight—compared with women not taking fluoxetine. Taking fluoxetine during the third trimester may increase the risk for perinatal complications,²⁷ although this has been inconsistently reported and requires further study. Effects of other SSRIs in the third trimester have not been systematically explored.

Case reports and one controlled study have addressed possible neonatal perinatal symptoms from in utero exposure to SSRIs.^28,29 Preliminary data show no adverse neurobehavioral function in exposed neonates.²⁶

Electroconvulsive therapy (ECT) has been proven effective for acute mania and depression, demonstrating few deleterious effects on neonates. ECT has few side effects and may be safer than drug therapy in this population. Two reviews support the efficacy and relative safety of ECT treatment during pregnancy, although more evidence is needed.^30,31

RECOMMENDATIONS

Discuss pregnancy and medication risks with all bipolar women, regardless of proximal plans for pregnancy. If psychotropic medication is used, prescribe carefully during the first trimester, using the minimum number of drugs and the lowest dosages needed to restore or maintain well-being.³²

Pros and cons of switching. Some clinicians may encourage a patient to taper a medication during the first trimester because of its unknown or high teratogenicity. Depending on the patient’s illness severity, this might not be the optimal decision. A more conservative option would be to switch to a lower-risk drug during pregnancy.

Lithium has both antidepressant and antimanic properties and is less teratogenic compared with first-trimester exposure to an anticonvulsant. However, if lithium has not been successful for the woman’s mania prophylaxis in the past and she has demonstrated antimanic response to an anticonvulsant, switching to lithium or another anticonvulsant is not recommended.

Algorithm Suggested approach to the bipolar patient who wishes to conceive or is pregnant

Low maternal folate levels are often associated with neural tube defects from any cause.³³ Valproate lowers folate levels by inhibiting one of the enzymes necessary for its formation, which may be a mechanism for the increased risk of spina bifida.³⁴

Folate supplementation. To date, no study has demonstrated that giving folate supplements to women taking anticonvulsants during pregnancy reduces the risk of neural tube defects.³⁵ Nonetheless, we recommend that women who continue to take valproate or carbamazepine during pregnancy receive folate, 3 to 4 mg/d, as a precaution.

Treating manic relapse. Data show high rates of relapse in patients who stop taking lithium, particularly if done abruptly.³ Counsel women taking lithium to plan their pregnancies to allow enough time to taper off the medication prior to conception, if they want to try this. Lithium should be decreased slowly—approximately 50% every 2 weeks—to avoid relapse.

Treat aggressively if relapse occurs during pregnancy. Consider:

• psychiatric hospitalization in case of suicidality or psychosis
• reinstituting drug therapy with a less-teratogenic agent
• ECT for a manic or depressive episode.

As the pregnancy advances and the mother’s volume of distribution increases, dosage increases may be needed to maintain therapeutic drug levels.

Treating depressive relapse. Should depression occur in pregnancy, SSRIs or tricyclics added to mood stabilizer therapy have been shown to be effective, with few teratogenic effects.

Cognitive-behavioral and interpersonal psychotherapies also have shown efficacy in pregnant women with major depressive disorder³⁶ and may be effective for women with bipolar disorder in pregnancy. Cognitive psychotherapies, when used with medication, have been reported effective in preventing relapse in nongravid bipolar patients.^36-37

Related resources

Psychiatric disorders during pregnancy. Massachusetts General Hospital Center for Women’s Health. Perinatal Resource Center. www.womensmentalhealth.org/topics/pregnancy_lib.html

Drug brand names

• Amitriptyline • Elavil
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Desipramine • Norpramin
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Lithobid et al
• Methylphenidate • Ritalin et al
• Nortriptyline • Pamelor
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Phenelzine • Nardil
• Risperidone • Risperdal
• Sertraline • Zoloft
• Topiramate • Topamax
• Tranylcypromine • Parnate
• Trifluoperazine • Stelazine
• Valproate • Depakote et al

Disclosure

Dr. Altshuler receives research support from Abbott Laboratories, is a consultant to Abbott Laboratories, Forest Laboratories, and Eli Lilly & Co., and is a speaker for GlaxoSmithKline and Janssen Pharmaceutica.

Ms. Richards reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Dr. Yonkers receives research support from GlaxoSmithKline and Berlex Laboratories, is a consultant to GlaxoSmithKline, and is a speaker for Eli Lilly and Co., Pfizer Inc., GlaxoSmithKline, and Wyeth Pharmaceuticals.

Prescribing drug therapy for pregnant bipolar women requires psychiatrists to balance the potential for neonatal malformations against the high risk of relapse when patients discontinue their medications.¹ To help you achieve this balance, we offer an evidence-based approach that includes:

• analysis of the FDA’s teratogenicity categories for psychotropics
• review of the safety profiles of drugs used in mood stabilization
• an algorithm for managing patients who are considering conception or are pregnant.

PSYCHOTROPIC RISKS TO OFFSPRING

All psychotropic medications diffuse across the placenta, which exposes the fetus to some degree. Risks include teratogenicity, obstetrical complications, perinatal syndromes, and long-term postnatal behavioral sequelae.

Teratogenicity. A medication is considered teratogenic when prenatal exposure significantly increases the risk of congenital deformities over the baseline risk, which is 2% in the United States.² The cause of most congenital malformations is unknown. Risk for teratogenicity occurs in the first 12 weeks of gestation, as organs are formed.

Table 1

FDA Use-in-Pregnancy ratings for medications The FDA system weighs the degree to which research findings have ruled out risk to the fetus

Obstetrical complications include preterm delivery, low birth weight, and delivery complications such as low Apgar scores or behavioral effects requiring intensive care.

Perinatal syndromes include physical and behavioral symptoms noticed shortly after birth (such as jitteriness). These consequences are putatively related to drug use at or near birth and have limited duration.

Postnatal behavioral sequelae include long-term neurobehavioral abnormalities in children who were exposed to psychotropics in utero.

BALANCING RISKS

Risks with medication. The FDA’s “use in pregnancy” rating system (Table 1) uses available data to assess the degree of teratogenic risk. These guidelines can be confusing and are one of many tools to use when considering a possible drug treatment.

Most psychotropics are category “C” or “D,” which imply a chance of harm to the exposed fetus. Category “B” drugs would appear safer, but this rating could simply indicate a lack of adequate human data or that no data have shown harm in animals.

Moreover, a category “D” drug may be chosen more often during pregnancy than a category “C” drug. This may occur when more human data exist on using the category “D” drug in patients with a particular disorder (such as using lithium versus valproate or olanzapine in pregnant bipolar women).

No psychotropics are classified as “A,” meaning either some risks are associated with every psychotropic or the risk of some agents has not been adequately explored. Furthermore, no psychotropics are FDA-approved for use during pregnancy.

Risks without medication. Teratogenicity notwithstanding, psychotropic intervention is the most effective treatment for women with bipolar disorder. Patients who discontinue mood-stabilizing medication after conception increase their risk of relapse into depression or mania,³ either of which could lead to complications and untoward effects on the fetus.

Depression during pregnancy has been linked to low birth weight and preterm delivery.^4,5 These effects may be mediated by the illness itself or by other factors that indirectly affect birth outcomes. For example, depression during pregnancy is associated with decreased appetite, substance use and abuse, and lower use of prenatal care.⁶