Current Psychiatry

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You are treating Mr. P, age 34, for schizoaffective disorder. He smokes 1 pack of cigarettes per day and has smoked for approximately 17 years. He has tried to stop but never has been able to quit for more than a few weeks. He reveals whenever he tries to quit, he starts feeling extremely lethargic and “depressed” and resumes smoking to prevent these symptoms from worsening. However, Mr. P expresses some interest in trying to quit again and asks whether any medications could prevent him from becoming depressed while he tries to quit.

Cigarette smoking is overrepresented and undertreated among individuals with psychiatric illness, in part because of the largely unfounded belief held by some patients and clinicians that smoking cessation might worsen psychiatric symptoms. In this article, we argue this challenge can be overcome and psychiatrists and other mental health professionals can and should help their patients reap the innumerable benefits of quitting smoking. We discuss:

• the short- and long-term effects of smoking cessation
• evidence-based treatment guidelines for working with motivated and unmotivated smokers
• unique issues that may arise when treating smokers who have psychiatric disorders.

Quitting: Profound benefits

Quitting smoking has substantial benefits beginning within minutes after taking the last puff. Some of the benefits that occur within the first few days of quitting include:

• decreased blood pressure and pulse rate
• improved circulation
• improved ability to smell and taste
• easier breathing.

Longer-term smoking abstinence drastically reduces risk of heart attack, stroke, cancer, respiratory disease, and a host of other illnesses that affect—and kill—individuals with psychiatric disorders several decades earlier than their counterparts in the general population.¹ There also are financial benefits to quitting; using the 2009 national average of $5.33 per pack, a 1-pack-per-day smoker who quits would save >$150 per month, which accounts for only the direct cost of cigarettes.²

Although the beneficial effects of quitting smoking are profound and far-reaching, in the short-term they are counterbalanced by nicotine withdrawal symptoms—including restlessness, irritability, depressed mood, concentration problems, and increased appetite/weight gain—that are formidable distractions from the positive aspects of quitting. Additionally, nicotine withdrawal symptoms tend to be more severe in smokers who have a psychiatric disorder.³ Fortunately, there are effective, evidence-based methods of reducing withdrawal symptoms and helping smokers cope with these and other challenges of quitting.

Combined treatment is best

Current treatment guidelines⁴ suggest all smokers should be offered pharmacotherapy and counseling to aid quitting because this combined approach has the highest success rate (Algorithm). Table 1 ⁴ provides information about dosing, efficacy, and side effect profile of each of the 7 FDA-approved medications for smoking cessation. Using any of the approved medications at least doubles the odds of successful quitting compared with placebo.⁴ These pharmacotherapies can reduce or prevent nicotine withdrawal symptoms and—at least in the case of bupropion and varenicline—decrease reinforcement from smoking, thereby lowering the likelihood a lapse (ie, smoking ≥1 cigarettes without returning to regular smoking) will develop into a full-blown relapse (ie, return to regular smoking).

Algorithm: Tobacco cessation treatment for psychiatric patients
Source: Adapted from reference 4 Medication selection depends on many factors, including:

• the patient’s psychiatric illness
• her/his prior response to smoking cessation pharmacotherapies
• concomitant psychiatric medications
• patient preference.⁵

Placebo-controlled trials of smoking cessation aids in psychiatrically ill patients are limited, but several studies of smokers with a history of major depression indicate treatment with bupropion SR or nortriptyline is effective.⁶ Similarly, although relapse rates generally are higher in patients with schizophrenia compared with non-mentally ill smokers, nicotine replacement therapy and bupropion SR are more effective than placebo in patients with this disorder.^7,8 When we prescribe these treatments, we tend to extend the duration of treatment beyond those described in Table 1 ,⁴ and to use combined treatments (eg, a transdermal patch with a shorter-acting gum or lozenge preparation) to better target the marked withdrawal symptoms more severely nicotine-dependent patients frequently experience.

Table 1

First-line pharmacotherapies for smoking cessation

Counseling. All smokers should be provided with brief interventions consistent with the 5 A’s—Ask, Advise, Assess, Assist, and Arrange (Table 2).⁴ For smokers who are not motivated to quit, the recommended approach follows the principles of the 5 R’s—Relevance, Risks, Rewards, Roadblocks, and Repetition (Table 3).⁴ Smokers who are motivated to quit and willing to participate in more intensive treatment may be offered face-to-face individual or group counseling (depending upon availability) or referred to a telephone quit line (see Related Resources). Intensive treatments such as these typically provide social support and assistance overcoming barriers to cessation and developing skills to initiate and maintain abstinence (eg, coping with a lapse or handling cravings, identifying and avoiding high-risk situations for smoking). As a general rule, greater intensity of counseling is associated with a greater likelihood of quitting.⁴

Table 2

The 5 A’s of tobacco treatment

Table 3

The 5 R’s: Principles of interventions for smokers not ready to quit

Q&A about treatment

How effective are smoking cessation interventions for individuals with psychiatric disorders? Several studies have demonstrated, on any given quit attempt, smokers with psychiatric or substance use disorders can be as successful as smokers without these disorders.^9-11 In fact, quit rates as high as approximately 70% for end-of-treatment¹¹ and 30% for 6-month follow-up¹⁰ have been reported. Of course, effectiveness varies by type and intensity of treatment as well as by individual characteristics of the smoker. Smokers with psychiatric disorders may fare better with more intensive interventions than briefer ones,^12,13 and factors such as high levels of nicotine dependence and exposure to smoking environments—both of which are characteristic of smokers with serious mental illness—can negatively impact treatment outcomes.⁴

Should the nature of the psychiatric disorder(s) guide decisions about the optimal pharmacotherapy or counseling approach? There have been numerous attempts to investigate the effectiveness of targeted interventions for particular subgroups of smokers with psychiatric disorders, including:

• studies of the efficacy of the antidepressants bupropion¹⁴ and nortriptyline¹⁵ as well as cognitive-behavioral therapy-based mood management counseling¹⁶ for depressed smokers
• integrative treatment approaches for smokers with posttraumatic stress disorder (PTSD)¹⁷
• group counseling designed specifically for smokers with schizophrenia.^18,19

Although more research is needed and there have been some promising early results (eg, McFall et al¹⁷), current literature does not provide consistent evidence supporting treatment matching solely on the basis of the psychiatric disorder. Rather, patient preference, safety considerations (eg, use of medications in children/adolescents, pregnant women), medication side effect profiles, prior experience with the treatment approach, and cost/availability of treatment should guide development of the treatment plan. When results from placebo-controlled trials are available for subgroups of patients (eg, those with a history of major depression), consider this information when selecting a pharmacologic smoking cessation aid.

What is the risk of psychiatric symptoms worsening as a result of quitting smoking? Little research on this topic is available because more often than not, smokers with psychiatric disorders are excluded from tobacco treatment studies. However, research examining psychiatric status changes among recent quitters with schizophrenia,^20,21 depression,^22,23 PTSD,¹⁷ and substance use disorders²⁴ suggests smoking cessation does not worsen symptoms of these disorders, and may be associated with symptom improvement.¹⁷ Nonetheless, driven largely by anecdotal evidence, the misconception that smoking cessation worsens psychiatric symptoms remains a substantial barrier to treatment.

Mr. P’s case is an example of how not probing about the nature of psychiatric complaints can be problematic. Mr. P reported what on first glance appeared to be a worsening of psychiatric symptoms starting when he stopped smoking and resolved when he resumed smoking. However, without gathering additional information about these events, we cannot conclude stopping smoking caused his psychiatric symptoms to worsen. Other potential explanations include nicotine withdrawal symptoms, side effects of smoking cessation medications, an increase in levels of psychotropic medications for which metabolism is affected by tobacco smoke, or the natural course of his mood disorder. The timing of the onset and offset of symptoms seems to argue against Mr. P’s symptoms reflecting the natural course of his mood disorder, but the other 3 explanations remain plausible.

It is important to distinguish whether Mr. P’s worsening symptoms are consistent with a depressive episode or whether they are a manifestation of the transient dysphoria that accompanies nicotine withdrawal. Assessing the severity and persistence of the mood disturbance as well as the timing of onset could help make this determination. Nicotine withdrawal symptoms typically emerge within 24 hours of quitting or significantly reducing smoking and tend to peak within approximately 1 week. Thus, depressive symptoms that develop after weeks or months of abstinence would be less consistent with nicotine withdrawal. Additionally, the lethargy Mr. P reported may be a symptom of depression, or it may stem from a cessation-induced increase in antipsychotic serum levels. Because tobacco smoke increases the metabolism of several antipsychotics and antidepressants—including olanzapine, clozapine, haloperidol, and fluoxetine²⁵—stopping smoking may increase medication levels and side effects. To rule out medication side effects as a cause of post-cessation mood changes, the psychiatrist should ask Mr. P about which smoking cessation pharmacotherapies (if any) he was using and which psychotropic medications he was taking. Unfortunately, such a detailed history is not always taken, and patient-generated theories of smoking cessation causing worsening psychiatric symptoms often are taken at face value.

When should smokers with psychiatric disorders be encouraged to quit? Are there times when smoking cessation should be discouraged? Tobacco treatment guidelines⁴ recommend advising users to quit at every clinical encounter, but there has been some debate about the timing of tobacco treatment for smokers with psychiatric disorders. There is minimal research to guide such treatment decisions. However, even if quit attempts are more successful during times of symptomatic stability—and there is no conclusive evidence to indicate they are—waiting for perfect mental health before initiating smoking cessation treatment is unnecessary and ill-advised. In some situations, such as when a patient has experienced an acute increase in psychiatric symptoms or when psychotropics are being titrated, a short-term postponement of quitting may be reasonable. However, discouraging smokers from trying to quit when they express readiness to try should be done sparingly, because it is uncertain how long that window of opportunity will be open, and the consequences of missed opportunities can be fatal.

Related Resources

• National Tobacco Quitline. 1-800-QUIT-NOW. www.smokefree.gov.
• University of California, San Francisco, Schools of Pharmacy and Medicine. Rx for Change (free online training program for clinicians). http://rxforchange.ucsf.edu.
• National Association of State Mental Health Program Directors. Tobacco-free living in psychiatric settings: a best-practices toolkit promoting wellness and recovery. www.nasmhpd.org/general_files/publications/NASMHPD.toolkitfinalupdated90707.pdf.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Varenicline • Chantix

Disclosures

Dr. Heffner was supported by National Institute on Drug Abuse grant#026517. She is a consultant to Pfizer Inc.

Dr. Anthenelli is supported by National Institute on Alcohol Abuse and Alcoholism grant#AA19720 and by the Department of Veterans Affairs. He is a consultant to GlaxoSmithKline and Pfizer Inc.

The Tri-State Tobacco and Alcohol Research Center receives research support from Eli Lilly and Company, Nabi Biopharmaceuticals, Pfizer Inc., and sanofi-aventis.

Discuss this article at www.facebook.com/CurrentPsychiatry

You are treating Mr. P, age 34, for schizoaffective disorder. He smokes 1 pack of cigarettes per day and has smoked for approximately 17 years. He has tried to stop but never has been able to quit for more than a few weeks. He reveals whenever he tries to quit, he starts feeling extremely lethargic and “depressed” and resumes smoking to prevent these symptoms from worsening. However, Mr. P expresses some interest in trying to quit again and asks whether any medications could prevent him from becoming depressed while he tries to quit.

Cigarette smoking is overrepresented and undertreated among individuals with psychiatric illness, in part because of the largely unfounded belief held by some patients and clinicians that smoking cessation might worsen psychiatric symptoms. In this article, we argue this challenge can be overcome and psychiatrists and other mental health professionals can and should help their patients reap the innumerable benefits of quitting smoking. We discuss:

• the short- and long-term effects of smoking cessation
• evidence-based treatment guidelines for working with motivated and unmotivated smokers
• unique issues that may arise when treating smokers who have psychiatric disorders.

Quitting: Profound benefits

Quitting smoking has substantial benefits beginning within minutes after taking the last puff. Some of the benefits that occur within the first few days of quitting include:

• decreased blood pressure and pulse rate
• improved circulation
• improved ability to smell and taste
• easier breathing.

Longer-term smoking abstinence drastically reduces risk of heart attack, stroke, cancer, respiratory disease, and a host of other illnesses that affect—and kill—individuals with psychiatric disorders several decades earlier than their counterparts in the general population.¹ There also are financial benefits to quitting; using the 2009 national average of $5.33 per pack, a 1-pack-per-day smoker who quits would save >$150 per month, which accounts for only the direct cost of cigarettes.²

Although the beneficial effects of quitting smoking are profound and far-reaching, in the short-term they are counterbalanced by nicotine withdrawal symptoms—including restlessness, irritability, depressed mood, concentration problems, and increased appetite/weight gain—that are formidable distractions from the positive aspects of quitting. Additionally, nicotine withdrawal symptoms tend to be more severe in smokers who have a psychiatric disorder.³ Fortunately, there are effective, evidence-based methods of reducing withdrawal symptoms and helping smokers cope with these and other challenges of quitting.

Combined treatment is best

Current treatment guidelines⁴ suggest all smokers should be offered pharmacotherapy and counseling to aid quitting because this combined approach has the highest success rate (Algorithm). Table 1 ⁴ provides information about dosing, efficacy, and side effect profile of each of the 7 FDA-approved medications for smoking cessation. Using any of the approved medications at least doubles the odds of successful quitting compared with placebo.⁴ These pharmacotherapies can reduce or prevent nicotine withdrawal symptoms and—at least in the case of bupropion and varenicline—decrease reinforcement from smoking, thereby lowering the likelihood a lapse (ie, smoking ≥1 cigarettes without returning to regular smoking) will develop into a full-blown relapse (ie, return to regular smoking).

Algorithm: Tobacco cessation treatment for psychiatric patients
Source: Adapted from reference 4 Medication selection depends on many factors, including:

• the patient’s psychiatric illness
• her/his prior response to smoking cessation pharmacotherapies
• concomitant psychiatric medications
• patient preference.⁵

Placebo-controlled trials of smoking cessation aids in psychiatrically ill patients are limited, but several studies of smokers with a history of major depression indicate treatment with bupropion SR or nortriptyline is effective.⁶ Similarly, although relapse rates generally are higher in patients with schizophrenia compared with non-mentally ill smokers, nicotine replacement therapy and bupropion SR are more effective than placebo in patients with this disorder.^7,8 When we prescribe these treatments, we tend to extend the duration of treatment beyond those described in Table 1 ,⁴ and to use combined treatments (eg, a transdermal patch with a shorter-acting gum or lozenge preparation) to better target the marked withdrawal symptoms more severely nicotine-dependent patients frequently experience.

Table 1

First-line pharmacotherapies for smoking cessation

Counseling. All smokers should be provided with brief interventions consistent with the 5 A’s—Ask, Advise, Assess, Assist, and Arrange (Table 2).⁴ For smokers who are not motivated to quit, the recommended approach follows the principles of the 5 R’s—Relevance, Risks, Rewards, Roadblocks, and Repetition (Table 3).⁴ Smokers who are motivated to quit and willing to participate in more intensive treatment may be offered face-to-face individual or group counseling (depending upon availability) or referred to a telephone quit line (see Related Resources). Intensive treatments such as these typically provide social support and assistance overcoming barriers to cessation and developing skills to initiate and maintain abstinence (eg, coping with a lapse or handling cravings, identifying and avoiding high-risk situations for smoking). As a general rule, greater intensity of counseling is associated with a greater likelihood of quitting.⁴

Table 2

The 5 A’s of tobacco treatment

Table 3

The 5 R’s: Principles of interventions for smokers not ready to quit

Q&A about treatment

How effective are smoking cessation interventions for individuals with psychiatric disorders? Several studies have demonstrated, on any given quit attempt, smokers with psychiatric or substance use disorders can be as successful as smokers without these disorders.^9-11 In fact, quit rates as high as approximately 70% for end-of-treatment¹¹ and 30% for 6-month follow-up¹⁰ have been reported. Of course, effectiveness varies by type and intensity of treatment as well as by individual characteristics of the smoker. Smokers with psychiatric disorders may fare better with more intensive interventions than briefer ones,^12,13 and factors such as high levels of nicotine dependence and exposure to smoking environments—both of which are characteristic of smokers with serious mental illness—can negatively impact treatment outcomes.⁴

Should the nature of the psychiatric disorder(s) guide decisions about the optimal pharmacotherapy or counseling approach? There have been numerous attempts to investigate the effectiveness of targeted interventions for particular subgroups of smokers with psychiatric disorders, including:

• studies of the efficacy of the antidepressants bupropion¹⁴ and nortriptyline¹⁵ as well as cognitive-behavioral therapy-based mood management counseling¹⁶ for depressed smokers
• integrative treatment approaches for smokers with posttraumatic stress disorder (PTSD)¹⁷
• group counseling designed specifically for smokers with schizophrenia.^18,19

Although more research is needed and there have been some promising early results (eg, McFall et al¹⁷), current literature does not provide consistent evidence supporting treatment matching solely on the basis of the psychiatric disorder. Rather, patient preference, safety considerations (eg, use of medications in children/adolescents, pregnant women), medication side effect profiles, prior experience with the treatment approach, and cost/availability of treatment should guide development of the treatment plan. When results from placebo-controlled trials are available for subgroups of patients (eg, those with a history of major depression), consider this information when selecting a pharmacologic smoking cessation aid.

What is the risk of psychiatric symptoms worsening as a result of quitting smoking? Little research on this topic is available because more often than not, smokers with psychiatric disorders are excluded from tobacco treatment studies. However, research examining psychiatric status changes among recent quitters with schizophrenia,^20,21 depression,^22,23 PTSD,¹⁷ and substance use disorders²⁴ suggests smoking cessation does not worsen symptoms of these disorders, and may be associated with symptom improvement.¹⁷ Nonetheless, driven largely by anecdotal evidence, the misconception that smoking cessation worsens psychiatric symptoms remains a substantial barrier to treatment.

Mr. P’s case is an example of how not probing about the nature of psychiatric complaints can be problematic. Mr. P reported what on first glance appeared to be a worsening of psychiatric symptoms starting when he stopped smoking and resolved when he resumed smoking. However, without gathering additional information about these events, we cannot conclude stopping smoking caused his psychiatric symptoms to worsen. Other potential explanations include nicotine withdrawal symptoms, side effects of smoking cessation medications, an increase in levels of psychotropic medications for which metabolism is affected by tobacco smoke, or the natural course of his mood disorder. The timing of the onset and offset of symptoms seems to argue against Mr. P’s symptoms reflecting the natural course of his mood disorder, but the other 3 explanations remain plausible.

It is important to distinguish whether Mr. P’s worsening symptoms are consistent with a depressive episode or whether they are a manifestation of the transient dysphoria that accompanies nicotine withdrawal. Assessing the severity and persistence of the mood disturbance as well as the timing of onset could help make this determination. Nicotine withdrawal symptoms typically emerge within 24 hours of quitting or significantly reducing smoking and tend to peak within approximately 1 week. Thus, depressive symptoms that develop after weeks or months of abstinence would be less consistent with nicotine withdrawal. Additionally, the lethargy Mr. P reported may be a symptom of depression, or it may stem from a cessation-induced increase in antipsychotic serum levels. Because tobacco smoke increases the metabolism of several antipsychotics and antidepressants—including olanzapine, clozapine, haloperidol, and fluoxetine²⁵—stopping smoking may increase medication levels and side effects. To rule out medication side effects as a cause of post-cessation mood changes, the psychiatrist should ask Mr. P about which smoking cessation pharmacotherapies (if any) he was using and which psychotropic medications he was taking. Unfortunately, such a detailed history is not always taken, and patient-generated theories of smoking cessation causing worsening psychiatric symptoms often are taken at face value.

When should smokers with psychiatric disorders be encouraged to quit? Are there times when smoking cessation should be discouraged? Tobacco treatment guidelines⁴ recommend advising users to quit at every clinical encounter, but there has been some debate about the timing of tobacco treatment for smokers with psychiatric disorders. There is minimal research to guide such treatment decisions. However, even if quit attempts are more successful during times of symptomatic stability—and there is no conclusive evidence to indicate they are—waiting for perfect mental health before initiating smoking cessation treatment is unnecessary and ill-advised. In some situations, such as when a patient has experienced an acute increase in psychiatric symptoms or when psychotropics are being titrated, a short-term postponement of quitting may be reasonable. However, discouraging smokers from trying to quit when they express readiness to try should be done sparingly, because it is uncertain how long that window of opportunity will be open, and the consequences of missed opportunities can be fatal.

Related Resources

• National Tobacco Quitline. 1-800-QUIT-NOW. www.smokefree.gov.
• University of California, San Francisco, Schools of Pharmacy and Medicine. Rx for Change (free online training program for clinicians). http://rxforchange.ucsf.edu.
• National Association of State Mental Health Program Directors. Tobacco-free living in psychiatric settings: a best-practices toolkit promoting wellness and recovery. www.nasmhpd.org/general_files/publications/NASMHPD.toolkitfinalupdated90707.pdf.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Varenicline • Chantix

Disclosures

Dr. Heffner was supported by National Institute on Drug Abuse grant#026517. She is a consultant to Pfizer Inc.

Dr. Anthenelli is supported by National Institute on Alcohol Abuse and Alcoholism grant#AA19720 and by the Department of Veterans Affairs. He is a consultant to GlaxoSmithKline and Pfizer Inc.

The Tri-State Tobacco and Alcohol Research Center receives research support from Eli Lilly and Company, Nabi Biopharmaceuticals, Pfizer Inc., and sanofi-aventis.

Discuss this article at www.facebook.com/CurrentPsychiatry

You are treating Mr. P, age 34, for schizoaffective disorder. He smokes 1 pack of cigarettes per day and has smoked for approximately 17 years. He has tried to stop but never has been able to quit for more than a few weeks. He reveals whenever he tries to quit, he starts feeling extremely lethargic and “depressed” and resumes smoking to prevent these symptoms from worsening. However, Mr. P expresses some interest in trying to quit again and asks whether any medications could prevent him from becoming depressed while he tries to quit.

Cigarette smoking is overrepresented and undertreated among individuals with psychiatric illness, in part because of the largely unfounded belief held by some patients and clinicians that smoking cessation might worsen psychiatric symptoms. In this article, we argue this challenge can be overcome and psychiatrists and other mental health professionals can and should help their patients reap the innumerable benefits of quitting smoking. We discuss:

• the short- and long-term effects of smoking cessation
• evidence-based treatment guidelines for working with motivated and unmotivated smokers
• unique issues that may arise when treating smokers who have psychiatric disorders.

Quitting: Profound benefits

Quitting smoking has substantial benefits beginning within minutes after taking the last puff. Some of the benefits that occur within the first few days of quitting include:

• decreased blood pressure and pulse rate
• improved circulation
• improved ability to smell and taste
• easier breathing.

Longer-term smoking abstinence drastically reduces risk of heart attack, stroke, cancer, respiratory disease, and a host of other illnesses that affect—and kill—individuals with psychiatric disorders several decades earlier than their counterparts in the general population.¹ There also are financial benefits to quitting; using the 2009 national average of $5.33 per pack, a 1-pack-per-day smoker who quits would save >$150 per month, which accounts for only the direct cost of cigarettes.²

Although the beneficial effects of quitting smoking are profound and far-reaching, in the short-term they are counterbalanced by nicotine withdrawal symptoms—including restlessness, irritability, depressed mood, concentration problems, and increased appetite/weight gain—that are formidable distractions from the positive aspects of quitting. Additionally, nicotine withdrawal symptoms tend to be more severe in smokers who have a psychiatric disorder.³ Fortunately, there are effective, evidence-based methods of reducing withdrawal symptoms and helping smokers cope with these and other challenges of quitting.

Combined treatment is best

Current treatment guidelines⁴ suggest all smokers should be offered pharmacotherapy and counseling to aid quitting because this combined approach has the highest success rate (Algorithm). Table 1 ⁴ provides information about dosing, efficacy, and side effect profile of each of the 7 FDA-approved medications for smoking cessation. Using any of the approved medications at least doubles the odds of successful quitting compared with placebo.⁴ These pharmacotherapies can reduce or prevent nicotine withdrawal symptoms and—at least in the case of bupropion and varenicline—decrease reinforcement from smoking, thereby lowering the likelihood a lapse (ie, smoking ≥1 cigarettes without returning to regular smoking) will develop into a full-blown relapse (ie, return to regular smoking).

Algorithm: Tobacco cessation treatment for psychiatric patients
Source: Adapted from reference 4 Medication selection depends on many factors, including:

• the patient’s psychiatric illness
• her/his prior response to smoking cessation pharmacotherapies
• concomitant psychiatric medications
• patient preference.⁵

Placebo-controlled trials of smoking cessation aids in psychiatrically ill patients are limited, but several studies of smokers with a history of major depression indicate treatment with bupropion SR or nortriptyline is effective.⁶ Similarly, although relapse rates generally are higher in patients with schizophrenia compared with non-mentally ill smokers, nicotine replacement therapy and bupropion SR are more effective than placebo in patients with this disorder.^7,8 When we prescribe these treatments, we tend to extend the duration of treatment beyond those described in Table 1 ,⁴ and to use combined treatments (eg, a transdermal patch with a shorter-acting gum or lozenge preparation) to better target the marked withdrawal symptoms more severely nicotine-dependent patients frequently experience.

Table 1

First-line pharmacotherapies for smoking cessation

Counseling. All smokers should be provided with brief interventions consistent with the 5 A’s—Ask, Advise, Assess, Assist, and Arrange (Table 2).⁴ For smokers who are not motivated to quit, the recommended approach follows the principles of the 5 R’s—Relevance, Risks, Rewards, Roadblocks, and Repetition (Table 3).⁴ Smokers who are motivated to quit and willing to participate in more intensive treatment may be offered face-to-face individual or group counseling (depending upon availability) or referred to a telephone quit line (see Related Resources). Intensive treatments such as these typically provide social support and assistance overcoming barriers to cessation and developing skills to initiate and maintain abstinence (eg, coping with a lapse or handling cravings, identifying and avoiding high-risk situations for smoking). As a general rule, greater intensity of counseling is associated with a greater likelihood of quitting.⁴

Table 2

The 5 A’s of tobacco treatment

Table 3

The 5 R’s: Principles of interventions for smokers not ready to quit

Q&A about treatment

How effective are smoking cessation interventions for individuals with psychiatric disorders? Several studies have demonstrated, on any given quit attempt, smokers with psychiatric or substance use disorders can be as successful as smokers without these disorders.^9-11 In fact, quit rates as high as approximately 70% for end-of-treatment¹¹ and 30% for 6-month follow-up¹⁰ have been reported. Of course, effectiveness varies by type and intensity of treatment as well as by individual characteristics of the smoker. Smokers with psychiatric disorders may fare better with more intensive interventions than briefer ones,^12,13 and factors such as high levels of nicotine dependence and exposure to smoking environments—both of which are characteristic of smokers with serious mental illness—can negatively impact treatment outcomes.⁴

Should the nature of the psychiatric disorder(s) guide decisions about the optimal pharmacotherapy or counseling approach? There have been numerous attempts to investigate the effectiveness of targeted interventions for particular subgroups of smokers with psychiatric disorders, including:

• studies of the efficacy of the antidepressants bupropion¹⁴ and nortriptyline¹⁵ as well as cognitive-behavioral therapy-based mood management counseling¹⁶ for depressed smokers
• integrative treatment approaches for smokers with posttraumatic stress disorder (PTSD)¹⁷
• group counseling designed specifically for smokers with schizophrenia.^18,19

Although more research is needed and there have been some promising early results (eg, McFall et al¹⁷), current literature does not provide consistent evidence supporting treatment matching solely on the basis of the psychiatric disorder. Rather, patient preference, safety considerations (eg, use of medications in children/adolescents, pregnant women), medication side effect profiles, prior experience with the treatment approach, and cost/availability of treatment should guide development of the treatment plan. When results from placebo-controlled trials are available for subgroups of patients (eg, those with a history of major depression), consider this information when selecting a pharmacologic smoking cessation aid.

What is the risk of psychiatric symptoms worsening as a result of quitting smoking? Little research on this topic is available because more often than not, smokers with psychiatric disorders are excluded from tobacco treatment studies. However, research examining psychiatric status changes among recent quitters with schizophrenia,^20,21 depression,^22,23 PTSD,¹⁷ and substance use disorders²⁴ suggests smoking cessation does not worsen symptoms of these disorders, and may be associated with symptom improvement.¹⁷ Nonetheless, driven largely by anecdotal evidence, the misconception that smoking cessation worsens psychiatric symptoms remains a substantial barrier to treatment.

Mr. P’s case is an example of how not probing about the nature of psychiatric complaints can be problematic. Mr. P reported what on first glance appeared to be a worsening of psychiatric symptoms starting when he stopped smoking and resolved when he resumed smoking. However, without gathering additional information about these events, we cannot conclude stopping smoking caused his psychiatric symptoms to worsen. Other potential explanations include nicotine withdrawal symptoms, side effects of smoking cessation medications, an increase in levels of psychotropic medications for which metabolism is affected by tobacco smoke, or the natural course of his mood disorder. The timing of the onset and offset of symptoms seems to argue against Mr. P’s symptoms reflecting the natural course of his mood disorder, but the other 3 explanations remain plausible.

It is important to distinguish whether Mr. P’s worsening symptoms are consistent with a depressive episode or whether they are a manifestation of the transient dysphoria that accompanies nicotine withdrawal. Assessing the severity and persistence of the mood disturbance as well as the timing of onset could help make this determination. Nicotine withdrawal symptoms typically emerge within 24 hours of quitting or significantly reducing smoking and tend to peak within approximately 1 week. Thus, depressive symptoms that develop after weeks or months of abstinence would be less consistent with nicotine withdrawal. Additionally, the lethargy Mr. P reported may be a symptom of depression, or it may stem from a cessation-induced increase in antipsychotic serum levels. Because tobacco smoke increases the metabolism of several antipsychotics and antidepressants—including olanzapine, clozapine, haloperidol, and fluoxetine²⁵—stopping smoking may increase medication levels and side effects. To rule out medication side effects as a cause of post-cessation mood changes, the psychiatrist should ask Mr. P about which smoking cessation pharmacotherapies (if any) he was using and which psychotropic medications he was taking. Unfortunately, such a detailed history is not always taken, and patient-generated theories of smoking cessation causing worsening psychiatric symptoms often are taken at face value.

When should smokers with psychiatric disorders be encouraged to quit? Are there times when smoking cessation should be discouraged? Tobacco treatment guidelines⁴ recommend advising users to quit at every clinical encounter, but there has been some debate about the timing of tobacco treatment for smokers with psychiatric disorders. There is minimal research to guide such treatment decisions. However, even if quit attempts are more successful during times of symptomatic stability—and there is no conclusive evidence to indicate they are—waiting for perfect mental health before initiating smoking cessation treatment is unnecessary and ill-advised. In some situations, such as when a patient has experienced an acute increase in psychiatric symptoms or when psychotropics are being titrated, a short-term postponement of quitting may be reasonable. However, discouraging smokers from trying to quit when they express readiness to try should be done sparingly, because it is uncertain how long that window of opportunity will be open, and the consequences of missed opportunities can be fatal.

Related Resources

• National Tobacco Quitline. 1-800-QUIT-NOW. www.smokefree.gov.
• University of California, San Francisco, Schools of Pharmacy and Medicine. Rx for Change (free online training program for clinicians). http://rxforchange.ucsf.edu.
• National Association of State Mental Health Program Directors. Tobacco-free living in psychiatric settings: a best-practices toolkit promoting wellness and recovery. www.nasmhpd.org/general_files/publications/NASMHPD.toolkitfinalupdated90707.pdf.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Nortriptyline • Aventyl, Pamelor
• Olanzapine • Zyprexa
• Varenicline • Chantix

Disclosures

Dr. Heffner was supported by National Institute on Drug Abuse grant#026517. She is a consultant to Pfizer Inc.

Dr. Anthenelli is supported by National Institute on Alcohol Abuse and Alcoholism grant#AA19720 and by the Department of Veterans Affairs. He is a consultant to GlaxoSmithKline and Pfizer Inc.

The Tri-State Tobacco and Alcohol Research Center receives research support from Eli Lilly and Company, Nabi Biopharmaceuticals, Pfizer Inc., and sanofi-aventis.

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

CASE: Gl surgery

Ms. X, age 61, presents to the emergency department (ED) complaining of nausea, vomiting, and abdominal pain and distension. CT scan of her abdomen reveals segmental ischemia in her colon with abscess formation, which leads to immediate surgery, including ileocecostomy with primary anastomosis. After surgery, Ms. X suffers from gastrointestinal (GI) dysmotility. The gastroenterology team recommends daily enemas along with a soft diet after she is discharged.

Ms. X has chronic paranoid schizophrenia, which has been treated successfully for 18 years with clozapine, 500 mg/d. During acute psychotic episodes, she experienced paranoid delusions and command auditory hallucinations telling her to kill herself. She had previous trials of several antipsychotics, including quetiapine, thiothixene, thioridazine, trifluoperazine, chlorpromazine, and haloperidol, all of which were ineffective and poorly tolerated because of serious side effects.

Within 1 month of discharge, Ms. X returns to the ED with nausea, vomiting, and abdominal distension. Abdominal CT scan suggests partial small bowel obstruction and significantly dilated loops of small bowel with decompressed rectum and sigmoid colon. Considering her recent GI surgery and absence of abdominal pain, she is managed with conservative measures, including nasogastric tube decompression and total parenteral nutrition. CT enterography demonstrates no areas of stricture formation with interval decompression.

The psychiatric service is consulted to evaluate the possibility of clozapine-induced paralytic ileus. During initial assessment, Ms. X denies any psychotic symptoms, including paranoid ideations, delusions, and auditory or visual hallucinations, and firmly believes that clozapine helps keep her stable. She also denies mood symptoms that could indicate mania or depression. She shows no signs or symptoms that suggest anticholinergic delirium.

The authors’ observations

Clozapine has proven efficacy in managing treatment-resistant schizophrenia,^1-3 but the drug has been associated with life-threatening side effects, including agranulocytosis/neutropenia, myocarditis/cardiomyopathy, arrhythmia, seizures, diabetic ketoacidosis, fulminant hepatic failure, pulmonary embolism, and GI complications.⁴

Clozapine-induced GI side effects include anorexia, nausea, vomiting, heartburn, abdominal discomfort, diarrhea, and constipation. Clozapine-induced gastrointestinal hypomotility (CIGH) can lead to fecalith formation, which may result in intestinal obstruction/pseudo-obstruction, intestinal distension, necrosis, perforation, sepsis, aspiration from inhalation of feculent vomitus, or dysphagia.⁵ Constipation has been reported in 14% to 60% of patients who take clozapine,⁶ although other psychiatric medications also can cause constipation (Table 1). Severe constipation can lead to potentially fatal GI complications such as intestinal obstruction, necrosis, perforation, and sepsis, which is associated with significant morbidity due to bowel resection and a 27.5% mortality rate.⁵

The underlying mechanism of clozapine-induced constipation has been well established. The gut is innervated mainly by cholinergic and serotonergic receptors (5-HT3) and these receptors are responsible for peristalsis. Clozapine has a potent anticholinergic effect and acts as a strong antagonist of serotonin receptors (5-HT2, 5-HT3, 5-HT6, 5-HT7), which can lead to gut hypomotility.⁷ Risk factors associated with CIGH include:

• high dose of clozapine (mean dosage >428 mg/d)
• high serum clozapine levels (>500 ng/mL)
• coadministration of anticholinergic medications
• concomitant use of cytochrome P450 (CYP) enzyme inhibitors (medications inhibiting CYP1A2 enzyme)
• comorbid medical illnesses
• fever
• history of surgical bowel resection, GI pathology, and constipation.⁵

Table 1

Psychotropics associated with constipation

HISTORY: Medical comorbidities

Ms. X’s medical history is significant for chronic constipation, hypertension, obstructive pulmonary disease, and hyperthyroidism. Her medications include trazodone, 25 mg/d; fluoxetine, 40 mg/d, for negative symptoms and insomnia; docusate sodium, 200 mg/d; polyethylene glycol, 17 g/d; and bisacodyl suppository, 10 mg as needed for constipation. On admission, her laboratory test results—including complete blood count, liver function tests, kidney function tests, thyroid function profile, and serum calcium levels—all were within normal range.

The authors’ observations

Because the prevalence and severity of clozapine-induced constipation seem to be dose-dependent,⁸ minimizing the dosage is a logical management strategy.⁹ The life-threatening nature of clozapine-induced GI complications may require rapid dose reduction, which could compromise a patient’s stability. There is a little evidence regarding systematic management of clozapine-induced GI complications (Table 2).

Table 2

Clinical pearls for treating clozapine-induced constipation

TREATMENT: Clozapine reduction

We obtain a serum clozapine level, which is elevated at 553 ng/mL. We recommend gradual reducing Ms. X’s clozapine dosage by 50 mg every 3 to 4 days to reach a target dose of 300 to 350 mg/d, to attain serum clozapine levels 350 to 400 ng/mL. Because of trazodone’s potential anticholinergic action, which could be worsening Ms. X’s constipation, we stop the drug and begin zolpidem, 5 to 10 mg/d, to manage her insomnia. During these medication changes, we closely monitor Ms. X for reemerging psychotic symptoms.

The authors’ observations

In addition to risk factors such as chronic constipation and recent GI surgery, Ms. X’s supra-therapeutic serum clozapine level (553 ng/mL) significantly increased her risk of clozapine-induced paralytic ileus. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are known to increase tissue concentrations of clozapine and its major metabolite, norclozapine, by primarily inhibiting CYP1A2 and perhaps CYP2D6.¹⁰ As a potent inhibitor of CYPA12, fluvoxamine can inhibit clozapine metabolism, resulting in higher plasma concentrations.¹¹ In Ms. X’s case, fluoxetine could have increased serum clozapine levels because of its ability to inhibit clozapine metabolism via CYP2D6-mediated mechanisms.¹²

Although clozapine serum levels are not routinely measured, such testing may be indicated in patients who do not respond to or are unable to tolerate clozapine. Clozapine levels should be obtained 12 hours after the bedtime dose (trough levels), several days after clozapine initiation. Serum clozapine levels <350 ng/mL are associated with lack of clinical response.¹³ Higher serum levels (500 to 700 ng/mL) have been associated with greater incidences of serious GI complications. Serum clozapine levels also help guide clozapine dosage reduction because of its linear kinetics—halving the dose will halve the serum clozapine level.¹⁴

OUTCOME: GI symptoms improve

Ms. X shows improved GI motility within few days of the first decrease in her clozapine dosage. Nausea, vomiting, and abdominal distension gradually resolve over 2 weeks with concomitant reduction in clozapine dosage to 300 mg/d (50 mg in the morning and 250 mg at bedtime) without reemergence of psychotic symptoms. She is able to tolerate a soft diet, and conservative GI measures are no longer required. She is discharged home with outpatient surgical and psychiatric follow-up.

The authors’ observations

Successful reversal of severe clozapine-induced constipation—occurring at serum clozapine level of 490 ng/mL—has been reported in a 45-year-old man with treatment-resistant schizophrenia. This was accomplished by cautious reduction of clozapine dosage (400 mg/d to 250 mg/d) over 1 week.¹⁵ Slower clozapine titration—reducing the dose by no more than 25 mg/d to a maximum of 100 mg/week—has been recommended.¹⁶ It also has been suggested to replace part of the clozapine dose with a less antimuscarinic antipsychotic, such as quetiapine or haloperidol, thereby using the second antipsychotic as a clozapine-sparing agent.⁹ For example, the clozapine dose could be reduced by 25% by substituting 2 mg of quetiapine for every 1 mg of clozapine.

Prevention

Psychiatrists who prescribe clozapine should take a careful history of risk factors that might predispose patients to clozapine-induced GI side effects. Caution patients to whom you prescribe clozapine about possible development of constipation and the risk of serious GI complications. Enlist family members and caseworkers to keep a close eye on GI side effects in patients receiving clozapine. Advise patients to prevent constipation by eating a high fiber diet, drinking adequate fluids, and getting regular exercise. Patients should be treated aggressively with laxatives to relieve constipation and educated about the warning signs of intestinal obstruction, such as worsening constipation, abdominal pain, vomiting, and inability to pass flatus.¹⁷

Rapidly fatal bowel ischemia caused by clozapine has been reported.¹⁸ Therefore, urgently refer patients for medical evaluation if you have any concerns about worsening constipation or observe signs of intestinal obstruction. Vigilant consideration of clozapine as a likely culprit in severe GI complications in inpatient settings can prevent morbidity and mortality.

In our case, cautious reduction of clozapine dosage, guided by serum clozapine levels, had obviated the need for surgery and prevented reemergence of psychotic symptoms.

Related Resources

• Drew L, Herdson P. Clozapine and constipation: a serious issue. Aust N Z J Psychiatry. 1997;31(1):149-150.
• Winstead NS, Winstead DK. 5-step plan to treat constipation in psychiatric patients. Current Psychiatry. 2008;7(5):29-39.

Drug Brand Names

• Amitriptyline • Elavil
• Benztropine • Cogentin
• Bisacodyl suppository • Dulcolax, others
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Docusate sodium • Colace, others
• Doxepin • Adapin, Sinequan
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Imipramine • Tofranil
• Nortriptyline • Aventyl, Pamelor
• Pimozide • Orap
• Polyethylene glycol • MiraLax
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trihexyphenidyl • Artane, Trihexane
• Trimipramine • Surmontil
• Zolpidem • Ambien

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY

Discuss this article at www.facebook.com/CurrentPsychiatry

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY

Discuss this article at www.facebook.com/CurrentPsychiatry

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY

Discuss this article at www.facebook.com/CurrentPsychiatry

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Discuss this article at www.facebook.com/CurrentPsychiatry

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Discuss this article at www.facebook.com/CurrentPsychiatry

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Discuss this article at www.facebook.com/CurrentPsychiatry

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

Discuss this article at www.facebook.com/CurrentPsychiatry

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

Discuss this article at www.facebook.com/CurrentPsychiatry

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

Discuss this article at www.facebook.com/CurrentPsychiatry

Differentiating NLD

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

Efficient pharmacotherapy

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

Glutamatergic dysfunction

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Treating delirium

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY

Discuss this article at www.facebook.com/CurrentPsychiatry

Differentiating NLD

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

Efficient pharmacotherapy

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

Glutamatergic dysfunction

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Treating delirium

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY

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Differentiating NLD

“Does your patient have a psychiatric illness or nonverbal learning disorder?” (Current Psychiatry, May 2011, p. 17-35) reviews the differential diagnosis of “nonverbal learning disorder.”

Nonverbal learning disorder (NLD) has yet to be established as a distinct, valid neurodevelopmental syndrome. Many of the proffered diagnostic criteria, clinical presentations, and laboratory findings (especially results from psychological/neuropsychological and psychoeducational testing) overlap considerably with other neurodevelopmental syndromes characterized by social inadequacy and peculiarity, including Asperger’s disorder.

Therefore, rather than representing a discrete diagnostic category with overlapping features as suggested by this article, this putative syndrome probably is best conceptualized as falling within the milder end of a neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception, accompanied by impaired daily functioning referable to these difficulties. The DSM-5 workgroup appears to recognize this problem of “splitting” vs “lumping.” Reports indicate that Asperger’s disorder may no longer be considered a “standalone” clinical syndrome and likely will be reconceptualized as a mild form of autism.

Many individuals have cognitive/neuropsychological and academic/learning difficulties compatible with nonverbal learning problems and do not exhibit the difficulties with social interactions the article cites. One way to advocate for NLD as a distinct clinical syndrome is to limit the diagnosis to a certain constellation of cognitive/neuropsychological and academic impairments that lead to educational, interpersonal, and/or vocational difficulties. Patients who also display clinically significant neurodevelopmentally based deficits in social competence/skills would fall outside this category and would be placed within the milder end of the autistic spectrum, or perhaps included within a broader “neuro-social disorder” spectrum. As the authors aptly point out, psychometric testing is important for diagnosis and psychoeducational planning for patients with the information processing difficulties and life struggles well described in this article.

Jerrold Pollak, PhD
Coordinator, Program in Medical and
Forensic Neuropsychology
Seacoast Mental Health Center
Portsmouth, NH

The authors respond

We thank Dr. Pollak for his comments. Although considerable overlap may exist among “neurodevelopmental syndromes characterized by social inadequacy and peculiarity,” we sought to draw attention to the specific neurocognitive differences in NLD as compared with other disorders that, despite potentially sharing features with NLD, are distinct disorders.

We agree with Dr. Pollak’s suggestion that NLD someday might be classified within the DSM along a “neurodevelopmental disorder spectrum characterized by deficits in social competence, judgment, and perception accompanied by impaired everyday functioning referable to these difficulties.” This process will require careful characterization of individuals with NLD—as well as other individuals with difficulties in visual-spatial integration, attention, nonverbal memory, and expression and integration of emotion—to establish convergent and discriminant validity for NLD. Further, we believe that recognition of NLD as a distinct disorder will facilitate research and development of specific treatment interventions as compared with other conditions, despite potential syndromic or symptomatic overlap with NLD.

Sergio V. Delgado, MD
Professor of Psychiatry, Pediatrics,
and Psychoanalysis

Elizabeth Wassenaar, MD
Resident in Psychiatry, Child and Adolescent
Psychiatry, and Pediatrics

Jeffrey R. Strawn, MD
Assistant Professor of Psychiatry
and Pediatrics
Cincinnati Children’s Hospital Medical Center
University of Cincinnati College of Medicine
Cincinnati, OH

Efficient pharmacotherapy

I agree with Dr. Nasrallah’s assertions that a single psychotropic can treat different disorders (“Parsimonious pharmacotherapy,” From the Editor, Current Psychiatry, May 2011, p. 12-16). During my consultation-liaison fellowship at MD Anderson Cancer Center, different forms of delirium were a daily occurrence in our hospitalized patients. A low dose of psychotropic—usually quetiapine—proved effective in controlling delirium; in acute and severe cases, low-dose IV haloperidol helped control agitation and psychosis.

Low-dose quetiapine also was beneficial in treating comorbidities such as increased anxiety, depression, pain, and insomnia, with minimal side effects. Because most of our patients suffered from several medical conditions and powerful, multiple-medication chemotherapies, in most cases psychotropic polypharmacy was contraindicated and avoided at all costs.

Corey Roman, MD
Psychiatrist, private practice
Miami, FL

Glutamatergic dysfunction

I read with interest the article by Drs. Kantrowitz and Javitt (“Glutamate: New hope for schizophrenia treatment,” Current Psychiatry, April 2011, p. 68-74) describing the glutamatergic model of schizophrenia. There is extensive evidence that in addition to neurocognitive deficits, schizophrenia is characterized by various neuromuscular abnormalities, including skeletal muscle fiber changes, alterations of alpha-motor neuron excitability, increased motor unit fiber densities, increased branching of terminal motor nerves, and elevated levels of muscular enzymes.^1,2 These neuromuscular abnormalities also are found in healthy first-degree relatives of patients with schizophrenia.³ Although the precise cause of these neuromuscular abnormalities has not been elucidated, one possible explanation is that they may be the result of neuronal injury mediated by excitatory amino acids.¹ For example, Stevens⁴ suggested that abnormal sprouting and reinnervation of neurons in schizophrenia might be caused by such injury.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative syndrome involving upper and lower alpha-motor neuron systems. A substantial body of evidence supports the hypothesis that glutamate-mediated excito-toxicity is responsible for the death of motor neurons in ALS.⁵ Evidence suggests that having schizophrenia may be associated with an increased risk of developing ALS, and this risk might be explained by the toxic effects of excitatory amino acids on neuronal function.^1,6 Recently, Stommel et al⁷ hypothesized that treating schizophrenia could protect against development of ALS, which is of interest because antipsychotics may have direct and indirect effects on modulating glutamate receptor systems.⁸

Robert H. Howland, MD
Associate Professor of Psychiatry
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, PA

Treating delirium

Regarding “Atypical antipsychotics for delirium: A reasonable alternative to haloperidol?” (Current Psychiatry, January 2011, p. 37-46): Delirium usually is an acute encephalopathy with cerebral dysfunction caused by varying pathologies, most of which are extracranial. Examples include mental confusion induced by hypoxia or hypoglycemia. Primary treatment of delirium must be aimed at the specific cause.

Antipsychotic drugs are only a symptomatic intervention for delirium. They can and do provide behavioral control; however, these medications may worsen cases of alcohol or sedative withdrawal, ictal-related problems, neuroleptic malignant syndrome, etc. An antipsychotic may complicate other conditions, thus creating additional clinical difficulties for some patients. Recommending antipsychotics as a treatment focuses on symptomatic aspects; however, the critical mandate is to diagnose and specifically manage the etiology. Once the cause is corrected, the delirium usually resolves.

While treating the primary pathology, if behavioral issues still urgently require immediate control, a benzodiazepine is safer than an antipsychotic. Both medications provide symptomatic control, but a benzodiazepine is less likely to add new clinical problems. The only major precaution with a benzodiazepine is to avoid overprescribing. It is simply safer to rely on benzodiazepines for short-term behavioral management.

Steven Lippmann, MD
Professor of Psychiatry
University of Louisville School of Medicine
Louisville, KY