Current Psychiatry

As an attorney with 2 decades of experience representing plaintiffs in suits against mental health facilities and professionals, I can say that Dr. Douglas Mossman is right on target about the drawbacks of defensive medicine (“Defensive medicine: Can it increase your malpractice risk?” Malpractice Rx, Current Psychiatry). This is particularly true in psychiatry, where an alliance and trusting relationship between doctor and patient are crucial. It’s hard for a patient to perceive a clinician’s empathy and concern if the clinician’s actions amount to treating the patient as a potential litigant or adversary.

The psychiatrists I admire and respect focus on caring and empathy, understanding the patient’s needs, and respectful treatment, and these professionals tend not to get sued. On the rare occasions that these psychiatrists initiate involuntary interventions—because these interventions often do disrupt therapeutic relationships, as Dr. Mossman says—they are straightforward and honest with the patient about their reasons (caring and concern, not fear of litigation) and apologize for the distress they are causing. Patients can tell that a doctor sincerely cares about and respects them, and they forgive a lot when they perceive that attitude. Patients hate being coerced and threatened with the psychiatrist’s power to involuntarily commit hanging over every interaction if the patient is not “compliant.”

I have seen psychiatrists negotiate with their patients brilliantly and respectfully, and, as Dr. Mossman suggests, patients generally don’t sue these doctors. The doctors who get sued often are those who are afraid to apologize or admit error, are controlling and disrespectful, really aren’t listening, and care more about following institutional rules than about their patients. I have never represented a patient in a lawsuit who would not have been satisfied with a sincere apology, even after pretty terrible events. These patients sought legal help only after being rebuffed or ignored when they sought to complain or protest their treatment.

Obviously, there are exceptions to all generalizations, but my observation is the product of 20 years of this work.

Susan Stefan, JD
Center for Public Representation
Newton, MA

As an attorney with 2 decades of experience representing plaintiffs in suits against mental health facilities and professionals, I can say that Dr. Douglas Mossman is right on target about the drawbacks of defensive medicine (“Defensive medicine: Can it increase your malpractice risk?” Malpractice Rx, Current Psychiatry). This is particularly true in psychiatry, where an alliance and trusting relationship between doctor and patient are crucial. It’s hard for a patient to perceive a clinician’s empathy and concern if the clinician’s actions amount to treating the patient as a potential litigant or adversary.

The psychiatrists I admire and respect focus on caring and empathy, understanding the patient’s needs, and respectful treatment, and these professionals tend not to get sued. On the rare occasions that these psychiatrists initiate involuntary interventions—because these interventions often do disrupt therapeutic relationships, as Dr. Mossman says—they are straightforward and honest with the patient about their reasons (caring and concern, not fear of litigation) and apologize for the distress they are causing. Patients can tell that a doctor sincerely cares about and respects them, and they forgive a lot when they perceive that attitude. Patients hate being coerced and threatened with the psychiatrist’s power to involuntarily commit hanging over every interaction if the patient is not “compliant.”

I have seen psychiatrists negotiate with their patients brilliantly and respectfully, and, as Dr. Mossman suggests, patients generally don’t sue these doctors. The doctors who get sued often are those who are afraid to apologize or admit error, are controlling and disrespectful, really aren’t listening, and care more about following institutional rules than about their patients. I have never represented a patient in a lawsuit who would not have been satisfied with a sincere apology, even after pretty terrible events. These patients sought legal help only after being rebuffed or ignored when they sought to complain or protest their treatment.

Obviously, there are exceptions to all generalizations, but my observation is the product of 20 years of this work.

Susan Stefan, JD
Center for Public Representation
Newton, MA

As an attorney with 2 decades of experience representing plaintiffs in suits against mental health facilities and professionals, I can say that Dr. Douglas Mossman is right on target about the drawbacks of defensive medicine (“Defensive medicine: Can it increase your malpractice risk?” Malpractice Rx, Current Psychiatry). This is particularly true in psychiatry, where an alliance and trusting relationship between doctor and patient are crucial. It’s hard for a patient to perceive a clinician’s empathy and concern if the clinician’s actions amount to treating the patient as a potential litigant or adversary.

The psychiatrists I admire and respect focus on caring and empathy, understanding the patient’s needs, and respectful treatment, and these professionals tend not to get sued. On the rare occasions that these psychiatrists initiate involuntary interventions—because these interventions often do disrupt therapeutic relationships, as Dr. Mossman says—they are straightforward and honest with the patient about their reasons (caring and concern, not fear of litigation) and apologize for the distress they are causing. Patients can tell that a doctor sincerely cares about and respects them, and they forgive a lot when they perceive that attitude. Patients hate being coerced and threatened with the psychiatrist’s power to involuntarily commit hanging over every interaction if the patient is not “compliant.”

I have seen psychiatrists negotiate with their patients brilliantly and respectfully, and, as Dr. Mossman suggests, patients generally don’t sue these doctors. The doctors who get sued often are those who are afraid to apologize or admit error, are controlling and disrespectful, really aren’t listening, and care more about following institutional rules than about their patients. I have never represented a patient in a lawsuit who would not have been satisfied with a sincere apology, even after pretty terrible events. These patients sought legal help only after being rebuffed or ignored when they sought to complain or protest their treatment.

Obviously, there are exceptions to all generalizations, but my observation is the product of 20 years of this work.

Susan Stefan, JD
Center for Public Representation
Newton, MA

Discuss this article

Researchers in Finland surprised psychiatrists this year by announcing that clozapine “seems to be associated with a substantially lower mortality than any other antipsychotic.”¹ This finding also surprised the researchers, who expected their 11-year study to link long-term use of second-generation (“atypical”) antipsychotics with increased mortality in patients with schizophrenia. Instead they found longer lives in patients who used antipsychotics (and particularly clozapine), compared with no antipsychotic use.

This study’s findings do not change clozapine’s association with potentially fatal agranulocytosis as well as weight gain, metabolic abnormalities, and other adverse effects. Clozapine also is difficult to administer ( Box 1 ),² and patients must be enrolled in FDA-mandated registries (see Related Resources ). These obstacles might discourage you from offering clozapine to patients who could benefit from it ( Box 2 ).^3-5

Why bother considering clozapine? Because recent data on decreased mortality, decreased suicidality, and control of aggressive behavior make clozapine a compelling choice for many patients. Careful attention to clozapine’s adverse effect profile is necessary, but you can manage these risks with appropriate monitoring.

Box 1

Box 2

Potential for longer life?

The population-based, cohort study from Finland demonstrated that—contrary to popular belief—the introduction of atypical antipsychotics during the 1990s did not adversely affect mortality of patients with schizophrenia, at least in Finland.¹

This study made specific drug comparisons and used perphenazine as the reference drug. The lowest risk for mortality was observed with clozapine, which showed a 26% relative advantage compared with perphenazine. Clozapine’s advantage was statistically significant when compared with all other antipsychotics tested.

The authors suggested provocatively that restrictions on clozapine use as a second- or third-line agent should be reassessed. A few caveats, however, might affect how one interprets this study or applies its findings to clinical practice:

• The main comparisons were for patients receiving outpatient antipsychotic monotherapy. No information was available about antipsychotics used during inhospital treatment.
  
• Only the most frequently used atypical antipsychotics (clozapine, olanzapine, oral risperidone, and quetiapine) or the most frequently prescribed first-generation antipsychotics (oral perphenazine, thioridazine, and oral haloperidol) were assessed individually.
  
• Data about patients’ marital status, diagnoses of substance abuse, socioeconomic status, and other social variables were not available.
  
• Not all antipsychotics were available throughout the study (quetiapine was the newest and available for the shortest time).
  
• The study population consisted of patients of all ages, including those under 20 and over 70 years of age. Although the number of deaths and mortality rates increased with age, causes of mortality may differ when younger and older persons are compared. A data supplement to the study—available at www.thelancet.com—contains information about odds ratios by age and other factors.
  

Recommendation. Consider clozapine earlier than as a “last resort” in the disease course of patients with schizophrenia. At the very least, routinely present clozapine to patients and their families as a possible treatment option.

Antiaggressive properties

Case series and retrospective studies have provided insights into clozapine’s antiaggressive properties, but the strongest evidence comes from a 12-week, double-blind, randomized trial that specifically enrolled patients with violent behavior.⁶ Clozapine, olanzapine, and haloperidol were directly compared in the treatment of assaults and other aggressive behaviors by physically assaultive in patients with schizophrenia and schizoaffective disorder:

• The Modified Overt Aggression Scale (MOAS) physical aggression score measured the number and severity of assaults.
  
• The Positive and Negative Syndrome Scale (PANSS) was used to assess psychiatric symptoms.
  

Recommendation. Offer clozapine as an option for patients with schizophrenia or schizoaffective disorder and persistent aggressive behavior. Another antipsychotic might not be “good enough.”

Reduced risk of suicidality

The International Suicide Prevention Trial (InterSePT) was a multicenter, randomized, 2-year clinical study that compared the risk for suicidal behavior in patients treated with clozapine vs olanzapine.⁷ Enrolled were 980 patients with schizophrenia or schizoaffective disorder who were considered at high risk for suicide because of past suicide attempts or current suicidal ideation. Approximately one-quarter had not responded adequately to previous treatment.

All patients were seen weekly for 6 months, then biweekly for 18 months. The weekly or biweekly contact required to monitor for clozapine-associated agranulocytosis was matched with a similar visit schedule for olanzapine-treated patients, during which clinicians obtained vital signs. Primary endpoints included suicide attempts (including death), hospitalization to prevent suicide, and a rating of “much worsening of suicidality” from baseline. Blinded raters, including an independent suicide monitoring board, determined when patients achieved endpoint criteria.

Patients receiving clozapine showed significantly less suicidal behavior than those treated with olanzapine (a 24% relative advantage in the hazard ratio for suicide attempts or hospitalizations to prevent suicide). Fewer patients in the clozapine group:

• attempted suicide (34 vs 55)
  
• required hospitalization (82 vs 107) or rescue interventions to prevent suicide (118 vs 155)
  
• required concomitant treatment with antidepressants (221 vs 258) or anxiolytics/soporifics (301 vs 331).
  

More deaths from suicide occurred in the clozapine group than the olanzapine group, but the numbers were small (5 vs 3) and the difference between clozapine and olanzapine on this outcome was not statistically significant (P=.73).

Recommendation. Clozapine is a first-line treatment for patients with schizophrenia or schizoaffective disorder who exhibit suicidal behavior. This is reflected in the drug’s product labeling.

Superior symptom management

CATIE findings. Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed clozapine to be more effective than other atypical antipsychotics, as measured by time to all-cause discontinuation.⁸ Patients in this phase of CATIE had discontinued another atypical antipsychotic in phase 1, principally because of lack of adequate efficacy. In phase 2, they were re-randomized to receive open-label clozapine or double-blinded risperidone, olanzapine, or quetiapine.

Only 90 patients were included in the time-to-discontinuation analysis, yet the greater amount of time that patients remained on clozapine (median 10.5 months) compared with quetiapine (median 3.3 months) or risperidone (median 2.8 months) was statistically significant. Time to discontinuation because of inadequate therapeutic effect also was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone.

The NNT for the outcome of all-cause discontinuation for clozapine was 4 compared with risperidone and 3 compared with quetiapine. This means for every 4 or 3 patients randomly assigned to clozapine instead of risperidone or quetiapine, respectively, 1 additional patient successfully completed the CATIE trial on the original phase 2 medication.⁹ The NNT for clozapine vs olanzapine was 7, indicating a respectable effect size difference that might have been statistically significant if the sample size had been larger.

Meta-analyses support CATIE results. Clozapine’s greater efficacy (and effectiveness) compared with other antipsychotics as demonstrated in CATIE is supported by 2 meta-analyses:

• A systematic review of clinical trials between January 1953 and May 2002 found clozapine’s effect size in reducing symptoms for patients with schizophrenia was greater than that of any other antipsychotic.¹⁰
  
• In a similar but more recent meta-analysis of 150 double-blind, mostly short-term studies totaling 21,533 participants, clozapine showed the largest effect size when atypical antipsychotics were compared with first-generation antipsychotics.¹¹
  

Caveats about clozapine

First-episode schizophrenia. Clozapine has been shown to be more effective than chlorpromazine in terms of time to remission and maintenance of remission for treatment-naïve patients with first-episode schizophrenia.¹³ Even so, most clinicians probably would not consider clozapine as a first-line treatment for an uncomplicated first-episode patient because of concerns about agranulocytosis. When genetic testing becomes available to determine individual risk for agranulocytosis, perhaps clozapine will be used earlier in the disease course.¹⁴

Table

Common adverse effects of clozapine

Adjunctive treatments. Patients with a low baseline white blood cell count (WBC) and/or absolute neutrophil count (ANC) may benefit from adjunctive lithium treatment to increase their WBC, as demonstrated in case reports.¹⁸

When no other alternatives were clinically feasible, chronic treatment with granulocyte colony-stimulating factor (filgrastim) has been used successfully for some patients whose clozapine course was interrupted because of a low WBC and/or ANC.¹⁹

Related resources

• Clozapine product information (as revised July 2009): www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf.
  
• Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419.
  

• Teva: www.clozapineregistry.com.
  
• Clozaril: www.clozarilcare.com.
  
• Caraco: www.caracoclozapine.com.
  
• FazaClo: www.fazacloregistry.com.
  
• Mylan: www.mylan-clozapine.com.
  

• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril, FazaClo
  
• Filgrastim • Neupogen
  
• Haloperidol • Haldol
  
• Lithium • Lithobid, others
  
• Olanzapine • Zyprexa
  
• Perphenazine • Trilafon
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Ziprasidone • Geodon
  

Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pfizer Inc., Schering-Plough Corporation, and Vanda Pharmaceuticals. No writing assistance or external financial support was utilized in the preparation of this review article.

Discuss this article

Researchers in Finland surprised psychiatrists this year by announcing that clozapine “seems to be associated with a substantially lower mortality than any other antipsychotic.”¹ This finding also surprised the researchers, who expected their 11-year study to link long-term use of second-generation (“atypical”) antipsychotics with increased mortality in patients with schizophrenia. Instead they found longer lives in patients who used antipsychotics (and particularly clozapine), compared with no antipsychotic use.

This study’s findings do not change clozapine’s association with potentially fatal agranulocytosis as well as weight gain, metabolic abnormalities, and other adverse effects. Clozapine also is difficult to administer ( Box 1 ),² and patients must be enrolled in FDA-mandated registries (see Related Resources ). These obstacles might discourage you from offering clozapine to patients who could benefit from it ( Box 2 ).^3-5

Why bother considering clozapine? Because recent data on decreased mortality, decreased suicidality, and control of aggressive behavior make clozapine a compelling choice for many patients. Careful attention to clozapine’s adverse effect profile is necessary, but you can manage these risks with appropriate monitoring.

Box 1

Box 2

Potential for longer life?

The population-based, cohort study from Finland demonstrated that—contrary to popular belief—the introduction of atypical antipsychotics during the 1990s did not adversely affect mortality of patients with schizophrenia, at least in Finland.¹

This study made specific drug comparisons and used perphenazine as the reference drug. The lowest risk for mortality was observed with clozapine, which showed a 26% relative advantage compared with perphenazine. Clozapine’s advantage was statistically significant when compared with all other antipsychotics tested.

The authors suggested provocatively that restrictions on clozapine use as a second- or third-line agent should be reassessed. A few caveats, however, might affect how one interprets this study or applies its findings to clinical practice:

• The main comparisons were for patients receiving outpatient antipsychotic monotherapy. No information was available about antipsychotics used during inhospital treatment.
  
• Only the most frequently used atypical antipsychotics (clozapine, olanzapine, oral risperidone, and quetiapine) or the most frequently prescribed first-generation antipsychotics (oral perphenazine, thioridazine, and oral haloperidol) were assessed individually.
  
• Data about patients’ marital status, diagnoses of substance abuse, socioeconomic status, and other social variables were not available.
  
• Not all antipsychotics were available throughout the study (quetiapine was the newest and available for the shortest time).
  
• The study population consisted of patients of all ages, including those under 20 and over 70 years of age. Although the number of deaths and mortality rates increased with age, causes of mortality may differ when younger and older persons are compared. A data supplement to the study—available at www.thelancet.com—contains information about odds ratios by age and other factors.
  

Recommendation. Consider clozapine earlier than as a “last resort” in the disease course of patients with schizophrenia. At the very least, routinely present clozapine to patients and their families as a possible treatment option.

Antiaggressive properties

Case series and retrospective studies have provided insights into clozapine’s antiaggressive properties, but the strongest evidence comes from a 12-week, double-blind, randomized trial that specifically enrolled patients with violent behavior.⁶ Clozapine, olanzapine, and haloperidol were directly compared in the treatment of assaults and other aggressive behaviors by physically assaultive in patients with schizophrenia and schizoaffective disorder:

• The Modified Overt Aggression Scale (MOAS) physical aggression score measured the number and severity of assaults.
  
• The Positive and Negative Syndrome Scale (PANSS) was used to assess psychiatric symptoms.
  

Recommendation. Offer clozapine as an option for patients with schizophrenia or schizoaffective disorder and persistent aggressive behavior. Another antipsychotic might not be “good enough.”

Reduced risk of suicidality

The International Suicide Prevention Trial (InterSePT) was a multicenter, randomized, 2-year clinical study that compared the risk for suicidal behavior in patients treated with clozapine vs olanzapine.⁷ Enrolled were 980 patients with schizophrenia or schizoaffective disorder who were considered at high risk for suicide because of past suicide attempts or current suicidal ideation. Approximately one-quarter had not responded adequately to previous treatment.

All patients were seen weekly for 6 months, then biweekly for 18 months. The weekly or biweekly contact required to monitor for clozapine-associated agranulocytosis was matched with a similar visit schedule for olanzapine-treated patients, during which clinicians obtained vital signs. Primary endpoints included suicide attempts (including death), hospitalization to prevent suicide, and a rating of “much worsening of suicidality” from baseline. Blinded raters, including an independent suicide monitoring board, determined when patients achieved endpoint criteria.

Patients receiving clozapine showed significantly less suicidal behavior than those treated with olanzapine (a 24% relative advantage in the hazard ratio for suicide attempts or hospitalizations to prevent suicide). Fewer patients in the clozapine group:

• attempted suicide (34 vs 55)
  
• required hospitalization (82 vs 107) or rescue interventions to prevent suicide (118 vs 155)
  
• required concomitant treatment with antidepressants (221 vs 258) or anxiolytics/soporifics (301 vs 331).
  

More deaths from suicide occurred in the clozapine group than the olanzapine group, but the numbers were small (5 vs 3) and the difference between clozapine and olanzapine on this outcome was not statistically significant (P=.73).

Recommendation. Clozapine is a first-line treatment for patients with schizophrenia or schizoaffective disorder who exhibit suicidal behavior. This is reflected in the drug’s product labeling.

Superior symptom management

CATIE findings. Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed clozapine to be more effective than other atypical antipsychotics, as measured by time to all-cause discontinuation.⁸ Patients in this phase of CATIE had discontinued another atypical antipsychotic in phase 1, principally because of lack of adequate efficacy. In phase 2, they were re-randomized to receive open-label clozapine or double-blinded risperidone, olanzapine, or quetiapine.

Only 90 patients were included in the time-to-discontinuation analysis, yet the greater amount of time that patients remained on clozapine (median 10.5 months) compared with quetiapine (median 3.3 months) or risperidone (median 2.8 months) was statistically significant. Time to discontinuation because of inadequate therapeutic effect also was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone.

The NNT for the outcome of all-cause discontinuation for clozapine was 4 compared with risperidone and 3 compared with quetiapine. This means for every 4 or 3 patients randomly assigned to clozapine instead of risperidone or quetiapine, respectively, 1 additional patient successfully completed the CATIE trial on the original phase 2 medication.⁹ The NNT for clozapine vs olanzapine was 7, indicating a respectable effect size difference that might have been statistically significant if the sample size had been larger.

Meta-analyses support CATIE results. Clozapine’s greater efficacy (and effectiveness) compared with other antipsychotics as demonstrated in CATIE is supported by 2 meta-analyses:

• A systematic review of clinical trials between January 1953 and May 2002 found clozapine’s effect size in reducing symptoms for patients with schizophrenia was greater than that of any other antipsychotic.¹⁰
  
• In a similar but more recent meta-analysis of 150 double-blind, mostly short-term studies totaling 21,533 participants, clozapine showed the largest effect size when atypical antipsychotics were compared with first-generation antipsychotics.¹¹
  

Caveats about clozapine

First-episode schizophrenia. Clozapine has been shown to be more effective than chlorpromazine in terms of time to remission and maintenance of remission for treatment-naïve patients with first-episode schizophrenia.¹³ Even so, most clinicians probably would not consider clozapine as a first-line treatment for an uncomplicated first-episode patient because of concerns about agranulocytosis. When genetic testing becomes available to determine individual risk for agranulocytosis, perhaps clozapine will be used earlier in the disease course.¹⁴

Table

Common adverse effects of clozapine

Adjunctive treatments. Patients with a low baseline white blood cell count (WBC) and/or absolute neutrophil count (ANC) may benefit from adjunctive lithium treatment to increase their WBC, as demonstrated in case reports.¹⁸

When no other alternatives were clinically feasible, chronic treatment with granulocyte colony-stimulating factor (filgrastim) has been used successfully for some patients whose clozapine course was interrupted because of a low WBC and/or ANC.¹⁹

Related resources

• Clozapine product information (as revised July 2009): www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf.
  
• Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419.
  

• Teva: www.clozapineregistry.com.
  
• Clozaril: www.clozarilcare.com.
  
• Caraco: www.caracoclozapine.com.
  
• FazaClo: www.fazacloregistry.com.
  
• Mylan: www.mylan-clozapine.com.
  

• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril, FazaClo
  
• Filgrastim • Neupogen
  
• Haloperidol • Haldol
  
• Lithium • Lithobid, others
  
• Olanzapine • Zyprexa
  
• Perphenazine • Trilafon
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Ziprasidone • Geodon
  

Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pfizer Inc., Schering-Plough Corporation, and Vanda Pharmaceuticals. No writing assistance or external financial support was utilized in the preparation of this review article.

Discuss this article

Researchers in Finland surprised psychiatrists this year by announcing that clozapine “seems to be associated with a substantially lower mortality than any other antipsychotic.”¹ This finding also surprised the researchers, who expected their 11-year study to link long-term use of second-generation (“atypical”) antipsychotics with increased mortality in patients with schizophrenia. Instead they found longer lives in patients who used antipsychotics (and particularly clozapine), compared with no antipsychotic use.

This study’s findings do not change clozapine’s association with potentially fatal agranulocytosis as well as weight gain, metabolic abnormalities, and other adverse effects. Clozapine also is difficult to administer ( Box 1 ),² and patients must be enrolled in FDA-mandated registries (see Related Resources ). These obstacles might discourage you from offering clozapine to patients who could benefit from it ( Box 2 ).^3-5

Why bother considering clozapine? Because recent data on decreased mortality, decreased suicidality, and control of aggressive behavior make clozapine a compelling choice for many patients. Careful attention to clozapine’s adverse effect profile is necessary, but you can manage these risks with appropriate monitoring.

Box 1

Box 2

Potential for longer life?

The population-based, cohort study from Finland demonstrated that—contrary to popular belief—the introduction of atypical antipsychotics during the 1990s did not adversely affect mortality of patients with schizophrenia, at least in Finland.¹

This study made specific drug comparisons and used perphenazine as the reference drug. The lowest risk for mortality was observed with clozapine, which showed a 26% relative advantage compared with perphenazine. Clozapine’s advantage was statistically significant when compared with all other antipsychotics tested.

The authors suggested provocatively that restrictions on clozapine use as a second- or third-line agent should be reassessed. A few caveats, however, might affect how one interprets this study or applies its findings to clinical practice:

• The main comparisons were for patients receiving outpatient antipsychotic monotherapy. No information was available about antipsychotics used during inhospital treatment.
  
• Only the most frequently used atypical antipsychotics (clozapine, olanzapine, oral risperidone, and quetiapine) or the most frequently prescribed first-generation antipsychotics (oral perphenazine, thioridazine, and oral haloperidol) were assessed individually.
  
• Data about patients’ marital status, diagnoses of substance abuse, socioeconomic status, and other social variables were not available.
  
• Not all antipsychotics were available throughout the study (quetiapine was the newest and available for the shortest time).
  
• The study population consisted of patients of all ages, including those under 20 and over 70 years of age. Although the number of deaths and mortality rates increased with age, causes of mortality may differ when younger and older persons are compared. A data supplement to the study—available at www.thelancet.com—contains information about odds ratios by age and other factors.
  

Recommendation. Consider clozapine earlier than as a “last resort” in the disease course of patients with schizophrenia. At the very least, routinely present clozapine to patients and their families as a possible treatment option.

Antiaggressive properties

Case series and retrospective studies have provided insights into clozapine’s antiaggressive properties, but the strongest evidence comes from a 12-week, double-blind, randomized trial that specifically enrolled patients with violent behavior.⁶ Clozapine, olanzapine, and haloperidol were directly compared in the treatment of assaults and other aggressive behaviors by physically assaultive in patients with schizophrenia and schizoaffective disorder:

• The Modified Overt Aggression Scale (MOAS) physical aggression score measured the number and severity of assaults.
  
• The Positive and Negative Syndrome Scale (PANSS) was used to assess psychiatric symptoms.
  

Recommendation. Offer clozapine as an option for patients with schizophrenia or schizoaffective disorder and persistent aggressive behavior. Another antipsychotic might not be “good enough.”

Reduced risk of suicidality

The International Suicide Prevention Trial (InterSePT) was a multicenter, randomized, 2-year clinical study that compared the risk for suicidal behavior in patients treated with clozapine vs olanzapine.⁷ Enrolled were 980 patients with schizophrenia or schizoaffective disorder who were considered at high risk for suicide because of past suicide attempts or current suicidal ideation. Approximately one-quarter had not responded adequately to previous treatment.

All patients were seen weekly for 6 months, then biweekly for 18 months. The weekly or biweekly contact required to monitor for clozapine-associated agranulocytosis was matched with a similar visit schedule for olanzapine-treated patients, during which clinicians obtained vital signs. Primary endpoints included suicide attempts (including death), hospitalization to prevent suicide, and a rating of “much worsening of suicidality” from baseline. Blinded raters, including an independent suicide monitoring board, determined when patients achieved endpoint criteria.

Patients receiving clozapine showed significantly less suicidal behavior than those treated with olanzapine (a 24% relative advantage in the hazard ratio for suicide attempts or hospitalizations to prevent suicide). Fewer patients in the clozapine group:

• attempted suicide (34 vs 55)
  
• required hospitalization (82 vs 107) or rescue interventions to prevent suicide (118 vs 155)
  
• required concomitant treatment with antidepressants (221 vs 258) or anxiolytics/soporifics (301 vs 331).
  

More deaths from suicide occurred in the clozapine group than the olanzapine group, but the numbers were small (5 vs 3) and the difference between clozapine and olanzapine on this outcome was not statistically significant (P=.73).

Recommendation. Clozapine is a first-line treatment for patients with schizophrenia or schizoaffective disorder who exhibit suicidal behavior. This is reflected in the drug’s product labeling.

Superior symptom management

CATIE findings. Phase 2 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed clozapine to be more effective than other atypical antipsychotics, as measured by time to all-cause discontinuation.⁸ Patients in this phase of CATIE had discontinued another atypical antipsychotic in phase 1, principally because of lack of adequate efficacy. In phase 2, they were re-randomized to receive open-label clozapine or double-blinded risperidone, olanzapine, or quetiapine.

Only 90 patients were included in the time-to-discontinuation analysis, yet the greater amount of time that patients remained on clozapine (median 10.5 months) compared with quetiapine (median 3.3 months) or risperidone (median 2.8 months) was statistically significant. Time to discontinuation because of inadequate therapeutic effect also was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone.

The NNT for the outcome of all-cause discontinuation for clozapine was 4 compared with risperidone and 3 compared with quetiapine. This means for every 4 or 3 patients randomly assigned to clozapine instead of risperidone or quetiapine, respectively, 1 additional patient successfully completed the CATIE trial on the original phase 2 medication.⁹ The NNT for clozapine vs olanzapine was 7, indicating a respectable effect size difference that might have been statistically significant if the sample size had been larger.

Meta-analyses support CATIE results. Clozapine’s greater efficacy (and effectiveness) compared with other antipsychotics as demonstrated in CATIE is supported by 2 meta-analyses:

• A systematic review of clinical trials between January 1953 and May 2002 found clozapine’s effect size in reducing symptoms for patients with schizophrenia was greater than that of any other antipsychotic.¹⁰
  
• In a similar but more recent meta-analysis of 150 double-blind, mostly short-term studies totaling 21,533 participants, clozapine showed the largest effect size when atypical antipsychotics were compared with first-generation antipsychotics.¹¹
  

Caveats about clozapine

First-episode schizophrenia. Clozapine has been shown to be more effective than chlorpromazine in terms of time to remission and maintenance of remission for treatment-naïve patients with first-episode schizophrenia.¹³ Even so, most clinicians probably would not consider clozapine as a first-line treatment for an uncomplicated first-episode patient because of concerns about agranulocytosis. When genetic testing becomes available to determine individual risk for agranulocytosis, perhaps clozapine will be used earlier in the disease course.¹⁴

Table

Common adverse effects of clozapine

Adjunctive treatments. Patients with a low baseline white blood cell count (WBC) and/or absolute neutrophil count (ANC) may benefit from adjunctive lithium treatment to increase their WBC, as demonstrated in case reports.¹⁸

When no other alternatives were clinically feasible, chronic treatment with granulocyte colony-stimulating factor (filgrastim) has been used successfully for some patients whose clozapine course was interrupted because of a low WBC and/or ANC.¹⁹

Related resources

• Clozapine product information (as revised July 2009): www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf.
  
• Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419.
  

• Teva: www.clozapineregistry.com.
  
• Clozaril: www.clozarilcare.com.
  
• Caraco: www.caracoclozapine.com.
  
• FazaClo: www.fazacloregistry.com.
  
• Mylan: www.mylan-clozapine.com.
  

• Chlorpromazine • Thorazine
  
• Clozapine • Clozaril, FazaClo
  
• Filgrastim • Neupogen
  
• Haloperidol • Haldol
  
• Lithium • Lithobid, others
  
• Olanzapine • Zyprexa
  
• Perphenazine • Trilafon
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Thioridazine • Mellaril
  
• Ziprasidone • Geodon
  

Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Pfizer Inc., Schering-Plough Corporation, and Vanda Pharmaceuticals. No writing assistance or external financial support was utilized in the preparation of this review article.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

In August 2009, the FDA approved asenapine for treating acute exacerbation of schizophrenia and acute manic or mixed episodes of bipolar disorder with or without psychosis in adults (Table 1). Asenapine is the first psychotropic to obtain simultaneous FDA approval for schizophrenia and bipolar disorder. The drug’s unique receptor binding profile shows promise in treatment of positive and negative symptoms of schizophrenia with a low risk of extrapyramidal and anticholinergic side effects.

Table 1

Asenapine: Fast facts

How it works

Asenapine is an atypical antipsychotic. Although the exact mechanism of these medications’ efficacy is unknown, their antipsychotic and antimanic activity is thought to be the result of antagonism of central dopamine receptors. According to dopamine theory proposed in the 1960s:

• dopaminergic hyperactivity in mesolimbic dopaminergic pathways contributes to positive symptoms of schizophrenia—hallucinations, delusions, disorganized thoughts and behaviors, and catatonia
• dopaminergic hypoactivity in mesocortical dopaminergic pathways (prefrontal cortex) contributes to negative symptoms of schizophrenia—alogia, avolition, anhedonia, autism, social withdrawal, attention problems, blunted affect, and abstract thinking difficulty.

Asenapine has high affinity for multiple dopamine, serotonin, noradrenergic α1 and α2, and histamine H1 receptors, where it works as an antagonist. Asenapine’s affinity for several serotonin, noradrenergic, and dopaminergic D3 and D4 receptors is higher than its affinity for D2 receptors (Table 2),¹ which distinguishes asenapine from other atypical antipsychotics except clozapine.

Blockade of 5-HT2A and 5-HT2C receptors in prefrontal cortex increases dopamine release in this area; theoretically, this effect should improve negative symptoms. Another mechanism that possibly improves cognition and negative symptoms is asenapine’s antagonism at central α2 noradrenergic receptors. Central α1 noradrenergic receptor antagonism also might be helpful in improving positive symptoms of schizophrenia.¹

Asenapine’s affinity for the muscarinic-1 cholinergic receptors is quite low, and adverse effects associated with antagonism at these receptors—dry mouth, blurred vision, constipation, and urinary retention—are minimal.²

Table 2

Asenapine’s binding affinity for receptor subtypes*

Pharmacokinetics

Absorption of asenapine after oral (swallowed) administration is 2%. To increase total bioavailability to 35%, the drug is manufactured as sublingual dissolvable tablets. After sublingual administration, asenapine is readily absorbed and achieves peak plasma concentration in approximately 1 hour. After absorption, 95% of asenapine binds to transport proteins albumin and α1 acid glycoprotein. The half-life of the medication is approximately 24 hours, and steady state usually is achieved in 3 days.

Metabolism creates about 40 metabolites via multiple metabolic pathways; the main ones are glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 (CYP)1A2. Asenapine is a weak inhibitor of CYP2D6, so coadministration of asenapine with other drugs that are substrates or inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2D6 (eg, paroxetine, fluoxetine) should be done cautiously. Because asenapine elimination is biphasic, twice-daily dosing is recommended.³

Efficacy in clinical trials

Schizophrenia. Asenapine’s efficacy for treating schizophrenia was evaluated in 3 fixed-dose, 6-week, randomized, double-blind, placebo- and active- (haloperidol, olanzapine, and risperidone) controlled clinical trials in adults.^3-5 Subjects in these studies met DSM-IV criteria for schizophrenia and had acute exacerbation of their illness, with Positive and Negative Syndrome Scale (PANSS) total scores ≥60. Symptom improvement was measured after 6 weeks by PANSS total score, PANSS positive subscale, and Clinical Global Impression scale (CGI).

The first trial (n=174) compared asenapine, 5 mg twice daily, to placebo and risperidone, 3 mg twice daily.^3-5 Asenapine was superior to placebo as demonstrated by symptom improvement on all 3 scales. Risperidone showed statistically significant symptom improvement on PANSS positive subscale and CGI but not on PANSS total score.

In the second trial (n=448), 2 fixed doses of asenapine (5 mg twice daily and 10 mg twice daily) and olanzapine, 15 mg/d, were compared with placebo.^3,5 The only statistically significant symptom improvement in the asenapine group compared with placebo was on the PANSS positive subscale among subjects receiving 5 mg twice daily. Improvements measured by CGI and PANSS total score were not statistically significant.

Olanzapine showed statistically significant symptom improvement on all 3 scales compared with placebo. This study is a negative trial for asenapine; asenapine failed to separate from placebo, whereas olanzapine—the active comparator—did.

The third trial (n=448) compared asenapine, 5 mg twice daily and 10 mg twice daily, with placebo and haloperidol, 4 mg twice daily.^3,5 Compared with placebo, asenapine at both doses and haloperidol improved symptoms on all 3 scales. The 10-mg twice-daily dosage did not provide any additional benefits compared with the 5 mg twice-daily dosage.

Bipolar disorder. Asenapine’s efficacy for bipolar disorder was established in two 3-week, randomized, double-blind, placebo- and olanzapine-controlled studies in adults with acute manic or mixed episodes with or without psychosis.^3,6-9 Symptoms were assessed using the Young Mania Rating Scale (YMRS) and Clinical Global Impression-Bipolar (CGI-BP) scale.

In both studies, subjects were randomly assigned to receive asenapine, 10 mg twice daily; olanzapine, 5 to 20 mg/d; or placebo. Depending on efficacy and tolerability, the asenapine dose could be adjusted within the dosing range of 5 mg to 10 mg twice daily starting on day 2. Ninety percent of subjects stayed on the 10 mg twice-daily dose. In both studies, asenapine and olanzapine were statistically superior to placebo on YMRS and CGI-BP severity of illness scores.

Currently no evidence supports asenapine’s efficacy for maintenance treatment of schizophrenia or bipolar disorder. American Psychiatric Association practice guidelines recommend continuing treatment for a minimum of 6 months after stabilization of acute episodes of schizophrenia or bipolar disorder to prevent recurrence.¹⁰

Tolerability in clinical trials

Tolerability information provided in this article was obtained from a Clinical Trial Database consisting of 3,350 subjects:¹¹

• 1,953 patients participated in multiple dose effectiveness trials (1,480 with schizophrenia and 473 with bipolar disorder manic/mixed episodes)
• 486 subjects were treated for at least 24 weeks
• 293 subjects were treated for at least 52 weeks.

Overall, asenapine was well tolerated (Table 3).¹¹ The most common adverse effects in schizophrenia trials were akathisia, oral hypoesthesia, and somnolence. The discontinuation rate due to adverse effects in schizophrenia trials was 9% in the asenapine group vs 10% in the placebo group.

Among patients with bipolar disorder, the most common side effects were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight. The discontinuation rate for subjects treated with asenapine was 10% vs 6% with placebo. The most common adverse reactions associated with discontinuation were anxiety and oral hypoesthesia. Oral hypoesthesia did not occur in the placebo group, and akathisia was the only dose-dependent adverse reaction.

Dizziness and weight gain. Clinically important adverse effects of asenapine include dizziness and weight gain. Dizziness is possibly related to orthostatic hypotension caused by the drug’s activity at the α1 receptor (antagonist). To prevent ischemic events or falls with subsequent injuries, use asenapine with caution in hypotensive patients and those with cardiovascular or cerebrovascular problems.

In clinical trials investigating asenapine’s efficacy, mean weight gain was greater in patients receiving asenapine than those receiving placebo. In short-term studies, mean weight gain in patients treated with asenapine was 1.1 kg for subjects with schizophrenia and 1.3 kg for subjects with bipolar mania.³ Mean weight gain in patients treated with placebo was 0.1 kg for subjects with schizophrenia and 0.2 kg for those with bipolar mania.

In a 52-week comparator study of patients with schizophrenia and schizoaffective disorder, mean weight gain was 0.9 kg in the asenapine group vs 4.2 kg in the olanzapine group.³ In both groups, the greatest weight increase occurred in subjects with body mass index <23.

There were no clinically relevant mean changes in serum fasting glucose, serum fasting triglycerides, fasting cholesterol, transaminases, and prolactin. Thrombocytopenia, anemia, tachycardia, temporary bundle branch block, visual accommodation disorder, oral paresthesia, glossodynia, swollen tongue, hyponatremia, and dysarthria occurred in 1 in 100 to 1 in 1,000 patients.

Table 3

Percentages of clinical trial patients who experienced adverse effects with asenapine vs placebo

Contraindications

There are no absolute contraindications to asenapine use; however, the medication is not recommended for treating:

• women who are pregnant if the risks of treatment outweigh the benefits (pregnancy risk C)
• breast-feeding mothers
• patients with severe hepatic impairment (Child-Pugh C).

Asenapine carries the same class warnings and precautions as other antipsychotic medications, including a “black box” warning of increased mortality risk in elderly patients with dementia-related psychosis. Other class warnings include an increased risk of transient ischemic attack and cerebrovascular accidents in elderly patients with dementia-related psychosis; neuroleptic malignant syndrome; tardive dyskinesia; glycemia/diabetes mellitus; hyperprolactinemia; leukopenia; neutropenia; and agranulocytosis.

Because asenapine is associated with QT prolongation, do not administer it with other QT-prolonging agents, such as procainamide, sotalol, quinidine, erythromycin, clarithromycin, methadone, or other antipsychotics.

Dosing

Asenapine is manufactured as 5-mg and 10-mg sublingual tablets. Advise patients to avoid eating or drinking for 10 minutes after taking asenapine.

The recommended starting and target dosage for patients with schizophrenia is 5 mg twice daily. The recommended starting dosage for patients with an acute mixed or manic episode of bipolar I disorder is 10 mg twice daily; however, this can be reduced to 5 mg twice daily if the patient experiences intolerable side effects.

Related resource

• Asenapine (Saphris) prescribing information. www.spfiles.com/pisaphrisv1.pdf.

Drug brand names

• Asenapine • Saphris
• Clarithromycin • Biaxin
• Clozapine • Clozaril
• Erythromycin • ERY-C, Ery-Tab
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Procainamide • Procanbid
• Quinidine • Quinidine
• Risperidone • Risperdal
• Sotalol • Betapace, Sorine

Disclosures

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

Dr. Preskorn receives grant/research support from AstraZeneca, Biovail, Boehringer-Ingleheim, Cyberonics, Eli Lilly and Company, EnVivo, GlaxoSmithKline, UNC Chapel Hill, and Wyeth. He is a consultant to Allergan, Covidien, Eli Lilly and Company, Evotec, Lundbeck/Takeda, Transcept, and Wyeth.

Up to 15% of the U.S. inmate population has a bona fide serious mental illness,¹ but psychiatrists working in jails or prisons also encounter manipulative inmates feigning psychiatric illness. Likewise, clinicians in the civilian sector who conduct worker’s compensation or disability evaluations need to be alert for malingering. My advice is to begin these evaluations with a thorough interview and mental status examination. Ask open-ended questions that allow patients to elaborate on their alleged complaints and their often atypical symptoms, and carefully observe the individual’s behavior and affect.

In my 20 years working in a state prison system, I have identified common clinical scenarios—represented by “3Ds”—that should raise a clinician’s suspicion about the presence of a legitimate, significant Axis I disorder.

Demanding medications. Patients with severe mental illness rarely engage in this behavior and often have to be encouraged or coaxed to adhere to medications. However, manipulative patients I have evaluated demand only certain medications. They do not request agents such as fluoxetine or risperidone but insist that only sedating psychotropics with abuse potential, such as alprazolam or quetiapine, can effectively treat their symptoms.

Divulging symptoms too eagerly or dramatically.² Typically, patients suffering from schizophrenia, bipolar disorder, or major depressive disorder are embarrassed by their symptoms and may attempt to minimize or conceal them until they have established a rapport with the clinician. To the contrary, I have seen numerous inmates feigning mental illness who immediately and openly declare, “I hear voices” or “I’m paranoid.”

Dependent or conditional threats of self-harm, violence, or litigation. Statements such as, “If you don’t do this for me, I will hurt myself or somebody else” or “I will sue you if you don’t do this” are more consistent with Axis II than Axis I pathology. Patients in the throes of severe depression or psychotic thinking usually do not possess the motivation or inclination to make conditional threats.

Although there is no substitute for a comprehensive diagnostic assessment that includes history, treatments, and mental status exam, my “3Ds” may put you on alert. These scenarios are not diagnostic, but encountering any of them is a signal to delve further into the authenticity of the individual’s presentation.

Up to 15% of the U.S. inmate population has a bona fide serious mental illness,¹ but psychiatrists working in jails or prisons also encounter manipulative inmates feigning psychiatric illness. Likewise, clinicians in the civilian sector who conduct worker’s compensation or disability evaluations need to be alert for malingering. My advice is to begin these evaluations with a thorough interview and mental status examination. Ask open-ended questions that allow patients to elaborate on their alleged complaints and their often atypical symptoms, and carefully observe the individual’s behavior and affect.

In my 20 years working in a state prison system, I have identified common clinical scenarios—represented by “3Ds”—that should raise a clinician’s suspicion about the presence of a legitimate, significant Axis I disorder.

Demanding medications. Patients with severe mental illness rarely engage in this behavior and often have to be encouraged or coaxed to adhere to medications. However, manipulative patients I have evaluated demand only certain medications. They do not request agents such as fluoxetine or risperidone but insist that only sedating psychotropics with abuse potential, such as alprazolam or quetiapine, can effectively treat their symptoms.

Divulging symptoms too eagerly or dramatically.² Typically, patients suffering from schizophrenia, bipolar disorder, or major depressive disorder are embarrassed by their symptoms and may attempt to minimize or conceal them until they have established a rapport with the clinician. To the contrary, I have seen numerous inmates feigning mental illness who immediately and openly declare, “I hear voices” or “I’m paranoid.”

Dependent or conditional threats of self-harm, violence, or litigation. Statements such as, “If you don’t do this for me, I will hurt myself or somebody else” or “I will sue you if you don’t do this” are more consistent with Axis II than Axis I pathology. Patients in the throes of severe depression or psychotic thinking usually do not possess the motivation or inclination to make conditional threats.

Although there is no substitute for a comprehensive diagnostic assessment that includes history, treatments, and mental status exam, my “3Ds” may put you on alert. These scenarios are not diagnostic, but encountering any of them is a signal to delve further into the authenticity of the individual’s presentation.

Up to 15% of the U.S. inmate population has a bona fide serious mental illness,¹ but psychiatrists working in jails or prisons also encounter manipulative inmates feigning psychiatric illness. Likewise, clinicians in the civilian sector who conduct worker’s compensation or disability evaluations need to be alert for malingering. My advice is to begin these evaluations with a thorough interview and mental status examination. Ask open-ended questions that allow patients to elaborate on their alleged complaints and their often atypical symptoms, and carefully observe the individual’s behavior and affect.

In my 20 years working in a state prison system, I have identified common clinical scenarios—represented by “3Ds”—that should raise a clinician’s suspicion about the presence of a legitimate, significant Axis I disorder.

Demanding medications. Patients with severe mental illness rarely engage in this behavior and often have to be encouraged or coaxed to adhere to medications. However, manipulative patients I have evaluated demand only certain medications. They do not request agents such as fluoxetine or risperidone but insist that only sedating psychotropics with abuse potential, such as alprazolam or quetiapine, can effectively treat their symptoms.

Divulging symptoms too eagerly or dramatically.² Typically, patients suffering from schizophrenia, bipolar disorder, or major depressive disorder are embarrassed by their symptoms and may attempt to minimize or conceal them until they have established a rapport with the clinician. To the contrary, I have seen numerous inmates feigning mental illness who immediately and openly declare, “I hear voices” or “I’m paranoid.”

Dependent or conditional threats of self-harm, violence, or litigation. Statements such as, “If you don’t do this for me, I will hurt myself or somebody else” or “I will sue you if you don’t do this” are more consistent with Axis II than Axis I pathology. Patients in the throes of severe depression or psychotic thinking usually do not possess the motivation or inclination to make conditional threats.

Although there is no substitute for a comprehensive diagnostic assessment that includes history, treatments, and mental status exam, my “3Ds” may put you on alert. These scenarios are not diagnostic, but encountering any of them is a signal to delve further into the authenticity of the individual’s presentation.

We read with interest Drs. Carroll and Rado’s article, “Is a medical illness causing your patient’s depression?” (Current Psychiatry, August 2009) and commend the authors for focusing attention upon the role medical illnesses can play in causing or contributing to depressive disorders. However, we believe the authors missed the opportunity to strongly urge behavioral health providers to routinely refer their patients for medical evaluations to better identify illnesses masquerading as psychiatric disorders.

Conservative estimates suggest that at least 10% of presenting psychological disorders are driven by medical or somatic conditions, yet many mental health providers—medically and non-medically trained clinicians alike—mistakenly believe psychological symptoms rarely are caused by a “hidden” medical etiology.^1,2 In fact, a recent sampling from a psychiatric inpatient setting found high rates of medical illnesses that were “missed” by mental health clinicians.³ We feel that these studies support a recommendation that persons diagnosed with new-onset or treatment-refractory psychiatric disorders be routinely referred for a medical evaluation.⁴

Although one might argue that it is more prudent to refer only individuals who are suspected of having a medical illness underlying their presenting symptoms, this approach ignores the reality of our behavioral health system. In most public behavioral health systems (eg, community mental health centers, crisis units, safety net clinics, etc.), the person who makes the initial diagnosis and develops a treatment plan is a behavioral health specialist with no formal medical training. Consequently, many of these frontline clinicians understandably are unable to recognize signs and symptoms of the most common medical illnesses that cause psychological symptoms.⁵ To ensure patient safety, behavioral health clinicians without medical training should strictly adhere to this recommendation.

After weighing the costs and benefits, medically trained mental health care providers should allow patient safety concerns to guide their decision to refer. We believe that in situations of new-onset or treatment-refractory mental illnesses, referring patients for a medical evaluation will lead to a treatment model that is efficacious, integrated, and comprehensive. Our patients who suffer the effects of comorbid conditions have a right to nothing less from those of us responsible for overseeing their care and healing.

Richard C. Christensen, MD, MA
Professor and chief division of public psychiatry
University of Florida College of Medicine

Glenn D. Grace, PhD, MS
Staff psychologist
North Florida/South Georgia Veterans Health
System

James C. Byrd, MD
Assistant professor of psychiatry
University of Florida College of Medicine
Gainesville, FL

References

1. Morrison J. When psychological problems mask medical disorders: a guide for psychotherapists. New York, NY: Guilford Press; 1997.

2. Koran LM, Sox HC, Marton KI, et al. Medical evaluation of psychiatric patients: I. Results in a state mental health system. Arch Gen Psychiatry. 1989;46:733-740.

3. Rothbard AB, Blank MB, Staab JP, et al. Previously undetected metabolic syndromes and infectious diseases among psychiatric inpatients. Psychiatr Serv. 2009;60:534-537.

4. Grace GD, Christensen RC. Medical evaluations for patients with psychiatric disorders. Psychiatr Serv. 2009;60:849.-

5. Grace GD, Christensen RC. Recognizing psychologically masked illnesses: the need for collaborative relationships in mental health care. Prim Care Companion J Clin Psychiatry. 2007;9:433-436.

Drs. Carroll and Rado respond

We thank Dr. Christensen and colleagues for their comments regarding promoting medical care in patients with mental illness. As physicians trained in internal medicine and psychiatry, we frequently are confronted with the lack of adequate medical care for psychiatrically ill patients. Our primary goal with this article was to educate and assist behavioral health providers in distinguishing depressive symptoms that might have an underlying medical cause.

Although we agree that patients with depression—and mental illness as a whole—are medically underserved, referring all patients with treatment-refractory or new-onset depression might not be fiscally responsible or always necessary. However, we wholeheartedly support encouraging regular follow-up with a primary care provider. Psychiatrists can order laboratory tests that might indicate medical diagnoses—for example, thyroid stimulating hormone or parathyroid hormone—and refer their patients if needed.

The discussion of public behavioral mental health systems is a different topic and outside the scope of our article. Our sentiments are not in disagreement with Dr. Christensen et al, and we are glad to see that our article prompted this discussion.

Virginia K. Carroll, MD
Fifth-year resident

Jeffrey T. Rado, MD
Assistant professor
Departments of psychiatry and internal medicine
Rush University Medical Center, Chicago, IL

We read with interest Drs. Carroll and Rado’s article, “Is a medical illness causing your patient’s depression?” (Current Psychiatry, August 2009) and commend the authors for focusing attention upon the role medical illnesses can play in causing or contributing to depressive disorders. However, we believe the authors missed the opportunity to strongly urge behavioral health providers to routinely refer their patients for medical evaluations to better identify illnesses masquerading as psychiatric disorders.

Conservative estimates suggest that at least 10% of presenting psychological disorders are driven by medical or somatic conditions, yet many mental health providers—medically and non-medically trained clinicians alike—mistakenly believe psychological symptoms rarely are caused by a “hidden” medical etiology.^1,2 In fact, a recent sampling from a psychiatric inpatient setting found high rates of medical illnesses that were “missed” by mental health clinicians.³ We feel that these studies support a recommendation that persons diagnosed with new-onset or treatment-refractory psychiatric disorders be routinely referred for a medical evaluation.⁴

Although one might argue that it is more prudent to refer only individuals who are suspected of having a medical illness underlying their presenting symptoms, this approach ignores the reality of our behavioral health system. In most public behavioral health systems (eg, community mental health centers, crisis units, safety net clinics, etc.), the person who makes the initial diagnosis and develops a treatment plan is a behavioral health specialist with no formal medical training. Consequently, many of these frontline clinicians understandably are unable to recognize signs and symptoms of the most common medical illnesses that cause psychological symptoms.⁵ To ensure patient safety, behavioral health clinicians without medical training should strictly adhere to this recommendation.

After weighing the costs and benefits, medically trained mental health care providers should allow patient safety concerns to guide their decision to refer. We believe that in situations of new-onset or treatment-refractory mental illnesses, referring patients for a medical evaluation will lead to a treatment model that is efficacious, integrated, and comprehensive. Our patients who suffer the effects of comorbid conditions have a right to nothing less from those of us responsible for overseeing their care and healing.

Richard C. Christensen, MD, MA
Professor and chief division of public psychiatry
University of Florida College of Medicine

Glenn D. Grace, PhD, MS
Staff psychologist
North Florida/South Georgia Veterans Health
System

James C. Byrd, MD
Assistant professor of psychiatry
University of Florida College of Medicine
Gainesville, FL

References

1. Morrison J. When psychological problems mask medical disorders: a guide for psychotherapists. New York, NY: Guilford Press; 1997.

2. Koran LM, Sox HC, Marton KI, et al. Medical evaluation of psychiatric patients: I. Results in a state mental health system. Arch Gen Psychiatry. 1989;46:733-740.

3. Rothbard AB, Blank MB, Staab JP, et al. Previously undetected metabolic syndromes and infectious diseases among psychiatric inpatients. Psychiatr Serv. 2009;60:534-537.

4. Grace GD, Christensen RC. Medical evaluations for patients with psychiatric disorders. Psychiatr Serv. 2009;60:849.-

5. Grace GD, Christensen RC. Recognizing psychologically masked illnesses: the need for collaborative relationships in mental health care. Prim Care Companion J Clin Psychiatry. 2007;9:433-436.

Drs. Carroll and Rado respond

We thank Dr. Christensen and colleagues for their comments regarding promoting medical care in patients with mental illness. As physicians trained in internal medicine and psychiatry, we frequently are confronted with the lack of adequate medical care for psychiatrically ill patients. Our primary goal with this article was to educate and assist behavioral health providers in distinguishing depressive symptoms that might have an underlying medical cause.

Although we agree that patients with depression—and mental illness as a whole—are medically underserved, referring all patients with treatment-refractory or new-onset depression might not be fiscally responsible or always necessary. However, we wholeheartedly support encouraging regular follow-up with a primary care provider. Psychiatrists can order laboratory tests that might indicate medical diagnoses—for example, thyroid stimulating hormone or parathyroid hormone—and refer their patients if needed.

The discussion of public behavioral mental health systems is a different topic and outside the scope of our article. Our sentiments are not in disagreement with Dr. Christensen et al, and we are glad to see that our article prompted this discussion.

Virginia K. Carroll, MD
Fifth-year resident

Jeffrey T. Rado, MD
Assistant professor
Departments of psychiatry and internal medicine
Rush University Medical Center, Chicago, IL

We read with interest Drs. Carroll and Rado’s article, “Is a medical illness causing your patient’s depression?” (Current Psychiatry, August 2009) and commend the authors for focusing attention upon the role medical illnesses can play in causing or contributing to depressive disorders. However, we believe the authors missed the opportunity to strongly urge behavioral health providers to routinely refer their patients for medical evaluations to better identify illnesses masquerading as psychiatric disorders.

Conservative estimates suggest that at least 10% of presenting psychological disorders are driven by medical or somatic conditions, yet many mental health providers—medically and non-medically trained clinicians alike—mistakenly believe psychological symptoms rarely are caused by a “hidden” medical etiology.^1,2 In fact, a recent sampling from a psychiatric inpatient setting found high rates of medical illnesses that were “missed” by mental health clinicians.³ We feel that these studies support a recommendation that persons diagnosed with new-onset or treatment-refractory psychiatric disorders be routinely referred for a medical evaluation.⁴

Although one might argue that it is more prudent to refer only individuals who are suspected of having a medical illness underlying their presenting symptoms, this approach ignores the reality of our behavioral health system. In most public behavioral health systems (eg, community mental health centers, crisis units, safety net clinics, etc.), the person who makes the initial diagnosis and develops a treatment plan is a behavioral health specialist with no formal medical training. Consequently, many of these frontline clinicians understandably are unable to recognize signs and symptoms of the most common medical illnesses that cause psychological symptoms.⁵ To ensure patient safety, behavioral health clinicians without medical training should strictly adhere to this recommendation.

After weighing the costs and benefits, medically trained mental health care providers should allow patient safety concerns to guide their decision to refer. We believe that in situations of new-onset or treatment-refractory mental illnesses, referring patients for a medical evaluation will lead to a treatment model that is efficacious, integrated, and comprehensive. Our patients who suffer the effects of comorbid conditions have a right to nothing less from those of us responsible for overseeing their care and healing.

Richard C. Christensen, MD, MA
Professor and chief division of public psychiatry
University of Florida College of Medicine

Glenn D. Grace, PhD, MS
Staff psychologist
North Florida/South Georgia Veterans Health
System

James C. Byrd, MD
Assistant professor of psychiatry
University of Florida College of Medicine
Gainesville, FL

References

1. Morrison J. When psychological problems mask medical disorders: a guide for psychotherapists. New York, NY: Guilford Press; 1997.

2. Koran LM, Sox HC, Marton KI, et al. Medical evaluation of psychiatric patients: I. Results in a state mental health system. Arch Gen Psychiatry. 1989;46:733-740.

3. Rothbard AB, Blank MB, Staab JP, et al. Previously undetected metabolic syndromes and infectious diseases among psychiatric inpatients. Psychiatr Serv. 2009;60:534-537.

4. Grace GD, Christensen RC. Medical evaluations for patients with psychiatric disorders. Psychiatr Serv. 2009;60:849.-

5. Grace GD, Christensen RC. Recognizing psychologically masked illnesses: the need for collaborative relationships in mental health care. Prim Care Companion J Clin Psychiatry. 2007;9:433-436.

Drs. Carroll and Rado respond

We thank Dr. Christensen and colleagues for their comments regarding promoting medical care in patients with mental illness. As physicians trained in internal medicine and psychiatry, we frequently are confronted with the lack of adequate medical care for psychiatrically ill patients. Our primary goal with this article was to educate and assist behavioral health providers in distinguishing depressive symptoms that might have an underlying medical cause.

Although we agree that patients with depression—and mental illness as a whole—are medically underserved, referring all patients with treatment-refractory or new-onset depression might not be fiscally responsible or always necessary. However, we wholeheartedly support encouraging regular follow-up with a primary care provider. Psychiatrists can order laboratory tests that might indicate medical diagnoses—for example, thyroid stimulating hormone or parathyroid hormone—and refer their patients if needed.

The discussion of public behavioral mental health systems is a different topic and outside the scope of our article. Our sentiments are not in disagreement with Dr. Christensen et al, and we are glad to see that our article prompted this discussion.

Virginia K. Carroll, MD
Fifth-year resident

Jeffrey T. Rado, MD
Assistant professor
Departments of psychiatry and internal medicine
Rush University Medical Center, Chicago, IL

As a former Canadian with many contacts still there, I would strongly advise against a single-payer system (“Health care debate: Do psychiatrists support the public option?” From the Editor, Current Psychiatry, November 2009). It will not solve our health care problems; in fact, many of our patients will be worse off than now.

The lack of choices for both the patient and doctor when the government makes therapeutic choices can lead to a situation where psychotherapy almost disappears from psychiatry. In the United States we are struggling with managed care and its disincentives for psychotherapy in psychiatry, but at least patients can choose a psychiatrist who uses a combined approach.

Norman Straker, MD
Clinical professor of psychiatry
Weil Cornell Medical College
New York, NY

As a former Canadian with many contacts still there, I would strongly advise against a single-payer system (“Health care debate: Do psychiatrists support the public option?” From the Editor, Current Psychiatry, November 2009). It will not solve our health care problems; in fact, many of our patients will be worse off than now.

The lack of choices for both the patient and doctor when the government makes therapeutic choices can lead to a situation where psychotherapy almost disappears from psychiatry. In the United States we are struggling with managed care and its disincentives for psychotherapy in psychiatry, but at least patients can choose a psychiatrist who uses a combined approach.

Norman Straker, MD
Clinical professor of psychiatry
Weil Cornell Medical College
New York, NY

As a former Canadian with many contacts still there, I would strongly advise against a single-payer system (“Health care debate: Do psychiatrists support the public option?” From the Editor, Current Psychiatry, November 2009). It will not solve our health care problems; in fact, many of our patients will be worse off than now.

The lack of choices for both the patient and doctor when the government makes therapeutic choices can lead to a situation where psychotherapy almost disappears from psychiatry. In the United States we are struggling with managed care and its disincentives for psychotherapy in psychiatry, but at least patients can choose a psychiatrist who uses a combined approach.

Norman Straker, MD
Clinical professor of psychiatry
Weil Cornell Medical College
New York, NY

Dr. Nasrallah should make us all proud. In his editorial, “Does psychiatric practice make us wise?” (From the Editor, Current Psychiatry, October 2009) he presents how deep, complex, and relevant our work as psychiatrists can be and how it can enhance our personal development and wisdom. I think this article should be required reading for every medical student. Dr. Nasrallah even provides suggestions on ways to research how our brains may change. However, this must be tempered with some irony.

Recently, I attended a lecture on “Irony” by University of Chicago professor Jonathan Lear. He asked profound questions of irony, such as: “Among all the pious, is there a pious person?” and “Among all the doctors, is there a doctor?” He explained his point by wondering how often we fall short of what we can be as doctors. Extending that idea to Dr. Nasrallah’s column, in our days of 15-minute med checks, we might ask, “Among all psychiatrists, how many are Nasrallah psychiatrists?” As the saying goes, it takes one to know one.

H. Steven Moffic, MD
Professor of psychiatry
Medical College of Wisconsin
Milwaukee, WI

Dr. Nasrallah should make us all proud. In his editorial, “Does psychiatric practice make us wise?” (From the Editor, Current Psychiatry, October 2009) he presents how deep, complex, and relevant our work as psychiatrists can be and how it can enhance our personal development and wisdom. I think this article should be required reading for every medical student. Dr. Nasrallah even provides suggestions on ways to research how our brains may change. However, this must be tempered with some irony.

Recently, I attended a lecture on “Irony” by University of Chicago professor Jonathan Lear. He asked profound questions of irony, such as: “Among all the pious, is there a pious person?” and “Among all the doctors, is there a doctor?” He explained his point by wondering how often we fall short of what we can be as doctors. Extending that idea to Dr. Nasrallah’s column, in our days of 15-minute med checks, we might ask, “Among all psychiatrists, how many are Nasrallah psychiatrists?” As the saying goes, it takes one to know one.

H. Steven Moffic, MD
Professor of psychiatry
Medical College of Wisconsin
Milwaukee, WI

Dr. Nasrallah should make us all proud. In his editorial, “Does psychiatric practice make us wise?” (From the Editor, Current Psychiatry, October 2009) he presents how deep, complex, and relevant our work as psychiatrists can be and how it can enhance our personal development and wisdom. I think this article should be required reading for every medical student. Dr. Nasrallah even provides suggestions on ways to research how our brains may change. However, this must be tempered with some irony.

Recently, I attended a lecture on “Irony” by University of Chicago professor Jonathan Lear. He asked profound questions of irony, such as: “Among all the pious, is there a pious person?” and “Among all the doctors, is there a doctor?” He explained his point by wondering how often we fall short of what we can be as doctors. Extending that idea to Dr. Nasrallah’s column, in our days of 15-minute med checks, we might ask, “Among all psychiatrists, how many are Nasrallah psychiatrists?” As the saying goes, it takes one to know one.

H. Steven Moffic, MD
Professor of psychiatry
Medical College of Wisconsin
Milwaukee, WI