Current Psychiatry

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In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

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

Discuss this article at www.facebook.com/CurrentPsychiatry

In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

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

Discuss this article at www.facebook.com/CurrentPsychiatry

In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

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

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia

The lack of laboratory tests to validate the clinical diagnosis of schizophrenia is widely accepted and lamented by psychiatric practitioners. In a recent survey I conducted on CurrentPsychiatry.com, most respondents guessed there are 3 known biomarkers for schizophrenia and 4 for major depression.

The media’s view tends to be harsh, exploiting the ostensible absence of diagnostic biomarkers in psychiatry to cast unfair aspersions on the scientific validity of DSM-5 and its diagnostic guidelines.¹ They seem to believe that lab tests for mental illness will never be feasible. Clearly, they have not done their homework.

Consider schizophrenia. It would come as a surprise to most people inside or outside the psychiatric community that 365 biomarkers for schizophrenia have been discovered, 273 of which are identifiable in plasma.² Of these, 81 are diagnostic, 77 are markers of drug response, and 115 are for both. Some of these tests have been replicated at least 5 times (brain-derived neurotrophic factor, S100B, prolactin, interleukin (IL) 6, IL2, IN5, leptin, IL 1 receptor antagonist, IL8, and IL2 receptor α). The biologic functions of these 273 biomarkers include inflammatory disease or response, respiratory disease, cellular movement, lipid metabolism, molecular transport, immunologic disease, hematologic disease, renal and urologic disease, cell-to-cell signaling, cellular growth and proliferation, cardiovascular disease, genetic disorders, psychological disorders, metabolic disease, small molecule biochemistry, molecular transport, nutritional disease, endocrine system disorders, cell death, tissue morphology, organismal survival, lymphoid tissue structure and development, antigen presentation, tissue development, carbohydrate metabolism, organ morphology, embryonic development, behavior, and digestive system development and functions.² Obviously, schizophrenia biomarkers overlap with multiple tissues and key biochemical and cellular processes in brain and body.

So why do none of these 273 blood tests appear in DSM-5, which had aspired to include objective methods in psychiatric diagnosis? The answer: heterogeneity. Schizophrenia and other major psychiatric illnesses are not 1 disorder but syndromes comprised of numerous clinically similar but biologically different disorders. There is extensive variability among the “schizophrenias” in genetic and nongenetic etiological factors and significant heterogeneity in neurobiology, treatment response, and clinical and functional outcomes. None of the individual 273 biomarkers alone can serve as a diagnostic tool for the schizophrenias because there will be high rates of false positives and false negatives. A lab test for a syndrome is impossible!

One company recently attempted to develop a blood test for schizophrenia. It used 51 biomarkers to comprise that test because none of them alone is a viable test (Table).³ The totality of the 51 biomarkers significantly increases the likelihood of diagnostic utility but still will be short of 100% specificity.

What is the point of identifying 273 blood tests if they have not been used to diagnose a heterogeneous syndrome? I believe there are many potentially useful applications for these biomarkers:

• To identify biologic subtypes of schizophrenia
• To shed light on the multiple pathophysiologies of schizophrenia, which may provide valuable clues for new treatments
• To help identify and characterize stages of schizophrenia. Some biomarkers have been found in the early stages, while others appear only in the chronic stages
• To help predict biologic predisposition to 1 of the schizophrenias. It is possible that the various susceptibility genes that have been identified in schizophrenia may be associated with certain biomarkers during fetal neurodevelopment, childhood, or the prodrome stage
• To explore the overlapping biologic features of psychotic disorders. For example, 21 biomarkers have been found to differentiate schizophrenia or bipolar disorder from healthy controls. Some biomarkers may point to the likelihood of psychiatric comorbidities such as depression or obsessive-compulsive disorder or medical comorbidities such as cardiovascular, immunologic, or gastrointestinal diseases
• Some biomarkers may identify state (ie, the psychotic phase only) vs trait (throughout life). Other biomarkers may be associated with the presence of a specific type of hallucination (auditory, visual, olfactory, or gustatory), delusion (bizarre vs simple), negative symptom (flat affect vs apathy vs avolition) or cognitive deficit (verbal memory vs learning deficit vs executive dysfunction)
• Biomarkers may assist in developing personalized medicine and designing customized evaluations and treatments for patients suffering from 1 of the many schizophrenias.

Lab tests for psychiatric disorders are indeed available but their use will not mirror traditional physical exam tests. The complex heterogeneity of most psychiatric syndromes means that biomarkers will help unravel the rich neurobiology of those disorders and help elucidate the multiple neurobiologic underpinnings of these syndromes. Psychiatrists should look forward with great optimism to a bright future for psychiatric diagnosis, combining a set of clinical signs and symptoms with a confirmatory cluster of lab tests. It may take time, but psychiatric clinicians will be using biomarkers in the future and the media and the public finally will perceive psychiatry as a “mature” medical discipline.

In the survey I mentioned at the beginning of this editorial, 60.5% of responders predicted that the DSM-6 (approximately a decade from now) will contain laboratory tests for psychiatric diagnosis. They may very well be right!

Table

Biomarkers for schizophrenia

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

Table 2

Potential concerns when treating pregnant women with psychotropics

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

Table 2

Potential concerns when treating pregnant women with psychotropics

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

Table 2

Potential concerns when treating pregnant women with psychotropics

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Like Dr. Nasrallah wrote in his October editorial (“Psychiatry and the politics of incarceration,” Current Psychiatry, October 2012, p. 4-5; http://bit.ly/1JWYa87), I, too, was distressed to learn of Dorothea Dix Hospital’s closing.

I am employed at a large county jail and see the deplorable state of our mental health system. There are only 401 psychiatric beds in Nevada; at the Clark County Detention Center we have 500 inmates taking psychotropics. A Nevada resident with a mental illness is 10 times more likely to be incarcerated than cared for in a hospital. I found the funding and treatment of mentally ill individuals in Moldova (formerly part of the Soviet Union) to be superior to ours.

Too often mentally ill persons are brought to jail for minor charges, such as trespassing or jaywalking. They may have more charges added such as assaulting another inmate or an officer. As a result of their mental illness, not taking medications, and poor judgment, they have problems adjusting to incarceration. This vicious cycle means they will be in jail longer and may even receive a prison sentence. If you have never seen the heartbreaking effects on a seriously mentally ill (SMI) or mentally retarded person placed in a jail cell, this scenario may be hard to understand.

It saddens me that the only difference in the treatment of the mentally ill today from Dorothea Dix’s time is that we are not charging admission fees to see “crazy people” in jail. Why the entire country continues to cut mental health budgets is a mystery. It should be no surprise that with the decrease in psychiatric beds there is an increase in SMI individuals in jails. I do not understand why the politics of incarceration cannot be turned around to where we are treating, not punishing, the mentally ill.

It’s quite easy to write about the injustice; the difficult and the right action is to make the needed change happen.

Virginia Singer, DNP, PMHNP, BCClark County Detention CenterLas Vegas, NV

Like Dr. Nasrallah wrote in his October editorial (“Psychiatry and the politics of incarceration,” Current Psychiatry, October 2012, p. 4-5; http://bit.ly/1JWYa87), I, too, was distressed to learn of Dorothea Dix Hospital’s closing.

I am employed at a large county jail and see the deplorable state of our mental health system. There are only 401 psychiatric beds in Nevada; at the Clark County Detention Center we have 500 inmates taking psychotropics. A Nevada resident with a mental illness is 10 times more likely to be incarcerated than cared for in a hospital. I found the funding and treatment of mentally ill individuals in Moldova (formerly part of the Soviet Union) to be superior to ours.

Too often mentally ill persons are brought to jail for minor charges, such as trespassing or jaywalking. They may have more charges added such as assaulting another inmate or an officer. As a result of their mental illness, not taking medications, and poor judgment, they have problems adjusting to incarceration. This vicious cycle means they will be in jail longer and may even receive a prison sentence. If you have never seen the heartbreaking effects on a seriously mentally ill (SMI) or mentally retarded person placed in a jail cell, this scenario may be hard to understand.

It saddens me that the only difference in the treatment of the mentally ill today from Dorothea Dix’s time is that we are not charging admission fees to see “crazy people” in jail. Why the entire country continues to cut mental health budgets is a mystery. It should be no surprise that with the decrease in psychiatric beds there is an increase in SMI individuals in jails. I do not understand why the politics of incarceration cannot be turned around to where we are treating, not punishing, the mentally ill.

It’s quite easy to write about the injustice; the difficult and the right action is to make the needed change happen.

Virginia Singer, DNP, PMHNP, BCClark County Detention CenterLas Vegas, NV

Like Dr. Nasrallah wrote in his October editorial (“Psychiatry and the politics of incarceration,” Current Psychiatry, October 2012, p. 4-5; http://bit.ly/1JWYa87), I, too, was distressed to learn of Dorothea Dix Hospital’s closing.

I am employed at a large county jail and see the deplorable state of our mental health system. There are only 401 psychiatric beds in Nevada; at the Clark County Detention Center we have 500 inmates taking psychotropics. A Nevada resident with a mental illness is 10 times more likely to be incarcerated than cared for in a hospital. I found the funding and treatment of mentally ill individuals in Moldova (formerly part of the Soviet Union) to be superior to ours.

Too often mentally ill persons are brought to jail for minor charges, such as trespassing or jaywalking. They may have more charges added such as assaulting another inmate or an officer. As a result of their mental illness, not taking medications, and poor judgment, they have problems adjusting to incarceration. This vicious cycle means they will be in jail longer and may even receive a prison sentence. If you have never seen the heartbreaking effects on a seriously mentally ill (SMI) or mentally retarded person placed in a jail cell, this scenario may be hard to understand.

It saddens me that the only difference in the treatment of the mentally ill today from Dorothea Dix’s time is that we are not charging admission fees to see “crazy people” in jail. Why the entire country continues to cut mental health budgets is a mystery. It should be no surprise that with the decrease in psychiatric beds there is an increase in SMI individuals in jails. I do not understand why the politics of incarceration cannot be turned around to where we are treating, not punishing, the mentally ill.

It’s quite easy to write about the injustice; the difficult and the right action is to make the needed change happen.

Virginia Singer, DNP, PMHNP, BCClark County Detention CenterLas Vegas, NV

I was surprised by the article, “How to collaborate effectively with psychiatric nurse practitioners” (Current Psychiatry, November 2012, p. 49-53; http://bit.ly/1QTTtkK). Although I found the article informative and appreciated the accurate description of psychiatric nurse practitioners’ education and scope of practice, I was confused by the article’s artwork that displayed a dominant male—presumably the physician—pointing a pen toward a somewhat cowering female. Because a picture is worth a thousand words, I’m hopeful this was not seen as a reasonable way to “collaborate” with psychiatric-mental health nurse practitioners.

Trish Canning, PMHNP-BCBrookings PsychiatryGold Beach, OR

I was surprised by the article, “How to collaborate effectively with psychiatric nurse practitioners” (Current Psychiatry, November 2012, p. 49-53; http://bit.ly/1QTTtkK). Although I found the article informative and appreciated the accurate description of psychiatric nurse practitioners’ education and scope of practice, I was confused by the article’s artwork that displayed a dominant male—presumably the physician—pointing a pen toward a somewhat cowering female. Because a picture is worth a thousand words, I’m hopeful this was not seen as a reasonable way to “collaborate” with psychiatric-mental health nurse practitioners.

Trish Canning, PMHNP-BCBrookings PsychiatryGold Beach, OR

I was surprised by the article, “How to collaborate effectively with psychiatric nurse practitioners” (Current Psychiatry, November 2012, p. 49-53; http://bit.ly/1QTTtkK). Although I found the article informative and appreciated the accurate description of psychiatric nurse practitioners’ education and scope of practice, I was confused by the article’s artwork that displayed a dominant male—presumably the physician—pointing a pen toward a somewhat cowering female. Because a picture is worth a thousand words, I’m hopeful this was not seen as a reasonable way to “collaborate” with psychiatric-mental health nurse practitioners.

Trish Canning, PMHNP-BCBrookings PsychiatryGold Beach, OR

Discuss this article at www.facebook.com/CurrentPsychiatry

Visual hallucinations in children and adolescents can be caused by many conditions other than psychosis. To prevent misdiagnosis and unnecessary antipsychotic use, it is important to rule out other causes of visual hallucinations. The mnemonic VISUALS reminds us of common causes.

Visions that are culturally sanctioned occur in non-Western societies—eg, images of fairy-like spirits are accepted and reinforced as part of the Filipino culture—and in several Christian denominations in the United States. Positive cultural connotations may increase the frequency of visual hallucinations as well as produce varied attitudes and emotional reactions to them.¹

Imaginary friends often fulfill a child’s need for a relationship, although even social children may have these “friends.” Children often refer to imaginary friends in conversations and play with them. Usually they are also children. They may be extensions of people the child admires or be named after characters from stories, movies, or television. Children rarely are able to explain the imaginary friend’s appearance and more than half the time there is no trigger for the appearance of such friends.^2,3

Stress and anxiety in preschool children may precipitate the onset of visual or tactile hallucinations. They often happen at night but also can occur when the child is awake. Typical visual hallucinations may include monsters, bugs, pets, or toys.²

Urine drug screens should be conducted for all adolescents and children. Cocaine, methamphetamine, and amphetamines—including high doses of prescribed stimulants—can cause visual hallucinations. Lysergic acid diethylamide (“LSD”), phencyclidine (“PCP”), 3,4-methylenedioxymethamphetamine (“ecstasy”), marijuana, nitrous oxide, and mescaline often cause visual hallucinations, although these substances may not be identified in a routine urine toxicology. Other considerations are withdrawal from benzodiazepines, sedative-hypnotics, or alcohol, and rare adverse reactions to antidepressants, antibiotics, or anticonvulsants.^4,5

Age and developmental immaturity may make it difficult for children to distinguish between reality and non-reality, including dreams and shadows in the dark. Underdeveloped communication may make it difficult to interpret what the child is trying to communicate.²

Look into other medical explanations, such as migraines, seizures, tumors, ophthalmologic disease, delirium, or metabolic disorders (Table).^4,5

Table

Medical causes of visual hallucinations in children and adolescents

Sleep-onset visual hallucinations (hypnagogic) and hallucinations upon awakening (hypnopompic) often are bizarre and dream-like. They may consist of geometric patterns, landscapes, faces, or figures. They mainly occur with narcolepsy but can be seen in insomnia or excessive daytime sleepiness.^4,5

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Visual hallucinations in children and adolescents can be caused by many conditions other than psychosis. To prevent misdiagnosis and unnecessary antipsychotic use, it is important to rule out other causes of visual hallucinations. The mnemonic VISUALS reminds us of common causes.

Visions that are culturally sanctioned occur in non-Western societies—eg, images of fairy-like spirits are accepted and reinforced as part of the Filipino culture—and in several Christian denominations in the United States. Positive cultural connotations may increase the frequency of visual hallucinations as well as produce varied attitudes and emotional reactions to them.¹

Imaginary friends often fulfill a child’s need for a relationship, although even social children may have these “friends.” Children often refer to imaginary friends in conversations and play with them. Usually they are also children. They may be extensions of people the child admires or be named after characters from stories, movies, or television. Children rarely are able to explain the imaginary friend’s appearance and more than half the time there is no trigger for the appearance of such friends.^2,3

Stress and anxiety in preschool children may precipitate the onset of visual or tactile hallucinations. They often happen at night but also can occur when the child is awake. Typical visual hallucinations may include monsters, bugs, pets, or toys.²

Urine drug screens should be conducted for all adolescents and children. Cocaine, methamphetamine, and amphetamines—including high doses of prescribed stimulants—can cause visual hallucinations. Lysergic acid diethylamide (“LSD”), phencyclidine (“PCP”), 3,4-methylenedioxymethamphetamine (“ecstasy”), marijuana, nitrous oxide, and mescaline often cause visual hallucinations, although these substances may not be identified in a routine urine toxicology. Other considerations are withdrawal from benzodiazepines, sedative-hypnotics, or alcohol, and rare adverse reactions to antidepressants, antibiotics, or anticonvulsants.^4,5

Age and developmental immaturity may make it difficult for children to distinguish between reality and non-reality, including dreams and shadows in the dark. Underdeveloped communication may make it difficult to interpret what the child is trying to communicate.²

Look into other medical explanations, such as migraines, seizures, tumors, ophthalmologic disease, delirium, or metabolic disorders (Table).^4,5

Table

Medical causes of visual hallucinations in children and adolescents

Sleep-onset visual hallucinations (hypnagogic) and hallucinations upon awakening (hypnopompic) often are bizarre and dream-like. They may consist of geometric patterns, landscapes, faces, or figures. They mainly occur with narcolepsy but can be seen in insomnia or excessive daytime sleepiness.^4,5

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Visual hallucinations in children and adolescents can be caused by many conditions other than psychosis. To prevent misdiagnosis and unnecessary antipsychotic use, it is important to rule out other causes of visual hallucinations. The mnemonic VISUALS reminds us of common causes.

Visions that are culturally sanctioned occur in non-Western societies—eg, images of fairy-like spirits are accepted and reinforced as part of the Filipino culture—and in several Christian denominations in the United States. Positive cultural connotations may increase the frequency of visual hallucinations as well as produce varied attitudes and emotional reactions to them.¹

Imaginary friends often fulfill a child’s need for a relationship, although even social children may have these “friends.” Children often refer to imaginary friends in conversations and play with them. Usually they are also children. They may be extensions of people the child admires or be named after characters from stories, movies, or television. Children rarely are able to explain the imaginary friend’s appearance and more than half the time there is no trigger for the appearance of such friends.^2,3

Stress and anxiety in preschool children may precipitate the onset of visual or tactile hallucinations. They often happen at night but also can occur when the child is awake. Typical visual hallucinations may include monsters, bugs, pets, or toys.²

Urine drug screens should be conducted for all adolescents and children. Cocaine, methamphetamine, and amphetamines—including high doses of prescribed stimulants—can cause visual hallucinations. Lysergic acid diethylamide (“LSD”), phencyclidine (“PCP”), 3,4-methylenedioxymethamphetamine (“ecstasy”), marijuana, nitrous oxide, and mescaline often cause visual hallucinations, although these substances may not be identified in a routine urine toxicology. Other considerations are withdrawal from benzodiazepines, sedative-hypnotics, or alcohol, and rare adverse reactions to antidepressants, antibiotics, or anticonvulsants.^4,5

Age and developmental immaturity may make it difficult for children to distinguish between reality and non-reality, including dreams and shadows in the dark. Underdeveloped communication may make it difficult to interpret what the child is trying to communicate.²

Look into other medical explanations, such as migraines, seizures, tumors, ophthalmologic disease, delirium, or metabolic disorders (Table).^4,5

Table

Medical causes of visual hallucinations in children and adolescents

Sleep-onset visual hallucinations (hypnagogic) and hallucinations upon awakening (hypnopompic) often are bizarre and dream-like. They may consist of geometric patterns, landscapes, faces, or figures. They mainly occur with narcolepsy but can be seen in insomnia or excessive daytime sleepiness.^4,5

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

With a lifetime prevalence of 30%, alcohol use disorders (AUDs)—which in DSM-IV-TR include alcohol abuse and alcohol dependence—are among the most common psychiatric disorders.¹ Depressive disorders, including major depressive disorder (MDD) and dysthymia, frequently co-occur with AUDs.^2-4 This pattern of comorbidity adversely affects the prognosis, course, and treatment of both MDD and AUDs.⁵ High severity in 1 of these disorders is associated with high severity in the other.^2,6 Alcohol dependence appears to prolong the course of depression^7,8 and increases the risk of suicidal symptoms and behaviors.^9,10 Patients with depression and AUDs are at increased risk of relapse to heavy drinking.^7,11

Whether the high comorbidity rate of depressive disorders and AUDs is a result of 1 disorder causing the other (ie, AUDs leading to depression or vice versa) or can be attributed to shared etiology is unknown. Clinicians need to consider this question when treating patients with this pattern of comorbidity because distinguishing primary depression from secondary depression influences treatment decisions.¹²

There is a great need for pharmacologic interventions that can concurrently treat both depression and AUDs. This article reviews the evidence for current treatments for dually diagnosed patients and highlights novel agents that are worthy of further study for this complex patient population.

Current treatment options

Pharmacotherapy for MDD and alcohol dependence is common when these conditions occur alone. FDA-approved medications for treating depression include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors.

SSRIs are the most widely used class of antidepressants. They gained FDA approval based on studies conducted in non-comorbid patients because patients with comorbid conditions usually are excluded from research studies.¹³ Few trials have evaluated patients with depression and AUDs; TCAs and SSRIs are best studied in these patients.

Serotonergic antidepressants

SSRIs are first-line medications for MDD because of their low abuse potential, favorable side effect profile, and relative safety in overdose.

Table 1

Serotonergic antidepressants for patients with AUDs and depression

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

Table 3

Can medications that target alcohol use also improve depression?

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

The atypical antipsychotic quetiapine acts as a serotonin (5-HT1A and 5-HT2) and dopamine (D1 and D2) antagonist, and reports suggest it reduces alcohol craving and affective symptoms in patients with AUDs.^34,35 In a 16-week, open-label study, quetiapine decreased alcohol consumption, alcohol craving, and intensity of some psychiatric symptoms in 28 alcohol-dependent patients with bipolar disorder, schizoaffective disorder, or borderline personality disorder.³⁶

See the Box for a description of the role CRF₁ antagonists may play in treating patients with concurrent MDD and AUDs. See Table 4 for studies of memantine and quetiapine in treating depression with AUDs.

Box

Other agents may play a role in treating depression with AUDs

Interpreting the evidence

Related Resources

• Pettinati H. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry. 2004;56(10):785-792.
  
• Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
  

• Acamprosate • Campral
  
• Amitriptyline • Elavil
  
• Desipramine • Norpramin
  
• Disulfiram • Antabuse
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Ketamine • Ketalar
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Naltrexone • Revia, Vivitrol
  
• Nefazodone • Serzone
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

Dr. Petrakis receives research or grant support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs.

This work has been supported by a grant from the Veterans Affairs New England Mental Illness Research, Education, and Clinical Center and by the National Institute of Mental Health (T32MH062994-07).

Acknowledgements

The authors thank Elizabeth Guidone for her helpful comments and Diana Limoncelli for her assistance in manuscript preparation.

Discuss this article at www.facebook.com/CurrentPsychiatry

With a lifetime prevalence of 30%, alcohol use disorders (AUDs)—which in DSM-IV-TR include alcohol abuse and alcohol dependence—are among the most common psychiatric disorders.¹ Depressive disorders, including major depressive disorder (MDD) and dysthymia, frequently co-occur with AUDs.^2-4 This pattern of comorbidity adversely affects the prognosis, course, and treatment of both MDD and AUDs.⁵ High severity in 1 of these disorders is associated with high severity in the other.^2,6 Alcohol dependence appears to prolong the course of depression^7,8 and increases the risk of suicidal symptoms and behaviors.^9,10 Patients with depression and AUDs are at increased risk of relapse to heavy drinking.^7,11

Whether the high comorbidity rate of depressive disorders and AUDs is a result of 1 disorder causing the other (ie, AUDs leading to depression or vice versa) or can be attributed to shared etiology is unknown. Clinicians need to consider this question when treating patients with this pattern of comorbidity because distinguishing primary depression from secondary depression influences treatment decisions.¹²

There is a great need for pharmacologic interventions that can concurrently treat both depression and AUDs. This article reviews the evidence for current treatments for dually diagnosed patients and highlights novel agents that are worthy of further study for this complex patient population.

Current treatment options

Pharmacotherapy for MDD and alcohol dependence is common when these conditions occur alone. FDA-approved medications for treating depression include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors.

SSRIs are the most widely used class of antidepressants. They gained FDA approval based on studies conducted in non-comorbid patients because patients with comorbid conditions usually are excluded from research studies.¹³ Few trials have evaluated patients with depression and AUDs; TCAs and SSRIs are best studied in these patients.

Serotonergic antidepressants

SSRIs are first-line medications for MDD because of their low abuse potential, favorable side effect profile, and relative safety in overdose.

Table 1

Serotonergic antidepressants for patients with AUDs and depression

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

Table 3

Can medications that target alcohol use also improve depression?

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

The atypical antipsychotic quetiapine acts as a serotonin (5-HT1A and 5-HT2) and dopamine (D1 and D2) antagonist, and reports suggest it reduces alcohol craving and affective symptoms in patients with AUDs.^34,35 In a 16-week, open-label study, quetiapine decreased alcohol consumption, alcohol craving, and intensity of some psychiatric symptoms in 28 alcohol-dependent patients with bipolar disorder, schizoaffective disorder, or borderline personality disorder.³⁶

See the Box for a description of the role CRF₁ antagonists may play in treating patients with concurrent MDD and AUDs. See Table 4 for studies of memantine and quetiapine in treating depression with AUDs.

Box

Other agents may play a role in treating depression with AUDs

Interpreting the evidence

Related Resources

• Pettinati H. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry. 2004;56(10):785-792.
  
• Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
  

• Acamprosate • Campral
  
• Amitriptyline • Elavil
  
• Desipramine • Norpramin
  
• Disulfiram • Antabuse
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Ketamine • Ketalar
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Naltrexone • Revia, Vivitrol
  
• Nefazodone • Serzone
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

Dr. Petrakis receives research or grant support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs.

This work has been supported by a grant from the Veterans Affairs New England Mental Illness Research, Education, and Clinical Center and by the National Institute of Mental Health (T32MH062994-07).

Acknowledgements

The authors thank Elizabeth Guidone for her helpful comments and Diana Limoncelli for her assistance in manuscript preparation.

Discuss this article at www.facebook.com/CurrentPsychiatry

With a lifetime prevalence of 30%, alcohol use disorders (AUDs)—which in DSM-IV-TR include alcohol abuse and alcohol dependence—are among the most common psychiatric disorders.¹ Depressive disorders, including major depressive disorder (MDD) and dysthymia, frequently co-occur with AUDs.^2-4 This pattern of comorbidity adversely affects the prognosis, course, and treatment of both MDD and AUDs.⁵ High severity in 1 of these disorders is associated with high severity in the other.^2,6 Alcohol dependence appears to prolong the course of depression^7,8 and increases the risk of suicidal symptoms and behaviors.^9,10 Patients with depression and AUDs are at increased risk of relapse to heavy drinking.^7,11

Whether the high comorbidity rate of depressive disorders and AUDs is a result of 1 disorder causing the other (ie, AUDs leading to depression or vice versa) or can be attributed to shared etiology is unknown. Clinicians need to consider this question when treating patients with this pattern of comorbidity because distinguishing primary depression from secondary depression influences treatment decisions.¹²

There is a great need for pharmacologic interventions that can concurrently treat both depression and AUDs. This article reviews the evidence for current treatments for dually diagnosed patients and highlights novel agents that are worthy of further study for this complex patient population.

Current treatment options

Pharmacotherapy for MDD and alcohol dependence is common when these conditions occur alone. FDA-approved medications for treating depression include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors.

SSRIs are the most widely used class of antidepressants. They gained FDA approval based on studies conducted in non-comorbid patients because patients with comorbid conditions usually are excluded from research studies.¹³ Few trials have evaluated patients with depression and AUDs; TCAs and SSRIs are best studied in these patients.

Serotonergic antidepressants

SSRIs are first-line medications for MDD because of their low abuse potential, favorable side effect profile, and relative safety in overdose.

Table 1

Serotonergic antidepressants for patients with AUDs and depression

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

Table 3

Can medications that target alcohol use also improve depression?

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

The atypical antipsychotic quetiapine acts as a serotonin (5-HT1A and 5-HT2) and dopamine (D1 and D2) antagonist, and reports suggest it reduces alcohol craving and affective symptoms in patients with AUDs.^34,35 In a 16-week, open-label study, quetiapine decreased alcohol consumption, alcohol craving, and intensity of some psychiatric symptoms in 28 alcohol-dependent patients with bipolar disorder, schizoaffective disorder, or borderline personality disorder.³⁶

See the Box for a description of the role CRF₁ antagonists may play in treating patients with concurrent MDD and AUDs. See Table 4 for studies of memantine and quetiapine in treating depression with AUDs.

Box

Other agents may play a role in treating depression with AUDs

Interpreting the evidence

Related Resources

• Pettinati H. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry. 2004;56(10):785-792.
  
• Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
  

• Acamprosate • Campral
  
• Amitriptyline • Elavil
  
• Desipramine • Norpramin
  
• Disulfiram • Antabuse
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Ketamine • Ketalar
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Naltrexone • Revia, Vivitrol
  
• Nefazodone • Serzone
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

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

Dr. Petrakis receives research or grant support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs.

This work has been supported by a grant from the Veterans Affairs New England Mental Illness Research, Education, and Clinical Center and by the National Institute of Mental Health (T32MH062994-07).

Acknowledgements

The authors thank Elizabeth Guidone for her helpful comments and Diana Limoncelli for her assistance in manuscript preparation.