Current Psychiatry

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

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

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

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

Just as psychiatrists are adapting to DSM-5, they have to cope with implementation of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). This challenge raises questions: What is the importance of understanding ICD-10? How will it affect the practice of psychiatry?

Furthermore, how does ICD-10 relate to DSM-5 and Current Procedural Terminology (CPT)? How does it differ from ICD-9? What are the ICD-10-Clinical Modification (CM) and ICD-10-Procedures (PCS)?Learning the essence of the changes, and understanding what impact they have on your clinical work, are necessary to ensure that your practice keeps pace with professional and legal standards of care. The effort involved is not onerous, however, and can improve the quality and efficiency of your care and how you document it.

In this article, we provide you with an overview of ICD-10; highlight major changes of the new classification; explain its relevance to clinical practice; and offer guidelines for implementing it effectively. We also emphasize that a good understanding of DSM-5 facilitates appreciation of ICD-10 and makes its implementation fairly easy and straightforward.

To begin, we provide a glossary of ICD-related terms and a review of additional definitions, distinctions, and dates (Box).^1-6

Major changes from ICD-9
No question: ICD-10 is going to significantly influence your practice and your reimbursement. Furthermore, a number of revisions in ICD-10 have the potential to meaningfully improve clinical documentation and communication and to enhance your ability to precisely describe the complexity of your patients—with implications for billing.

ICD-10 differs from ICD-9 in organization, structure, code composition, and level of detail. In addition, ICD-10 makes some changes in terminology and definitions, with the goal of improving precision.

ICD-10 also is much larger than ICD-9.The total number of medical diagnostic codes has increased more than 5-fold—from approximately 13,000 to 69,000. This expansion allows for greater specificity in diagnosis and enables differentiation of an initial clinical encounter from a subsequent encounter.

To accommodate the expansion in the number of codes, the 5-digit numeric codes used in ICD-9 have been replaced in ICD-10 by 7-digit alphanumeric codes:

• the first digit always is a letter
• the second and third digits are numbers followed by a decimal point
• the fourth though seventh digits can be letters or numbers
• the first 3 digits denote the diagnostic category
• the fourth through sixth digits provide diagnostic detail
• the seventh digit provides information about the nature of the encounter (eg, initial, subsequent, or sequel, denoted respectively by “A,” “D,” and “S” in the seventh digit).

The number of 3-digit categories for psychiatric disorders has increased from 30 in ICD-9 (290-319) to 100 in ICD-10 (F00-F99). Only the first 5 digits are used for the section on mental disorders in ICD-10, with the first digit always “F” and the second digit a number denoting the broad type of disorders. The second and third digits in conjunction define the major category of the disorder; the fourth and fifth digits provide additional descriptive detail about the disorder (Table).

Examples of “Z” codes relevant to psychiatry are:

Z00 General psychiatric examination (eg, of a person who does not have a complaint or diagnosis)

Z03 Examination for suspected mental and behavioral disorder

Z04 Examination for medicolegal or other purposes; Z04.8 is relevant laboratory testing, such as drug testing of urine or blood

Z50 Care involving rehabilitation (substance use disorder, etc.)

Z60 Problem related to social environment

Z61 Problem related to negative life events in childhood

Z63 Problem related to primary support group, including family circumstances

Z64-Z65 Problem related to other psychosocial circumstances

Z70-Z71 Condition requiring counseling, not elsewhere classified

Z73 Problem related to difficulty with life management (burnout, stress, role conflict, etc.)

Z75 Problem related to medical facilities and other aspects of health care (eg, awaiting admission)

Z81 Family history of mental or behavioral disorders

Z85-Z91 Personal history of various disorders (must be absent or in full remission at the moment); Z86.51, for example, refers to a history of combat and operational stress reaction.

Greater precision is now possible when coding for treatment-related adverse effects. A particular adverse effect now is coded under the relevant system, along with its attribution to the specific substance. Obesity attributable to antipsychotic treatment,^7,8 for example, is coded as E66.1.

Integrating DSM-5 and ICD-10
Because DSM-5 lists corresponding ICD-10-CM codes for all disorders, you will find it much easier than other physicians to implement ICD-10. DSM-5 includes ICD-9-CM and ICD-10-CM codes for each DSM-5 disorder (for example, the ICD-9-CM code for schizophrenia is 295.x; the ICD-10-CM code is F20.9).⁹

Furthermore, a number of changes from ICD-9-CM to ICD-10-CM enable documentation of greater diagnostic specificity; for example, DSM-5 schizoaffective disorder, bipolar type, and schizoaffective disorder, depressive type, are distinctly coded as F25.0 and F25.1, respectively, in ICD-10-CM, whereas both were coded as 295.7 in ICD-9-CM.¹⁰

You will continue to use DSM-5 criteria to guide your diagnostic process, translating the DSM-5 diagnosis (diagnoses) into corresponding ICD-10-CM codes. Experience with DSM-5 substantially simplifies the transition to ICD-10.

Key differences between DSM-5 and ICD-10
There are notable differences in organization and content between DSM-5 and ICD-10.

The 20 chapters in DSM-5 begin with neuro­developmental disorders; neurocognitive disorders are toward the end (ie, childhood to late life). In contrast, neurocognitive disorders (ie, “dementia”) appear at the beginning of ICD-10; neurodevelopmental disorders are at the end.

Elimination of schizophrenia subtypes in DSM-5 necessitates coding of all schizophrenia as F20.9 in ICD-10-CM because F20.0-F20.8 are specific subtypes. DSM-5 schizophreniform disorder is coded F20.81.

Substance abuse and substance dependence continue to be separate in ICD-10-CM, but they are combined in a single category of substance use disorders in DSM-5. The correct ICD-10-CM code (ie, abuse vs dependence) is determined by the severity of the substance use disorder: “Mild” coding as abuse (F1x.1) and “moderate” and “severe” coding as dependence (F2x.2), with x denoting the substance abused.

There can be multiple applicable diagnoses associated with a clinical encounter, as there was with ICD-9-CM. Give precedence to the diagnosis that best represents the nature of the presenting problem; list other diagnoses in the order of their relevance. DSM-5 and ICD-10-CM are similar in this regard.

ICD-10-CM uses only subtypes, in contrast to the use of subtypes and specifiers in DSM-5 to describe variability in disorders across patients. It is possible, however, to code certain DSM-5 specifiers in ICD-10-CM. (This is discussed in the “Recording Procedures” section of the DSM-5 text and summarized at the beginning of the manual, and appears in the “Appendix.”) To code the catatonia specifier in the context of schizoaffective disorder, depressive type, for example, use ICD-10-CM code F25.1 for the disorder and add code F06.1 for the catatonia specifier.¹¹

How will ICD-10 affect your practice?
As of October 1, 2015, all health care facilities were to have become ICD-10 compliant. Furthermore, any Health Insurance Portability and Accountability Act-covered entity must use ICD-10-CM codes if it expects to be reimbursed for health care services.

Mental health practitioners might think that the transition from ICD-9-CM to ICD-10-CM involves only billers and coders, not them. They are wrong. All clinicians are responsible for documenting their diagnostic and treatment services properly. Medical records must contain adequate information to support any diagnostic (ICD-10-CM) and treatment (CPT) codes that are applied to a given clinical encounter.

The greater detail and specificity that are provided by ICD-10-CM allow more accurate recording of clinical complexity, which, in turn, influences reimbursement. However, good documentation is necessary for proper coding. Because clinicians are ultimately responsible for proper diagnostic coding, good understanding of ICD-10-CM is essential to be able to code properly.

Similar to the expansion of ICD-10-CM (from volumes 1 and 2 of ICD-9-CM), ICD-10-PCS has undergone similar expansion (from volume 3 of ICD-9-CM), with a corresponding increase in specificity. For example, there are now 5 distinct codes for electroconvulsive therapy (GZB0ZZZ-GZB4ZZZ) that distinguish unilateral from bilateral electrode placement and single from multiple stimulations.

DSM-5 will continue to be the frameworkfor psychiatric assessment and diagnosis. ICD-10-CM will be the coding system to accurately denote DSM-5 diagnoses. The Centers for Medicare and Medicaid Services (CMS) and the National Center for Health Statistics recognize DSM-5 as the means to identify proper ICD-10-CM codes for mental disorders. CMS also has announced that, although ICD-10-CM codes are necessary for reimbursement, use of an incorrect code will not be the basis for denying a Medicare claim for 1 year.

Making ICD-10 part of practice
Here are several keys to implementing ICD-10 with minimum pain and maximum benefit.

Multiple diagnosis codes should be listed in the order of their relevance to the clinical encounter.

Visit type. The seventh character of the ICD-10-CM code denotes the type of visit (initial, subsequent, or sequela) and must be provided:

• An initial encounter is one in which the patient first receives active treatment.
• A subsequent encounter refers to a follow-up visit in which the patient receives routine care during the healing or recovery phase.
• A sequel encounter is one in which a patient receives treatment for complications or conditions that arise as a direct result of the initial condition.

The transition to ICD-10 should be facilitated by adoption of DSM-5. Continue using DSM-5 to determine the correct diagnosis or diagnoses of the mental disorder, then apply the corresponding ICD-10-CM code(s). The better you understand and apply DSM-5, the more precise you can be in utilizing the greater specificity and accuracy afforded by ICD-10-CM coding.

Document well. Good understanding of the structure and organization of ICD-10-CM facilitates efficient, comprehensive documentation. This, in turn, will foster better clinical communication and appropriate reimbursement.

Know your payers—in particular, their policies regarding differential reimbursement for clinical complexity (based on ICD-10-CM/PCS). Medical practices that are part of an accountable care organization, and those that have risk-adjusted contracts must pay special attention to documenting clinical complexity when coding.

Know your electronic health care record, understand what tools it offers to efficiently translate DSM-5 diagnoses into appropriate ICD-10-CM codes, and use those tools efficiently.

Review your medical record documentation for the top 20 conditions in your practice, in the context of their definition in ICD-10-CM.

If you have coders who do ICD-10-CM coding for you, review a few patient charts with them to compare your sense of the patient’s clinical complexity and their coding based on your documentation.

Changes in DSM-5 have encouraged clinicians to improve their assessment of patients and provide measurement-based care. The significant changes in ICD-10-CM should provide the impetus for you to hone your ability to provide documentation. Sufficient flexibility exists within guidelines to permit individualization of the style of documentation.

Because all DSM-5 diagnoses map to appropriate ICD-10-CM codes, effective use of DSM-5 should make the transition to ICD-10 easy.

Bottom Line
Compared with ICD-9, definitions of mental health diagnoses have been improved in ICD-10, and more elaborate code descriptions in ICD-10-CM provide for greater precision when you report a diagnosis. The result? More accurate and efficient documentation of the care you provide and better reimbursement. Understanding what impact the changes in ICD-10 will have on your clinical work will ensure that your practice keeps pace with professional and legal standards of care.

Related Resources
• Blue Cross Blue Shield of Michigan ICD-10 update: mental and behavioral health ICD-10-CM codes. http://www.bcbsm.com/content/dam/public/Providers/Documents/help/faqs/icd10-update-mentalhealth.pdf.
• American Psychiatric Association ICD-10 tutorial. http://www.psychiatry.org/psychiatrists/practice/dsm/icd-10.

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

Such decisions can be made at any time, but the dawn of a year is a powerful signal of a new beginning—another lease on life, a potential turning point. Imbedded in those resolutions is a subliminal sense of urgency to correct one’s long-neglected shortcomings as the calendar ruthlessly points to inevitable aging and the relentless march of time.

A psychiatric perspective
For psychiatrists, New Year’s resolutions transcend the (often ephemeral) impulse to go on a diet or buy a membership at the local gym. We have a unique perspective on the challenges that our patients face every day as they cope with the complex demands of life despite their anxiety, depression, or psychosis.

We are aware of the many unmet needs in managing complex neuropsychiatric brain disorders and the major challenges of erasing the burdensome stigma that engulfs our patients and the practice of psychiatry itself—despite its noble mission of repairing fractured brains, mending tortured souls, and restoring peace of mind and wellness. We are proud of our clinical and scientific accomplishments but are painfully cognizant of our limitations and the huge chasm between what we know and what we will eventually know once the brain reveals its glorious mysteries through neuroscientific research.

What can you resolve?
Here is my proposed list of pragmatic resolutions that most psychiatrists would regard as part of a perpetual to-do list—a must-do bucket of cherished goals and brave new horizons to bring complete mental health for our patients and immeasurable gratification for us, who dream of cures for brain disorders that trigger various ailments of the mind.

• Practice like a physician to emphasize the medical foundation of psychiatry: Always check on a patient’s physical health, and monitor his (her) cardiometabolic status. Wear the symbolic white coat that often enhances the physician−patient relationship.
• Dedicate a significant percentage of your practice to the sickest patients. There are enough non-physician mental health professionals to handle the walking wounded and worried well.
• Advocate relentlessly throughout your sphere of influence, and publicly, for true parity between psychiatric and non-mental medical disorders—not only for insurance coverage but for overall societal acceptance and compassion as well.
• Lobby vigorously for hospitalization instead of imprisonment of the seriously mentally ill because psychosis is a brain disease, not a criminal offense.
• Adopt evidence-based psychiatric practice whenever possible to achieve the best outcomes. Judiciously implement off-label practices, however, if no evidence-based treatments exist for a suffering patient.
• Avoid senseless and irrational polypharmacy but do not hesitate to use rational, beneficial combination therapy.
• Provide 1 hour a week of pro bono psychiatric work for the indigent and underserved. The rewards of giving what amounts to 1 week a year are immeasurably more gratifying than a few more dollars in your bank account.
• Resist calling an ill person a ‘client’ or ‘consumer’—at least until oncologists and cardiologists start doing so. Refuse to give up your medical identify in the many de-medicalized mental health clinics.
• Never let a patient leave your office without some psychotherapy, even as part of a 15-minute med-check.
• Stay current and on the cutting edge of evolving psychiatric practice by logging into PubMed every day (even briefly) to read a few abstracts of the latest studies related to patients you saw that day.
• Think like a neurologist by identifying the neural circuits of psychiatric symptoms. Act like a cardiologist by doing everything medically possible to prevent recurrence of psychotic, manic, or depressive episodes because they damage brain tissue just as a myocardial infarction damages the heart.
• Support research with words, money, and passion. Psychiatric neuroscientific breakthroughs generate superior treatments, erase stigma, and advance the quality of life for patients. Donate annually to the researchers of your choice, at the medical school where you were trained, or at a nonprofit research institute.
• Make time to write for publication, annually, at least 1 case report or a letter to the editor about observations from your practice. You can contribute immensely to the discovery process by sharing novel clinical insights.
• Never give up on any patient or set expectations too low, regardless of the diagnosis or severity of illness. Giving up destroys hope and ushers in despondency. Get a second opinion if you run out of options for a patient.
• Always set remission followed by recovery as the therapeutic goal for every patient. Let the patient know this and ask him (her) commit to that goal with you.
• Be genuinely proud to be a psychiatrist. You assess and rectify disorders of the mind, the most complex and magical product of the human brain that determines who we are and how we think, emote, communicate, verbalize, empathize, love, hate, remember, plan, problem-solve, and, of course, make resolutions.

Back to diet and exercise—for our patients and for us!
It’s OK to include, among your New Year’s resolutions, a pledge to strongly encourage patients to diet and exercise. Given the tendency of many of them to gain weight and die prematurely as a consequence of obesity-related cardiometabolic risk factors, you should urge them to eat healthy and exercise every time you see them, not only on New Year’s Day.

Such decisions can be made at any time, but the dawn of a year is a powerful signal of a new beginning—another lease on life, a potential turning point. Imbedded in those resolutions is a subliminal sense of urgency to correct one’s long-neglected shortcomings as the calendar ruthlessly points to inevitable aging and the relentless march of time.

A psychiatric perspective
For psychiatrists, New Year’s resolutions transcend the (often ephemeral) impulse to go on a diet or buy a membership at the local gym. We have a unique perspective on the challenges that our patients face every day as they cope with the complex demands of life despite their anxiety, depression, or psychosis.

We are aware of the many unmet needs in managing complex neuropsychiatric brain disorders and the major challenges of erasing the burdensome stigma that engulfs our patients and the practice of psychiatry itself—despite its noble mission of repairing fractured brains, mending tortured souls, and restoring peace of mind and wellness. We are proud of our clinical and scientific accomplishments but are painfully cognizant of our limitations and the huge chasm between what we know and what we will eventually know once the brain reveals its glorious mysteries through neuroscientific research.

What can you resolve?
Here is my proposed list of pragmatic resolutions that most psychiatrists would regard as part of a perpetual to-do list—a must-do bucket of cherished goals and brave new horizons to bring complete mental health for our patients and immeasurable gratification for us, who dream of cures for brain disorders that trigger various ailments of the mind.

• Practice like a physician to emphasize the medical foundation of psychiatry: Always check on a patient’s physical health, and monitor his (her) cardiometabolic status. Wear the symbolic white coat that often enhances the physician−patient relationship.
• Dedicate a significant percentage of your practice to the sickest patients. There are enough non-physician mental health professionals to handle the walking wounded and worried well.
• Advocate relentlessly throughout your sphere of influence, and publicly, for true parity between psychiatric and non-mental medical disorders—not only for insurance coverage but for overall societal acceptance and compassion as well.
• Lobby vigorously for hospitalization instead of imprisonment of the seriously mentally ill because psychosis is a brain disease, not a criminal offense.
• Adopt evidence-based psychiatric practice whenever possible to achieve the best outcomes. Judiciously implement off-label practices, however, if no evidence-based treatments exist for a suffering patient.
• Avoid senseless and irrational polypharmacy but do not hesitate to use rational, beneficial combination therapy.
• Provide 1 hour a week of pro bono psychiatric work for the indigent and underserved. The rewards of giving what amounts to 1 week a year are immeasurably more gratifying than a few more dollars in your bank account.
• Resist calling an ill person a ‘client’ or ‘consumer’—at least until oncologists and cardiologists start doing so. Refuse to give up your medical identify in the many de-medicalized mental health clinics.
• Never let a patient leave your office without some psychotherapy, even as part of a 15-minute med-check.
• Stay current and on the cutting edge of evolving psychiatric practice by logging into PubMed every day (even briefly) to read a few abstracts of the latest studies related to patients you saw that day.
• Think like a neurologist by identifying the neural circuits of psychiatric symptoms. Act like a cardiologist by doing everything medically possible to prevent recurrence of psychotic, manic, or depressive episodes because they damage brain tissue just as a myocardial infarction damages the heart.
• Support research with words, money, and passion. Psychiatric neuroscientific breakthroughs generate superior treatments, erase stigma, and advance the quality of life for patients. Donate annually to the researchers of your choice, at the medical school where you were trained, or at a nonprofit research institute.
• Make time to write for publication, annually, at least 1 case report or a letter to the editor about observations from your practice. You can contribute immensely to the discovery process by sharing novel clinical insights.
• Never give up on any patient or set expectations too low, regardless of the diagnosis or severity of illness. Giving up destroys hope and ushers in despondency. Get a second opinion if you run out of options for a patient.
• Always set remission followed by recovery as the therapeutic goal for every patient. Let the patient know this and ask him (her) commit to that goal with you.
• Be genuinely proud to be a psychiatrist. You assess and rectify disorders of the mind, the most complex and magical product of the human brain that determines who we are and how we think, emote, communicate, verbalize, empathize, love, hate, remember, plan, problem-solve, and, of course, make resolutions.

Back to diet and exercise—for our patients and for us!
It’s OK to include, among your New Year’s resolutions, a pledge to strongly encourage patients to diet and exercise. Given the tendency of many of them to gain weight and die prematurely as a consequence of obesity-related cardiometabolic risk factors, you should urge them to eat healthy and exercise every time you see them, not only on New Year’s Day.

Such decisions can be made at any time, but the dawn of a year is a powerful signal of a new beginning—another lease on life, a potential turning point. Imbedded in those resolutions is a subliminal sense of urgency to correct one’s long-neglected shortcomings as the calendar ruthlessly points to inevitable aging and the relentless march of time.

A psychiatric perspective
For psychiatrists, New Year’s resolutions transcend the (often ephemeral) impulse to go on a diet or buy a membership at the local gym. We have a unique perspective on the challenges that our patients face every day as they cope with the complex demands of life despite their anxiety, depression, or psychosis.

We are aware of the many unmet needs in managing complex neuropsychiatric brain disorders and the major challenges of erasing the burdensome stigma that engulfs our patients and the practice of psychiatry itself—despite its noble mission of repairing fractured brains, mending tortured souls, and restoring peace of mind and wellness. We are proud of our clinical and scientific accomplishments but are painfully cognizant of our limitations and the huge chasm between what we know and what we will eventually know once the brain reveals its glorious mysteries through neuroscientific research.

What can you resolve?
Here is my proposed list of pragmatic resolutions that most psychiatrists would regard as part of a perpetual to-do list—a must-do bucket of cherished goals and brave new horizons to bring complete mental health for our patients and immeasurable gratification for us, who dream of cures for brain disorders that trigger various ailments of the mind.

• Practice like a physician to emphasize the medical foundation of psychiatry: Always check on a patient’s physical health, and monitor his (her) cardiometabolic status. Wear the symbolic white coat that often enhances the physician−patient relationship.
• Dedicate a significant percentage of your practice to the sickest patients. There are enough non-physician mental health professionals to handle the walking wounded and worried well.
• Advocate relentlessly throughout your sphere of influence, and publicly, for true parity between psychiatric and non-mental medical disorders—not only for insurance coverage but for overall societal acceptance and compassion as well.
• Lobby vigorously for hospitalization instead of imprisonment of the seriously mentally ill because psychosis is a brain disease, not a criminal offense.
• Adopt evidence-based psychiatric practice whenever possible to achieve the best outcomes. Judiciously implement off-label practices, however, if no evidence-based treatments exist for a suffering patient.
• Avoid senseless and irrational polypharmacy but do not hesitate to use rational, beneficial combination therapy.
• Provide 1 hour a week of pro bono psychiatric work for the indigent and underserved. The rewards of giving what amounts to 1 week a year are immeasurably more gratifying than a few more dollars in your bank account.
• Resist calling an ill person a ‘client’ or ‘consumer’—at least until oncologists and cardiologists start doing so. Refuse to give up your medical identify in the many de-medicalized mental health clinics.
• Never let a patient leave your office without some psychotherapy, even as part of a 15-minute med-check.
• Stay current and on the cutting edge of evolving psychiatric practice by logging into PubMed every day (even briefly) to read a few abstracts of the latest studies related to patients you saw that day.
• Think like a neurologist by identifying the neural circuits of psychiatric symptoms. Act like a cardiologist by doing everything medically possible to prevent recurrence of psychotic, manic, or depressive episodes because they damage brain tissue just as a myocardial infarction damages the heart.
• Support research with words, money, and passion. Psychiatric neuroscientific breakthroughs generate superior treatments, erase stigma, and advance the quality of life for patients. Donate annually to the researchers of your choice, at the medical school where you were trained, or at a nonprofit research institute.
• Make time to write for publication, annually, at least 1 case report or a letter to the editor about observations from your practice. You can contribute immensely to the discovery process by sharing novel clinical insights.
• Never give up on any patient or set expectations too low, regardless of the diagnosis or severity of illness. Giving up destroys hope and ushers in despondency. Get a second opinion if you run out of options for a patient.
• Always set remission followed by recovery as the therapeutic goal for every patient. Let the patient know this and ask him (her) commit to that goal with you.
• Be genuinely proud to be a psychiatrist. You assess and rectify disorders of the mind, the most complex and magical product of the human brain that determines who we are and how we think, emote, communicate, verbalize, empathize, love, hate, remember, plan, problem-solve, and, of course, make resolutions.

Back to diet and exercise—for our patients and for us!
It’s OK to include, among your New Year’s resolutions, a pledge to strongly encourage patients to diet and exercise. Given the tendency of many of them to gain weight and die prematurely as a consequence of obesity-related cardiometabolic risk factors, you should urge them to eat healthy and exercise every time you see them, not only on New Year’s Day.

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

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

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

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

Dementia—“major neurocognitive disorder” in DSM-5—manifests as progressive decline in cognitive function.In tandem with that decline, approximately 80% of nursing home patients with dementia exhibit behavioral disturbances,¹ including irritability, insomnia, wandering, and repetitive questioning.^1,2 These disturbances can erode their quality of life and can frustrate caregivers and providers.³

Causative pathology
Before designing a therapeutic intervention for cognitively impaired people with behavioral disturbances, a precise diagnosis of the causative pathology must be determined. This affords therapies that specifically address the patient’s problems. Other related and unrelated somatic or mental health concerns should be identified to specify the optimal approach.

Patients in whom dementia is suspected require that a thorough medical, psychiatric, substance use, and family history be taken to identify predisposing factors for their illness²; exhaustive review of the history might reveal drug interactions or polypharmacy that can cause or exacerbate symptoms, including behavioral manifestations. Physical examination, cognitive function testing, laboratory tests, and neuroimaging also help reveal the etiologic diagnosis of the dementia.^1,3

Identifying the diagnosis directs the treatment; for example, a behaviorally discontrolled person with a cognitive, stroke-induced encephalopathy requires an entirely different regimen than a comparatively compromised individual with Alzheimer’s disease or frontotemporal dementia. Early detection of dementia also is helpful for managing its cognitive and behavioral problems more effectively.¹Once a diagnosis of dementia is established, it might be behavioral symptoms and poor insight that become more worrisome to the patient’s caregivers and providers than cognitive deficits. Your task is then to apply behavioral approaches to management, with consistency, to maximize, at all times, the patient’s safety and comfort.⁴

How you approach behavioral management is important
Consider these interventions:

• Ensure that you appropriately treat associated depression, pain, and somatic illness—whether related or unrelated to dementia.
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.
• Provide family and caregivers with disease education, social support, and management tips^1,2; be respectful to family members in all interactions.³
• Offer caregivers and staff a plan for attending to supportive measures, including nutrition, hydration, and socialization.

Minimize psychosocial and environmental stressors

• Avoid unnecessary environmental changes, such as rearranging or refurbishing the patient’s living space.¹
• As noted, ensure that the patient is comfortable and safe in his (her) surroundings, such as providing wall-mounted handrails and other aids for ambulation.
• Provide access to television, proper lighting, and other indicated life-enhancing devices.^1,2
• Consider a pet for the patient; pets can be an important adjunct in providing comfort.
• Provide music to reduce agitation and anxiety.⁴
• Appeal to institutional administration to provide a higher staff−patient ratio for comfort and security.^2,5
• Because social contact is helpful to build a pleasant environment, preserve opportunities for the patient to communicate with others, and facilitate socialization by encouraging friendly interactions.¹
• Provide stimulation and diversion with social activities, support programs, and physical exercise—sources of interaction that can promote health and improve sleep.
• Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.^2,5
• Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.¹
• Provide access to television, proper lighting, and other indicated life-enhancing devices.Provide music to reduce agitation and anxiety.Redirection and validation are helpful to divert a patient’s attention from stressful situations and keep him (her) calm.Pharmacotherapy should be implemented if psychosocial methods of behavioral management fail or the patient’s behavior becomes threatening.

Other considerations

• Identify and treat primary and secondary causes of the underlying major neurocognitive disorder.
• Use an integrative, multidisciplinary approach to manage behavioral problems in dementia.
• Utilize a social worker’s expertise to faciliate family, financial, or related social issues and better cooperation. This promotes comfort for patients, families, and staff.
• Physical therapy aids in maintaining physical function, especially preservation of gait, balance, and range of motion. Thus, with greater stability avoiding a fall can be a life-saving event.
• Socialization, mental outlook, and emotional health are improved by occupational therapist interventions.
• Individual psychotherapy helps to improve self-esteem and personal adjustment. Group activities reinforces interpersonal connections.
• Refer the family and caregivers for supportive therapy and education on dementia; such resources help minimize deleterious effects of the patient’s behavioral problems on those key people.

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

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”

Since 2005, I’ve had the opportunity to review “Pearls” articles submitted for publication in Current Psychiatry. In that time, I have read many worthwhile papers written by authors who may not be entirely clear about what constitutes a “Pearl." The mnemonic PEARL could help authors:

• decide if their article or idea is appropriate for “Pearls”
• construct the article to conform to the “Pearls” format.

Easy to remember. Lengthy, highly detailed articles may be helpful and informative but are not consistent with the purpose of “Pearls.

Alert. A “Pearl” should alert a physician to identify a problem, diagnosis, or adverse effect that they might otherwise miss or take unnecessary time to identify. Classic examples are the “handshake diagnosis” of hyperthyroidism,¹ or the “3 little words that can diagnose mild cognitive impairment.”²

References. A professional article of any length should include references. References add immediate credibility to the information presented. For a “Pearl,” even 1 reference is acceptable. A writer can easily search PubMed and the Internet to find references to confirm or support their ideas.
 

Less is more. Architect Mies van der Rohe’s minimalist concept applies to “Pearls.” A “Pearl”—like its namesake—is small, polished, and valuable. Simplicity is its essence.

I hope this mnemonic is useful for clinicians interested in sharing their ideas or experiences to help others in the field. I look forward to reviewing many more “Pearls.”

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Diagnosis, mood changes
Ms. A, age 58, is a white female with a history of chronic bipolar I disorder who is being evaluated as a new patient in an academic psychiatric clinic. Recently, she was diagnosed with ER+, PR+, and HER2+ ductal carcinoma. She does not take her prescribed mood stabilizers.

After her cancer diagnosis, Ms. A experiences new-onset agitation, including irritable mood, suicidal thoughts, tearfulness, decreased need for sleep, fast speech, excessive spending, and anorexia. She reports that she hears the voice of God telling her that she could cure her breast cancer through prayer and herbal remedies. Her treatment team, comprising her primary care provider and surgical oncologist, consider several medication adjustments, but are unsure of their effects on Ms. A’s mental health, progression of cancer, and cancer treatment.

What is the most likely cause of Ms. A’s psychiatric symptoms?
   a) anxiety from having a diagnosis of cancer
   b) stress reaction
   c) panic attack
   d) manic or mixed phase of bipolar I disorder

The authors’ observations
Treating breast cancer with concurrent severe mental illness is complex and challenging for the patient, family, and health care providers. Mental health and oncology clinicians must collaborate when treating these patients because of overlapping pathophysiology and medication interactions. A comprehensive evaluation is required to tease apart whether a patient is simply demoralized by her new diagnosis, or if a more serious mood disorder is present.

Worldwide, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women.¹ The mean age of women diagnosed with breast cancer is 61 years; 61% of these women are alive 15 years after diagnosis, representing the largest group of female cancer survivors.

The incidence of breast cancer is reported to be higher in women with bipolar disorder compared with the general population.^2-4 This positive correlation might be associated with a high rate of smoking, poor health-related behaviors, and, possibly, medication side effects. A genome-wide association study found significant associations between bipolar disorder and the breast cancer-related genes BRCA2 and PALB2.⁵

Antipsychotics and prolactin
Antipsychotics play an important role in managing bipolar disorder; several, however, are known to raise the serum prolactin level 10- to 20-fold. A high prolactin level could be associated with progression of breast cancer. All antipsychotics have label warnings regarding their use in women with breast cancer.

The prolactin receptor is overexpressed in >95% of breast cancer cells, regardless of estrogen-receptor status. The role of prolactin in development of new breast cancer is open to debate. The effect of a high prolactin level in women with diagnosed breast cancer is unknown, although available preclinical data suggest that high levels should be avoided. Psychiatric clinicians should consider checking the serum prolactin level or switching to a treatment strategy that avoids iatrogenic prolactin elevation. This risk must be carefully weighed against the mood-stabilizing properties of antipsychotics.⁶

TREATMENT Consider comorbidities
Ms. A receives supportive psychotherapy in addition to quetiapine, 400 mg/d, and valproic acid, 1,500 mg/d. This regimen helps her successfully complete the initial phase of breast cancer treatment, which consists of a single mastectomy, adjuvant chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab). She is now on endocrine therapy with tamoxifen.

Ms. A, calm, much improved mood symptoms, and euthymic, has questions regarding her mental health, cancer prognosis, and potential medication side effects with continued cancer treatment.

Which drug used to treat breast cancer might relieve Ms. A’s manic symptoms?
   a) cyclophosphamide
   b) tamoxifen
   c) trastuzumab
   d) pamidronate

The authors’ observations
Recent evidence suggests that tamoxifen reduces symptoms of bipolar mania more rapidly than many standard medications for bipolar disorder. Tamoxifen is the only available centrally active protein kinase C (PKC) inhibitor,⁷ although lithium and valproic acid also might inhibit PKC activity. PKC regulates presynaptic and postsynaptic neurotransmission, neuronal excitability, and neurotransmitter release. PKC is thought to be overactive during mania, possibly because of an increase in membrane-bound PKC and PKC translocation from the cytosol to membrane.^7,8

Preliminary clinical trials suggest that tamoxifen significantly reduces manic symptoms in patients with bipolar disorder within 5 days of initiation.⁷ These findings have been confirmed in animal studies and in 1 single-blind and 4 double-blind placebo-controlled clinical studies over the past 15 years.⁹

Tamoxifen is a selective estrogen-receptor modulator used to prevent recurrence in receptor-positive breast cancer. Cytochrome P450 (CYP) 2D6 is the principal enzyme that converts tamoxifen to its active metabolite, endoxifen. Inhibition of tamoxifen conversion to endoxifen by CYP2D6 inhibitors could decrease the efficacy of tamoxifen therapy and might increase the risk of breast cancer recurrence. Although antidepressants generally are not recommended as a first-line agent for bipolar disorder, several selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are potent, moderate, or mild inhibitors of CYP2D6¹⁰ (Table 1). Approximately 7% of women have nonfunctional CYP2D6 alleles and have a lower endoxifen level.¹¹

Treating breast cancer
The mainstays of breast cancer treatment are surgery, radiation therapy, chemotherapy, hormone therapy, and targeted monoclonal antibody therapy. The protocol of choice depends on the stage of cancer, estrogen receptor status, expression of human epidermal growth factor receptor 2 (HER-2), treatment history, and the patient’s menopausal status. Overexpression of HER-2 oncoprotein, found in 25% to 30% of breast cancers, has been shown to promote cell transformation. HER-2 overexpression is associated with aggressive tumor phenotypes, lymph node involvement, and resistance to chemotherapy and endocrine therapy. Therefore, the HER-2 oncoprotein is a key target for treatment. Often, several therapies are combined to prevent recurrence of disease.

Breast cancer treatment often can cause demoralization, menopausal symptoms, sleep disturbance, impaired sexual function, infertility, and disturbed body image. It also can trigger psychiatric symptoms in patients with, or without, a history of mental illness.

Trastuzumab is a recombinant humanized monoclonal antibody against HER-2, and is approved for treating HER-2 positive breast cancer. However, approximately 50% of patients with HER-2 overexpression do not respond to trastuzumab alone or combined with chemotherapy, and nearly all patients develop resistance to trastuzumab, leading to recurrence.¹² This medication is still used in practice, and research regarding antiepileptic drugs working in synergy with this monoclonal antibody is underway.

OUTCOME Stability achieved
Quetiapine and valproic acid are first-line choices for Ms. A because (1) she would be on long-term tamoxifen to maintain cancer remission maintenance and (2) she is in a manic phase of bipolar disorder. Tamoxifen also could improve her manic symptoms. This medication regimen might enhance the action of cancer treatments and also could reduce adverse effects of cancer treatment, such as insomnia associated with tamoxifen.

After the team educates Ms. A about how her psychiatric medications could benefit her cancer treatment, she becomes more motivated to stay on her regimen. Ms. A does well on these medications and after 18 months has not experienced exacerbation of psychiatric symptoms or recurrence of cancer. 

The authors’ observations
There are 3 major classes of mood stabilizers for treating bipolar disorder: lithium, antiepileptic drugs, and atypical antipsychotics.¹³ In a setting of cancer, mood stabilizers are prescribed for managing mania or drug-induced agitation or anxiety associated with steroid use, brain metastases, and other medical conditions. They also can be used to treat neuropathic pain and hot flashes and seizure prophylaxis.¹³

Valproic acid
Valproic acid can help treat mood lability, impulsivity, and disinhibition, whether these symptoms are due to primary psychiatric illness or secondary to cancer metastasis. It is a first-line agent for manic and mixed bipolar states, and can be titrated quickly to achieve optimal benefit. Valproic acid also has been described as a histone deacetylase (HDAC) inhibitor, known to attenuate apoptotic activity, making it of interest as a treatment for cancer.¹⁴ HDAC inhibitors have been shown to:

• induce differentiation and cell cycle arrest
• activate the extrinsic or intrinsic pathways of apoptosis
• inhibit invasion, migration, and angiogenesis in different cancer cell lines.¹⁵

In regard to breast cancer, valproic acid inhibits growth of cell lines independent of estrogen receptors, increases the action of such breast cancer treatments as tamoxifen, raloxifene, fulvestrant, and letrozole, and induces solid tumor regression.¹⁴ Valproic acid also reduces cancer cell viability and could act as a powerful antiproliferative agent in estrogen-sensitive breast cancer cells.¹⁶

Valproic acid reduces cell growth-inducing apoptosis and cell cycle arrest in ERα-positive breast cancer cells, although it has no significant apoptotic effect in ERα-negative cells.¹⁶ However, evidence does support the ability of valproic acid to restore an estrogen-sensitive phenotype in ERα-negative breast cancer cells, allowing successful treatment with the anti-estrogen tamoxifen in vitro.¹⁰

Antipsychotics
Antipsychotics act as dopamine D2 receptor antagonists within the hypothalamic-pituitary-adrenal axis, thus increasing the serum prolactin level. Among atypicals, risperidone and its active metabolite, paliperidone, produce the greatest increase in the prolactin level, whereas quetiapine, clozapine, and aripiprazole minimally elevate the prolactin level.

Hyperprolactinemia correlates with rapid breast cancer progression and inferior prognosis, regardless of breast cancer receptor typing. Therefore, prolactin-sparing antipsychotics are preferred when treating a patient with comorbid bipolar disorder and breast cancer. Checking the serum prolactin level might help guide treatment. The literature is mixed regarding antipsychotic use and new mammary tumorigenesis; current research does not support antipsychotic choice based on future risk of breast cancer.⁶

Other adverse effects from antipsychotic use for bipolar disorder could have an impact on patients with breast cancer. Several of these medications could ameliorate side effects of advanced cancer and chemotherapy. Quetiapine, for example, might improve tamoxifen-induced insomnia in women with breast cancer because of its high affinity for serotonergic receptors, thus enhancing central serotonergic neurotransmitters and decreasing excitatory glutamatergic transmission.¹⁷

In any type of advanced cancer, nausea and vomiting are common, independent of chemotherapy and medication regimens. Metabolic derangement, vestibular dysfunction, CNS disorders, and visceral metastasis all contribute to hyperemesis. Olanzapine has been shown to significantly reduce refractory nausea and can cause weight gain and improved appetite, which benefits cachectic patients.¹⁸

Last, clozapine is one of the more effective antipsychotic medications, but also carries a risk of neutropenia. In patients with neutropenia secondary to chemotherapy, clozapine could increase the risk of infection in an immunocompromised patient.¹⁹ Granulocyte colony stimulating factor might be useful as a rescue medication for treatment-emergent neutropenia.¹⁹

Treatment considerations
Cancer patients might be unable or unwilling to seek services for mental health during their cancer treatment, and many who have a diagnosis of psychiatric illness might stop following up with psychiatric care when cancer treatment takes priority. It is critical for clinicians to be aware of the current literature regarding the impact of mood-stabilizing medication on cancer treatment. Monitoring for drug interactions is essential, and electronic drug interaction tools, such as Lexicomp, may be useful for this purpose.¹³ Because of special vulnerabilities in this population, cautious and judicious prescribing practices are advised.

The risk-benefit profile for medications for bipolar disorder must be considered before they are initiated or changes are made to the regimen (Table 2). Changing an effective mood stabilizer to gain benefits in breast cancer prognosis is not recommended in most cases, because benefits have been shown to be only significant in preclinical research; currently, there are no clinical guidelines. However, medication adjustments should be made with these theoretical benefits in mind, as long as the treatment of bipolar disorder remains effective.

Regardless of what treatment regimen the health team decides on, several underlying issues that affect patient care must be considered in this population. Successfully treating breast cancer in a woman with severe mental illness only can be accomplished when her mental illness is under control. Once she is psychiatrically stable, it is important for her to have a basic understanding of how cancer can affect the body and know the reasons behind treatment.

It is imperative that physicians provide their patients with a general understanding of their comorbid disorders, and find ways to help patients remain adherent with treatment of both diseases. Many patients feel demoralized by a cancer diagnosis and adherence to a medication regimen might be a difficult task among those with bipolar disorder who also are socially isolated, lack education, or have poor recall of treatment recommendations.²⁰

Bottom Line
Managing comorbid bipolar disorder and breast cancer might seem daunting,
but treatments for the 2 diseases can work in synergy. You have an opportunity to
educate patients and colleagues in treating bipolar disorder and comorbid breast
cancer. Optimizing care using known psychopharmacologic data can not only lead
to better outcomes, but might additionally offer some hope and reason to remain
treatment-adherent for patients suffering from this complex comorbidity.

Related Resources
• Agarwala P, Riba MB. Tailoring depression treatment for women with breast cancer. Current Psychiatry. 2010;9(11): 39-40,45-46,48-49.
• Cunningham R, Sarfati D, Stanley J, et al. Cancer survival in the context of mental illness: a national cohort study. Gen Hosp Psychiatry. 2015;37(6):501-506.

Drug Brand Names
Amiodarone • Cordarone
Aripiprazole • Abilify
Asenapine • Saphris
Bupropion • Wellbutrin
Carbamazepine • Tegretol
Citalopram • Celexa
Clozapine • Clozaril
Cyclophosphamide • Cytoxan, Neosar
Doxorubicin • Doxil, Adriamycin
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fulvestrant • Faslodex
Iloperidone • Fanapt
Lamotrigine • Lamictal
Letrozole • Femara
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Olanzapine • Zyprexa
Paclitaxel • Onxol
Paliperidone • Invega
Pamidronate • Aredia
Paroxetine • Paxil
Quetiapine • Seroquel
Raloxifene • Evista
Risperidone • Risperdal
Sertraline • Zoloft
Tamoxifen • Nolvadex
Thioridazine • Mellaril
Trastuzumab • Herceptin
Valproic acid • Depakene
Venlafaxine • Effexor
Ziprasidone • Geodon

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

CASE Psychotic, and nonadherent
Mr. K, a 42-year-old Fijian man, is brought to the emergency department by his older brother for evaluation of behavioral agitation. Mr. K is belligerent and threatens to kill his family members. Three years earlier, he was given a diagnosis of schizophrenia and treated at an inpatient psychiatric unit.

At that time, Mr. K was stabilized on risperidone, 4 mg/d. However, he did not follow-up with treatment after discharge and has not taken any psychotropic medications since that time.

His brother reports that Mr. K has been slowly deteriorating, talking to himself, staying up at night, and getting into arguments with his family over his delusional beliefs. Although Mr. K once worked as a security guard, he has not worked in 8 years. He has been living with his family, who are no longer willing to accept him into their home because they fear he might harm them.

In the emergency department, Mr. K reports that he has a throbbing headache. Blood pressure is 177/101 mm Hg; heart rate is 103 beats per minute; respiratory rate is 18 breaths per minute; weight is 185 lb; and body mass index (BMI) is 31.8. Physical examination is unremarkable.

Laboratory values show that sodium is 131 mEq/L; potassium, 3.7 mEq/L; bicarbonate, 26 mEq/L; glucose, 420 mg/dL; hemoglobin A_1c,12.7; and urine glucose, 3+. Mr. K denies being told he has diabetes.

What are Mr. K’s risk factors for diabetes?
   a) schizophrenia
   b) physical inactivity
   c) obesity
   d) Fijian ethnicity
   e) all of the above

The authors’ observations
The prevalence of type 2 diabetes mellitus (T2DM) in persons with schizophrenia or a schizoaffective disorder is twice that of the general population.^1-4 Multiple variables contribute to the increased prevalence of diabetes in this population, including genetic predisposition, environmental and cultural factors related to diet and physical activity, a high rate of smoking,^5,6 iatrogenic causes (metabolic dysregulation and weight gain from antipsychotic treatment), and socioeconomic factors (poverty, lack of access to health care). In addition, symptoms of psychosis such as thought disorder, delusions, hallucinations, and cognitive decline in persons with chronic schizophrenia and schizoaffective disorder can make basic health maintenance difficult.

In Mr. K’s case, premorbid risk of diabetes was elevated because of his Fijian ethnicity.⁷ With a BMI of 31.8, obesity further increased that risk.^5,6,8 In addition, his untreated chronic mental illness, lack of access to health care, low socioeconomic status, long-standing smoking habit, and previous exposure to antipsychotics also increased his risk of T2DM.

The interaction between diabetes and psychosis contributes to a vicious cycle that makes both conditions worse if either, or both, are untreated. In general, medical comorbidities are associated with depression and neurocognitive impairment in persons with schizophrenia.⁹ Specifically, diabetes is associated with lower global cognitive functioning among persons with schizophrenia.¹⁰ Poor cognitive functioning can, in turn, decrease the patient’s ability to manage his medical illness. Also, persons with schizophrenia are less likely to be treated for diabetes, dyslipidemia, and hypertension, as in Mr. K’s case.¹¹

How would you treat Mr. K’s newly diagnosed diabetes?
   a) refer him to a primary care physician
   b) start an oral agent
   c) start sliding-scale insulin
   d) start long-acting insulin
   e) recommend a carbohydrate-controlled diet=

TREATMENT Stabilization
Mr. K is admitted to the medical unit for treatment of hyperglycemia. The team starts him on amlodipine, 5 mg/d, for hypertension; aripiprazole, 10 mg/d, for psychosis; and sliding-scale insulin (lispro) and 20 units of insulin (glargine) nightly for diabetes. Mr. K’s blood glucose level is well regulated on this regimen; after being medically cleared, he is transferred to the inpatient psychiatric unit.

EVALUATION Denies symptoms
Mr. K appears older than his stated age, is poorly groomed, and is dressed in a hospital gown. He is isolated and appears to be internally preoccupied. He repeatedly denies hearing auditory hallucinations, but often is overheard responding to internal stimuli and mumbling indecipherably in a low tone. His speech is decreased and his affect is flat and guarded. He states that he is not “mental” but that he came to the hospital for “tooth pain.” Every day he asks when he can return home and he asks the staff to call his family to take him home. When informed that his family is not able to care for him, Mr. K states that he would live in a house he owns in Fiji, which his family members state is untrue.

How would you treat Mr. K’s psychosis?
   a) continue aripiprazole
   b) switch to risperidone, an agent to which he previously responded
   c) switch to olanzapine because he has not been sleeping well
   d) switch to haloperidol because of diabetes

The authors’ observations
Pharmacotherapy for patients with comorbid schizophrenia and diabetes requires consideration of clinical and psychosocial factors unique to this population.

Antipsychotic choice
Selection of an antipsychotic agent to address psychosis requires considering its efficacy, side-effect profile, and adherence rates, as well as its potential effects on metabolic regulation and weight (Table 1). Typical antipsychotics are less likely than atypical antipsychotics to cause metabolic dysregulation.¹² When treatment with atypical antipsychotics cannot be avoided—such as when side effects or an allergic reaction develop—consider selecting a relatively weight-neutral drug with a lower potential for metabolic dysregulation, such as aripiprazole. However, many times, using an agent with significant effects on metabolic regulation cannot be avoided, making treating and monitoring the resulting metabolic effects even more significant.

Glycemic control
Initiating an agent for glycemic control in persons with newly diagnosed diabetes requires weighing many factors, including mode of delivery (oral or subcutaneous), level of glycemic control required, comorbid medical illness (such as renal impairment and heart failure), cost, and potential long-term side effects of the medication (Table 2).¹³ Oral agents have a slower effect on lowering the blood glucose level, and each agent carries contraindications, but generally they are more affordable. Many present a low risk of hypoglycemia but sulfonylureas are an exception. In addition, metformin could lead to weight loss over the long term, which further lowers the risk of diabetes.

If, however, tight and immediate glycemic control is needed, subcutaneous insulin injections might be required, although this method is more costly, carries an increased risk of hypoglycemic episodes acutely, and leads to weight gain in the long run because of induced hunger and increased appetite.

Psychosocial factors
In addition to the clinical variables above, treating diabetes in patients with comorbid schizophrenia requires considering other psychosocial factors that might not be readily apparent (Table 3). For example, patients with schizophrenia might have decreased motivation, self-efficacy, and capacity for self-care when it comes to health maintenance and medication adherence.¹⁴ Chronically mentally ill persons might have reduced cognitive functioning that could affect their ability to maintain complicated medication regimens, such as administering insulin and monitoring blood glucose.

In addition, easy access to hypodermic needles and large amounts of insulin could become a safety concern in patients with ongoing hallucinations, delusions, and thought disorder, despite antipsychotic treatment. For example, a patient with schizophrenia and diabetes who has been maintained on insulin might begin hearing voices that tell her to inject her eyeballs with insulin. Similarly, although the risk of hypoglycemic episodes in patients treated with insulin is well known, patients with schizophrenia have a higher risk of acute complications of diabetes than other patients with diabetes.¹⁵Psychosocial factors, such as placement, support system, and follow-up care need to be considered. In some instances, the need to administer daily subcutaneous insulin could be a barrier to placement if the facility does not have the staff or expertise to monitor blood glucose and administer insulin.

If the patient is returning home, then the patient or a caretaker will need to be trained to monitor blood glucose and administer insulin. This might be difficult for persons with chronic mental illness who have lost the support and care of their family. Also, consider the issue of storing insulin, which requires refrigeration. Because of the potential complications involved in using insulin in patients with schizophrenia, practitioners should consider managing non-insulin dependent diabetes with an oral hypoglycemic agent, when possible, along with lifestyle modifications.

OUTCOME Weight loss, discharge
Mr. K is transitioned from aripiprazole to higher-potency oral risperidone, titrated to 6 mg/d. At this dosage, he continues to maintain a delusion about owning a house in Fiji, but was seen responding to internal stimuli less often. The treatment team places him on a diabetic and low-sodium diet of 1,800 kcal/d. His fasting blood glucose levels range in the 70s to 110s mg/dL during his first week of hospitalization.

The treatment team starts Mr. K on oral metformin, titrated to 1,000 mg twice daily, while tapering him off insulin lispro and glargine over the course of hospitalization. The transition from insulin to metformin also is considered because Mr. K’s daily insulin requirement is rather low (<0.5 units/kg).

Mr. K’s course is prolonged because his treatment team initiates the process of conservatorship and placement in the community. Approximately 6 months after his admission, Mr. K is discharged to an unlocked facility with support from an intensive outpatient mental health program. At 6 months follow-up with his outpatient provider, Mr. K’s hemoglobin A_1c is 7.0 and he weighs 155 lb with a BMI of 26.5.

The authors’ observations
Despite Mr. K’s initial elevated hemoglobin A_1c of 12.7 and weight of 185 lb, over approximately 6 months he experiences a 5.7-unit drop in hemoglobin A_1c and weight loss of 30 lb with dietary management and metformin—without the need for other agents. Other options for weight-neutral treatment of T2DM include exenatide, which also is available as a once weekly injectable formulation, canagliflozin, and the gliptins (sitagliptin, saxagliptin, and linagliptin) (Table 4).

Mr. K’s improved control of his diabetes occurred despite initiation of an atypical antipsychotic, which would have been expected to cause additional weight gain and make his diabetes worse secondary to metabolic effects.¹² Treatment with metformin in particular has been associated with weight loss in patients with¹⁶ and without¹⁷ comorbid schizophrenia, including those with antipsychotic-induced weight gain.^18-20

Bottom Line
Persons with schizophrenia are at higher risk of type 2 diabetes mellitus for many reasons, including metabolic effects of antipsychotics, reduced cognitive functioning, poor self-care, and limited access to health care. Typical antipsychotics are less likely to cause metabolic dysregulation but, if an atypical is needed, one that is relatively weight-neutral should be selected. When choosing an agent for glycemic control, consider a patient’s or a caretaker’s ability to administer medications, monitor blood glucose, and follow dietary recommendations.

Related Resources
• Cohn T. The link between schizophrenia and diabetes. Current Psychiatry. 2012;11(10):28-34,46.
• Annamalai A, Tek C. An overview of diabetes management in schizophrenia patients: office based strategies for primary care practitioners and endocrinologists [published online March 23, 2015]. Int J Endocrinol. 2015;2015:969182. doi: 10.1155/2015/969182.


Drug Brand Names
Amlodipine • Norvasc
Aripiprazole • Abilify
Asenapine • Saphris
Canagliflozin • Invokana
Exenatide • Bydureon, Byetta
Glargine • Lantus
Linagliptin • Tradjenta
Lispro • Humalog
Lurasidone • Latuda
Metformin • Glucophage
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Saxagliptin • Onglyza
Sitagliptin • Januvia

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

CASE Refusing solid food
Ms. B, age 11, is admitted to a pediatric medical inpatient unit for unintentional weight loss of 14 lb (15% total body weight) over the past month. She reports having 2 traumatic episodes last month: choking on a piece of cheese and having a swab specimen taken for a rapid strep test, which required several people to restrain her (the test was positive). Since then, she has refused to ingest solids, despite hunger and a desire to eat.

Ms. B reports diffuse abdominal pain merely “at the sight of food” and a fear of swallowing solids. She denies difficulty or pain upon swallowing, nausea, vomiting, or any change in bowel habits.

Her mother reports that, on the rare occasion that Ms. B has attempted to eat solid food, she spent as long as an hour cutting it into small pieces before bringing it to her mouth—after which she put the food down without eating. Her mother also witnessed Ms. B holding food in her mouth for “a very long time,” then spitting it out.

Ms. B says she is distressed about the weight loss and recognizes that her fear of solid food is excessive.

What would your diagnosis of Ms. B’s problem be?
   a) anorexia nervosa
   b) avoidant/restrictive food intake disorder (ARFID)
   c) specific phobia (swallowing solids or choking)
   d) generalized anxiety disorder (GAD)

The authors’ observations
DSM-5 describes a new eating disorder called ARFID, which replaces the DSM-IV-TR diagnosis of feeding disorder of infancy or early childhood</keyword>. DSM-5 diagnostic criteria define ARFID as:

An eating or feeding disturbance (eg, avoidance based on the sensory characteristics of food…) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with at least one of the following: 1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children). 2. Significant nutritional deficiency. 3. Dependence on enteral feeding or oral nutritional supplements. 4. Marked interference with psychosocial functioning.¹

DSM-5 also specifies that the disorder cannot be caused by lack of available food or traditional cultural practices; cannot co­exist with anorexia or bulimia nervosa; and is not attributable to a concurrent medical or psychiatric disorder.

Because it is a newly defined diagnosis, the epidemiology of ARFID is unclear. Patients with ARFID have a wide variety of eating symptoms that do not meet diagnostic criteria for anorexia or bulimia nervosa. One study found that, among a cohort of mostly adolescent patients who presented for evaluation of an eating disorder, 14% met diagnostic criteria for ARFID.² Another retrospective case-control study found a similar prevalence among patients age 8 to 18 (13.8% of 712 patients).³ Because of the variety of maladaptive feeding behaviors seen in ARFID, there is little evidence that pharmaco­therapy is effective.⁴

HISTORY Premature birth
Ms. B’s medical history states that she is twin A of a premature birth at 26 weeks (birth weight, 1,060 g), with a 90-day neonatal intensive care unit hospitalization, during which she required supplemental oxygen and nasogastric tube feeding. She has mild cerebral palsy, and had motor delay of walking at 2.5 years old. Currently, she has no motor difficulties.

Ms. B does not have a psychiatric history and does not take medications. Her mother has a history of major depressive disorder that is well controlled with an unspecified selective serotonin reuptake inhibitor. Ms. B’s maternal uncle has poorly controlled schizophrenia.

During Ms. B’s 6-day hospitalization, her mental status exams are unremarkable. She is shy but cooperative and open. Her mood ranges from “sad” and “nervous” on admission to “fine” with mood-congruent affect. She denies suicidal or homicidal thoughts and hallucinations, and demonstrates good insight and judgment. All laboratory values are within normal limits except for mild hypophosphatemia (3.7 mg/dL) and mild hyperalbuminemia (4.9 g/dL) on admission, which may have been related to her nutritional status.

DIAGNOSIS Not solely psychiatric
The psychiatric differential diagnosis includes:

• ARFID
• specific phobia of swallowing solids or choking (pseudodysphagia)
• GAD
• unspecified feeding disorder.

Ms. B meets diagnostic criteria for ARFID, particularly that of profound acute weight loss due to restrictive eating behaviors. Her presentation also is similar to that of a specific phobia, namely profound anxiety upon even the thought of solid food (phobic stimulus) and recognition that her fear is excessive. However, she fails to meet diagnostic criteria for phobia in children, which require duration of at least 6 months. GAD also is less likely because she has had symptoms for 1 month (also requires 6-month duration) and her anxiety is limited to feeding behaviors.

The treatment team starts exposure therapy, encouraging Ms. B to begin taking small bites of textured foods, such as oatmeal.

On hospital Day 5, barium esophagogram reveals extrinsic compression of the esophagus. To identify the precise cause of compression, chest magnetic resonance angiogram reveals that Ms. B has a right-sided aortic arch with an aberrant left subclavian artery at T4 that, with the ligamentum arteriosum and left pulmonary artery, form a vascular ring impinging around the esophagus.

The authors’ observations
Dysphagia lusoria, coined in 1789 from the root for “natural abnormality,”⁵ is caused by an aberrant right subclavian artery, which persists because of abnormal involution of the right fourth aortic arch during embryogenesis⁶ (Figure 1). The condition is diagnosed incidentally in most affected adults, who are asymptomatic throughout life and do not require operative management.⁶

Symptoms of dysphagia lusoria can include dysphagia and recurrent aspiration if significant esophageal impingement is present.⁷ It is thought that patients tend to show more symptoms as they age because of sclerosis, aneurysm, or atherosclerosis of the impinging vessel.⁷ Cough and dyspnea caused by impingement of the trachea also have been reported, and might be more common in children because of tracheal flexibility.⁵

This case illustrates the complex interrelationship of physical and psychiatric conditions. After the treatment team discovered a physical cause of Ms. B’s symptoms, the initial psychiatric diagnosis became problematic, but remained critically important for long-term treatment of her comorbid eating phobia.

TREATMENT Therapy, surgery
The treatment team is faced with the question of whether dysphagia lusoria fully accounts for Ms. B’s status. The anatomic anomaly might explain the initial choking incident if the food particle was lodged at the site of impingement, but does not account for development of a severe acute eating disorder and subsequent malnutrition.

Because of the presence of dysphagia lusoria, the team concludes that Ms. B does not meet diagnostic criteria for ARFID. She is given a diagnosis of unspecified eating disorder.

Ms. B is discharged and referred to a pediatric cardiothoracic surgeon for operative consult of symptomatic dysphagia lusoria. By discharge, she is successfully eating yogurt with fruit chunks, which she had rejected earlier. She also expresses optimism about eating cake at her birthday party, scheduled for 2 weeks after discharge.

The treatment team strongly recommends outpatient psychiatric follow-up to manage Ms. B’s unspecified eating disorder with cognitive-behavioral therapy and exposure and response prevention, which helped to mildly decrease her anxiety during the hospital stay.

Ms. B’s surgeon deems the case severe enough to warrant surgery. Surgery for dysphagia lusoria can be indicated to prevent progression of symptoms into adulthood⁸; options include division of the ligamentum arteriosum to loosen the vascular ring and re-implantation of the aberrant subclavian artery.^9,10 (On the other hand, dietary modification might be therapeutic in patients whose symptoms are mild.⁵)

The surgeon elects to divide the ligamentum arteriosum to relieve the pressure of the vascular ring on the esophagus. Intraoperatively, he discovers that Ms. B has a mildly patent ductus arteriosus (PDA) (Figure 2), which is more common in premature infants than in full-term births. The PDA is clipped on both sides and divided. This immediately causes the vascular ring created by the aberrant left subclavian artery, right-sided aorta, and PDA to spring open, releasing pressure on the esophagus.

The aberrant left subclavian artery emerges from an abnormal bulging of aorta, known as Kommerell’s diverticulum. After the vascular ring is released, the diverticulum is not observed to impinge on the esophagus; however, as a preventive measure, the surgeon sutures it to the anterior spinous ligament. This will prevent the diverticulum from enlarging and impinging on the esophagus as Ms. B grows to adulthood.

The surgery is completed without complications. Ms. B tolerates the procedure well.

Ten days after surgery, Ms. B is recovering well. She and her mother report satisfaction with the procedure to release the vascular ring. She discontinues her pain medication after 2 days and slowly begins reintroducing solid foods. Her fear of dysphagia and choking rapidly diminish.


Bottom Line
The diagnosis and management of eating disorders, including avoidant/restrictive food intake disorder and choking phobia, can be challenging. Furthermore, if an anatomical or organic anomaly is found, it is important to question how a patient’s eating disorder can be managed best through interdisciplinary collaboration between medical and behavioral specialties.

Related Resources
• Bryant-Waugh R. Feeding and eating disorders in children. Curr Opin Psychiatry. 2013;26(6):537-542.
• Norris ML, Robinson A, Obeid N, et al. Exploring avoidant/restrictive food intake disorder in eating disordered patients: a descriptive study. Int J Eat Disord. 2014;47(5):495-499.

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

CASE Refusing solid food
Ms. B, age 11, is admitted to a pediatric medical inpatient unit for unintentional weight loss of 14 lb (15% total body weight) over the past month. She reports having 2 traumatic episodes last month: choking on a piece of cheese and having a swab specimen taken for a rapid strep test, which required several people to restrain her (the test was positive). Since then, she has refused to ingest solids, despite hunger and a desire to eat.

Ms. B reports diffuse abdominal pain merely “at the sight of food” and a fear of swallowing solids. She denies difficulty or pain upon swallowing, nausea, vomiting, or any change in bowel habits.

Her mother reports that, on the rare occasion that Ms. B has attempted to eat solid food, she spent as long as an hour cutting it into small pieces before bringing it to her mouth—after which she put the food down without eating. Her mother also witnessed Ms. B holding food in her mouth for “a very long time,” then spitting it out.

Ms. B says she is distressed about the weight loss and recognizes that her fear of solid food is excessive.

What would your diagnosis of Ms. B’s problem be?
   a) anorexia nervosa
   b) avoidant/restrictive food intake disorder (ARFID)
   c) specific phobia (swallowing solids or choking)
   d) generalized anxiety disorder (GAD)

The authors’ observations
DSM-5 describes a new eating disorder called ARFID, which replaces the DSM-IV-TR diagnosis of feeding disorder of infancy or early childhood</keyword>. DSM-5 diagnostic criteria define ARFID as:

An eating or feeding disturbance (eg, avoidance based on the sensory characteristics of food…) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with at least one of the following: 1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children). 2. Significant nutritional deficiency. 3. Dependence on enteral feeding or oral nutritional supplements. 4. Marked interference with psychosocial functioning.¹

DSM-5 also specifies that the disorder cannot be caused by lack of available food or traditional cultural practices; cannot co­exist with anorexia or bulimia nervosa; and is not attributable to a concurrent medical or psychiatric disorder.

Because it is a newly defined diagnosis, the epidemiology of ARFID is unclear. Patients with ARFID have a wide variety of eating symptoms that do not meet diagnostic criteria for anorexia or bulimia nervosa. One study found that, among a cohort of mostly adolescent patients who presented for evaluation of an eating disorder, 14% met diagnostic criteria for ARFID.² Another retrospective case-control study found a similar prevalence among patients age 8 to 18 (13.8% of 712 patients).³ Because of the variety of maladaptive feeding behaviors seen in ARFID, there is little evidence that pharmaco­therapy is effective.⁴

HISTORY Premature birth
Ms. B’s medical history states that she is twin A of a premature birth at 26 weeks (birth weight, 1,060 g), with a 90-day neonatal intensive care unit hospitalization, during which she required supplemental oxygen and nasogastric tube feeding. She has mild cerebral palsy, and had motor delay of walking at 2.5 years old. Currently, she has no motor difficulties.

Ms. B does not have a psychiatric history and does not take medications. Her mother has a history of major depressive disorder that is well controlled with an unspecified selective serotonin reuptake inhibitor. Ms. B’s maternal uncle has poorly controlled schizophrenia.

During Ms. B’s 6-day hospitalization, her mental status exams are unremarkable. She is shy but cooperative and open. Her mood ranges from “sad” and “nervous” on admission to “fine” with mood-congruent affect. She denies suicidal or homicidal thoughts and hallucinations, and demonstrates good insight and judgment. All laboratory values are within normal limits except for mild hypophosphatemia (3.7 mg/dL) and mild hyperalbuminemia (4.9 g/dL) on admission, which may have been related to her nutritional status.

DIAGNOSIS Not solely psychiatric
The psychiatric differential diagnosis includes:

• ARFID
• specific phobia of swallowing solids or choking (pseudodysphagia)
• GAD
• unspecified feeding disorder.

Ms. B meets diagnostic criteria for ARFID, particularly that of profound acute weight loss due to restrictive eating behaviors. Her presentation also is similar to that of a specific phobia, namely profound anxiety upon even the thought of solid food (phobic stimulus) and recognition that her fear is excessive. However, she fails to meet diagnostic criteria for phobia in children, which require duration of at least 6 months. GAD also is less likely because she has had symptoms for 1 month (also requires 6-month duration) and her anxiety is limited to feeding behaviors.

The treatment team starts exposure therapy, encouraging Ms. B to begin taking small bites of textured foods, such as oatmeal.

On hospital Day 5, barium esophagogram reveals extrinsic compression of the esophagus. To identify the precise cause of compression, chest magnetic resonance angiogram reveals that Ms. B has a right-sided aortic arch with an aberrant left subclavian artery at T4 that, with the ligamentum arteriosum and left pulmonary artery, form a vascular ring impinging around the esophagus.

The authors’ observations
Dysphagia lusoria, coined in 1789 from the root for “natural abnormality,”⁵ is caused by an aberrant right subclavian artery, which persists because of abnormal involution of the right fourth aortic arch during embryogenesis⁶ (Figure 1). The condition is diagnosed incidentally in most affected adults, who are asymptomatic throughout life and do not require operative management.⁶

Symptoms of dysphagia lusoria can include dysphagia and recurrent aspiration if significant esophageal impingement is present.⁷ It is thought that patients tend to show more symptoms as they age because of sclerosis, aneurysm, or atherosclerosis of the impinging vessel.⁷ Cough and dyspnea caused by impingement of the trachea also have been reported, and might be more common in children because of tracheal flexibility.⁵

This case illustrates the complex interrelationship of physical and psychiatric conditions. After the treatment team discovered a physical cause of Ms. B’s symptoms, the initial psychiatric diagnosis became problematic, but remained critically important for long-term treatment of her comorbid eating phobia.

TREATMENT Therapy, surgery
The treatment team is faced with the question of whether dysphagia lusoria fully accounts for Ms. B’s status. The anatomic anomaly might explain the initial choking incident if the food particle was lodged at the site of impingement, but does not account for development of a severe acute eating disorder and subsequent malnutrition.

Because of the presence of dysphagia lusoria, the team concludes that Ms. B does not meet diagnostic criteria for ARFID. She is given a diagnosis of unspecified eating disorder.

Ms. B is discharged and referred to a pediatric cardiothoracic surgeon for operative consult of symptomatic dysphagia lusoria. By discharge, she is successfully eating yogurt with fruit chunks, which she had rejected earlier. She also expresses optimism about eating cake at her birthday party, scheduled for 2 weeks after discharge.

The treatment team strongly recommends outpatient psychiatric follow-up to manage Ms. B’s unspecified eating disorder with cognitive-behavioral therapy and exposure and response prevention, which helped to mildly decrease her anxiety during the hospital stay.

Ms. B’s surgeon deems the case severe enough to warrant surgery. Surgery for dysphagia lusoria can be indicated to prevent progression of symptoms into adulthood⁸; options include division of the ligamentum arteriosum to loosen the vascular ring and re-implantation of the aberrant subclavian artery.^9,10 (On the other hand, dietary modification might be therapeutic in patients whose symptoms are mild.⁵)

The surgeon elects to divide the ligamentum arteriosum to relieve the pressure of the vascular ring on the esophagus. Intraoperatively, he discovers that Ms. B has a mildly patent ductus arteriosus (PDA) (Figure 2), which is more common in premature infants than in full-term births. The PDA is clipped on both sides and divided. This immediately causes the vascular ring created by the aberrant left subclavian artery, right-sided aorta, and PDA to spring open, releasing pressure on the esophagus.

The aberrant left subclavian artery emerges from an abnormal bulging of aorta, known as Kommerell’s diverticulum. After the vascular ring is released, the diverticulum is not observed to impinge on the esophagus; however, as a preventive measure, the surgeon sutures it to the anterior spinous ligament. This will prevent the diverticulum from enlarging and impinging on the esophagus as Ms. B grows to adulthood.

The surgery is completed without complications. Ms. B tolerates the procedure well.

Ten days after surgery, Ms. B is recovering well. She and her mother report satisfaction with the procedure to release the vascular ring. She discontinues her pain medication after 2 days and slowly begins reintroducing solid foods. Her fear of dysphagia and choking rapidly diminish.


Bottom Line
The diagnosis and management of eating disorders, including avoidant/restrictive food intake disorder and choking phobia, can be challenging. Furthermore, if an anatomical or organic anomaly is found, it is important to question how a patient’s eating disorder can be managed best through interdisciplinary collaboration between medical and behavioral specialties.

Related Resources
• Bryant-Waugh R. Feeding and eating disorders in children. Curr Opin Psychiatry. 2013;26(6):537-542.
• Norris ML, Robinson A, Obeid N, et al. Exploring avoidant/restrictive food intake disorder in eating disordered patients: a descriptive study. Int J Eat Disord. 2014;47(5):495-499.

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

CASE Refusing solid food
Ms. B, age 11, is admitted to a pediatric medical inpatient unit for unintentional weight loss of 14 lb (15% total body weight) over the past month. She reports having 2 traumatic episodes last month: choking on a piece of cheese and having a swab specimen taken for a rapid strep test, which required several people to restrain her (the test was positive). Since then, she has refused to ingest solids, despite hunger and a desire to eat.

Ms. B reports diffuse abdominal pain merely “at the sight of food” and a fear of swallowing solids. She denies difficulty or pain upon swallowing, nausea, vomiting, or any change in bowel habits.

Her mother reports that, on the rare occasion that Ms. B has attempted to eat solid food, she spent as long as an hour cutting it into small pieces before bringing it to her mouth—after which she put the food down without eating. Her mother also witnessed Ms. B holding food in her mouth for “a very long time,” then spitting it out.

Ms. B says she is distressed about the weight loss and recognizes that her fear of solid food is excessive.

What would your diagnosis of Ms. B’s problem be?
   a) anorexia nervosa
   b) avoidant/restrictive food intake disorder (ARFID)
   c) specific phobia (swallowing solids or choking)
   d) generalized anxiety disorder (GAD)

The authors’ observations
DSM-5 describes a new eating disorder called ARFID, which replaces the DSM-IV-TR diagnosis of feeding disorder of infancy or early childhood</keyword>. DSM-5 diagnostic criteria define ARFID as:

An eating or feeding disturbance (eg, avoidance based on the sensory characteristics of food…) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with at least one of the following: 1. Significant weight loss (or failure to achieve expected weight gain or faltering growth in children). 2. Significant nutritional deficiency. 3. Dependence on enteral feeding or oral nutritional supplements. 4. Marked interference with psychosocial functioning.¹

DSM-5 also specifies that the disorder cannot be caused by lack of available food or traditional cultural practices; cannot co­exist with anorexia or bulimia nervosa; and is not attributable to a concurrent medical or psychiatric disorder.

Because it is a newly defined diagnosis, the epidemiology of ARFID is unclear. Patients with ARFID have a wide variety of eating symptoms that do not meet diagnostic criteria for anorexia or bulimia nervosa. One study found that, among a cohort of mostly adolescent patients who presented for evaluation of an eating disorder, 14% met diagnostic criteria for ARFID.² Another retrospective case-control study found a similar prevalence among patients age 8 to 18 (13.8% of 712 patients).³ Because of the variety of maladaptive feeding behaviors seen in ARFID, there is little evidence that pharmaco­therapy is effective.⁴

HISTORY Premature birth
Ms. B’s medical history states that she is twin A of a premature birth at 26 weeks (birth weight, 1,060 g), with a 90-day neonatal intensive care unit hospitalization, during which she required supplemental oxygen and nasogastric tube feeding. She has mild cerebral palsy, and had motor delay of walking at 2.5 years old. Currently, she has no motor difficulties.

Ms. B does not have a psychiatric history and does not take medications. Her mother has a history of major depressive disorder that is well controlled with an unspecified selective serotonin reuptake inhibitor. Ms. B’s maternal uncle has poorly controlled schizophrenia.

During Ms. B’s 6-day hospitalization, her mental status exams are unremarkable. She is shy but cooperative and open. Her mood ranges from “sad” and “nervous” on admission to “fine” with mood-congruent affect. She denies suicidal or homicidal thoughts and hallucinations, and demonstrates good insight and judgment. All laboratory values are within normal limits except for mild hypophosphatemia (3.7 mg/dL) and mild hyperalbuminemia (4.9 g/dL) on admission, which may have been related to her nutritional status.

DIAGNOSIS Not solely psychiatric
The psychiatric differential diagnosis includes:

• ARFID
• specific phobia of swallowing solids or choking (pseudodysphagia)
• GAD
• unspecified feeding disorder.

Ms. B meets diagnostic criteria for ARFID, particularly that of profound acute weight loss due to restrictive eating behaviors. Her presentation also is similar to that of a specific phobia, namely profound anxiety upon even the thought of solid food (phobic stimulus) and recognition that her fear is excessive. However, she fails to meet diagnostic criteria for phobia in children, which require duration of at least 6 months. GAD also is less likely because she has had symptoms for 1 month (also requires 6-month duration) and her anxiety is limited to feeding behaviors.

The treatment team starts exposure therapy, encouraging Ms. B to begin taking small bites of textured foods, such as oatmeal.

On hospital Day 5, barium esophagogram reveals extrinsic compression of the esophagus. To identify the precise cause of compression, chest magnetic resonance angiogram reveals that Ms. B has a right-sided aortic arch with an aberrant left subclavian artery at T4 that, with the ligamentum arteriosum and left pulmonary artery, form a vascular ring impinging around the esophagus.

The authors’ observations
Dysphagia lusoria, coined in 1789 from the root for “natural abnormality,”⁵ is caused by an aberrant right subclavian artery, which persists because of abnormal involution of the right fourth aortic arch during embryogenesis⁶ (Figure 1). The condition is diagnosed incidentally in most affected adults, who are asymptomatic throughout life and do not require operative management.⁶

Symptoms of dysphagia lusoria can include dysphagia and recurrent aspiration if significant esophageal impingement is present.⁷ It is thought that patients tend to show more symptoms as they age because of sclerosis, aneurysm, or atherosclerosis of the impinging vessel.⁷ Cough and dyspnea caused by impingement of the trachea also have been reported, and might be more common in children because of tracheal flexibility.⁵

This case illustrates the complex interrelationship of physical and psychiatric conditions. After the treatment team discovered a physical cause of Ms. B’s symptoms, the initial psychiatric diagnosis became problematic, but remained critically important for long-term treatment of her comorbid eating phobia.

TREATMENT Therapy, surgery
The treatment team is faced with the question of whether dysphagia lusoria fully accounts for Ms. B’s status. The anatomic anomaly might explain the initial choking incident if the food particle was lodged at the site of impingement, but does not account for development of a severe acute eating disorder and subsequent malnutrition.

Because of the presence of dysphagia lusoria, the team concludes that Ms. B does not meet diagnostic criteria for ARFID. She is given a diagnosis of unspecified eating disorder.

Ms. B is discharged and referred to a pediatric cardiothoracic surgeon for operative consult of symptomatic dysphagia lusoria. By discharge, she is successfully eating yogurt with fruit chunks, which she had rejected earlier. She also expresses optimism about eating cake at her birthday party, scheduled for 2 weeks after discharge.

The treatment team strongly recommends outpatient psychiatric follow-up to manage Ms. B’s unspecified eating disorder with cognitive-behavioral therapy and exposure and response prevention, which helped to mildly decrease her anxiety during the hospital stay.

Ms. B’s surgeon deems the case severe enough to warrant surgery. Surgery for dysphagia lusoria can be indicated to prevent progression of symptoms into adulthood⁸; options include division of the ligamentum arteriosum to loosen the vascular ring and re-implantation of the aberrant subclavian artery.^9,10 (On the other hand, dietary modification might be therapeutic in patients whose symptoms are mild.⁵)

The surgeon elects to divide the ligamentum arteriosum to relieve the pressure of the vascular ring on the esophagus. Intraoperatively, he discovers that Ms. B has a mildly patent ductus arteriosus (PDA) (Figure 2), which is more common in premature infants than in full-term births. The PDA is clipped on both sides and divided. This immediately causes the vascular ring created by the aberrant left subclavian artery, right-sided aorta, and PDA to spring open, releasing pressure on the esophagus.

The aberrant left subclavian artery emerges from an abnormal bulging of aorta, known as Kommerell’s diverticulum. After the vascular ring is released, the diverticulum is not observed to impinge on the esophagus; however, as a preventive measure, the surgeon sutures it to the anterior spinous ligament. This will prevent the diverticulum from enlarging and impinging on the esophagus as Ms. B grows to adulthood.

The surgery is completed without complications. Ms. B tolerates the procedure well.

Ten days after surgery, Ms. B is recovering well. She and her mother report satisfaction with the procedure to release the vascular ring. She discontinues her pain medication after 2 days and slowly begins reintroducing solid foods. Her fear of dysphagia and choking rapidly diminish.


Bottom Line
The diagnosis and management of eating disorders, including avoidant/restrictive food intake disorder and choking phobia, can be challenging. Furthermore, if an anatomical or organic anomaly is found, it is important to question how a patient’s eating disorder can be managed best through interdisciplinary collaboration between medical and behavioral specialties.

Related Resources
• Bryant-Waugh R. Feeding and eating disorders in children. Curr Opin Psychiatry. 2013;26(6):537-542.
• Norris ML, Robinson A, Obeid N, et al. Exploring avoidant/restrictive food intake disorder in eating disordered patients: a descriptive study. Int J Eat Disord. 2014;47(5):495-499.

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

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

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

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

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

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien

The prevalence of obesity and obesity-related conditions in the United States is increasing. Many weight-loss prod­ucts and dietary supplements are used in an attempt to combat this epidemic, but little evi­dence exists of their efficacy and safety.

We present a case report of a middle-age woman who developed severe psychotic symptoms while taking phentermine hydro­chloride (HCl), a psychostimulant similar to amphetamine that is used as a weight-loss agent and for recreational purposes. Phentermine has been associated with mood and psychotic symptoms and has a tendency to cause psychological dependence and tolerance.

To investigate the risks and potential effects of using this drug, we searched OVID and PubMed databases using the search string “phentermine + psychosis.” We conclude that there is a need for awareness about early detection and treatment of reversible psy­chotic and mood symptoms caused by what might appear to be harmless weight-loss and energy pills.

Obesity epidemic, wide-ranging weight-loss effortsThere has been a dramatic increase in obesity in the United States in the past 20 years: More than one-third of adults and approximately 17% of children and adolescents are obese. Obesity-related conditions, such as heart dis­ease, stroke, and type 2 diabetes mellitus, are leading causes of preventable death.¹ Weight monitoring, a healthy lifestyle, surgical inter­vention, traditional herbs, and diet-pill sup­plements are some of the modalities used to address this epidemic.

Most so-called supplements for weight loss are exempt from FDA regulation. They do not undergo rigorous testing for safety. Furthermore, many contain controlled sub­stances; some supplements are anti-seizure medications or other prescription drugs; and some are drugs not approved in the United States.² Since the 1930s, such drugs as dini­trophenol, ephedrine, amphetamine, fenflu­ramine, and phentermine have flooded the market with the promise of quick weight loss.^3,4

Phentermine, a contraction of “phenyltertiary-butylamine,” and its various types (Table) is a psychostimu­lant of the phenethylamine class, with a pharmacologic profile similar to that of amphetamine. It is known to yield false-positive immunoassay screening results for amphetamines.
 

Speech is pressured, fast, and difficult to comprehend at times; affect is labile and irri­table. Ms. B denies suicidal ideation and is oriented to time, place, and person.

A urine drug screen is positive for amphetamine.

Pre-admission medications include alpra­zolam, 1 mg as needed, and zolpidem, 10 mg at bedtime, prescribed by Ms. B’s primary care physician for anxiety and insomnia. She discontinued these medications 3 weeks ago because of increased drowsiness at work. She denies other substance use and is unable to account for the positive urine drug screen.

Her medical history, physical examination, and a CT scan of the head are unremarkable. The components of a comprehensive meta­bolic panel and complete blood count are within normal limits.

After admission, in-depth assessment reveals that Ms. B has been taking phen­termine, 37.5 mg (under the brand name Adipex-P), once daily since age 16 for weight loss. She recently discontinued the drug, abruptly, for 1 month, then resumed taking it at an unspecified higher dosage 1 week before she came to the emergency room, for what she said was recreational use and to meet the demands of her job, which required shift work and long hours.

Over the next few days in the hospital, Ms. B’s symptoms resolve as the drug is eliminated from her body. Speech becomes comprehensible and sleep improves. Affective distress diminishes considerably after admission; slight mood lability per­sists. She no longer reports perceptual dis­turbances or distress secondary to intrusive thoughts.

Ms. B is discharged 1 week after admis­sion, with instructions to follow up at a dual-diagnosis outpatient program.
Pharmacologic profilePhentermine acts through sympathomi­metic pathways by increasing brain nor­adrenaline and dopamine. The drug has no effect on serotonin.^4,5 Phentermine can lead to elevated blood pressure and heart rate, palpitations, restlessness, and insomnia, and can suppress appetite. Increased sympatho­mimetic activity has been implicated in the ability of phentermine to induce psychotic symptoms.

The literature. Our PubMed search of “phentermine + psychosis” produced 13 results, including 6 case reports of phen­termine use. Five citations were more than 4 decades old^5-12; only 1 could be considered recent (2011).¹³

Patients in these reports developed psy­chotic or manic features after chronic or acute phentermine use, mainly for weight reduction. The most recent article¹³ men­tioned 4 patients who were abusing diet pills recreationally (including “for lethargy”). As with Ms. B, in all 4 of those patients, phen­termine precipitated the primary pathol­ogy (mania in bipolar disorder; depression in postpartum depression and substance abuse) or revealed underlying illness.
Changing landscape of use and abuseThere has been a trend observed in the pattern of diet pill use: Initially marketed as an appetite suppressant, these pills are now being abused across ethnic, racial, and socioeconomic groups, by males and females.¹⁴ There is also a scarcity of useful guidance for clinicians.

Not only are diet pills used by people with an eating disorder; their recreational use is an emerging problem. If reports^12,13 continue to reveal that phentermine is a substance of abuse and has catastrophic effects on the user’s psyche, the need for stronger warnings and guidelines might be warranted to allow consumers to make an informed choice about using the drug.
Call for awarenessThe case we presented here exemplifies the importance of tighter regulation of both over-the-counter and prescription stimu­lant analogs. There is a need for awareness among practitioners about early detection and treatment of reversible psychotic and mood symptoms secondary to what might be promoted as, or appear to be, “harmless” weight loss and energy pills.
 

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

This unfunded study was presented as a case report poster at the Annual Meeting of the Academy of Psychosomatic Medicine, November 2013, Tucson, Arizona, and at the Colloquium of Scholars of the Philadelphia Psychiatric Society, March 2014, Philadelphia, Pennsylvania.
 

Drug Brand Names
Alprazolam • Xanax
Fenfluramine • Pondimin
Phentermine HCl • Adipex-P, Fen-Phen, Qsymia, Suprenza
Topiramate • Topamax, Trokendi XR                
Zolpidem • Ambien