Current Psychiatry

Relapse is common during recovery from alcohol or substance abuse. It’s estimated that >90% of patients will experience a relapse with 1 year of initiating abstinence.¹ How clinicians approach relapse may make the difference between a prolonged relapse or a brief one, and whether the patient has multiple occurrences or infrequent “slips.” We use the mnemonic RELAPSE to teach our medical students and residents the key components involved in addressing and preventing relapse in our patients.

Reconnection. After a relapse, patients often feel shame and guilt. They may be hesitant to talk about it and may skip appointments. It is critical to reconnect with patients through a clinical posture that is welcoming, accepting, and nonjudgmental.

Education. When a patient relapses, you have the opportunity to educate the patient, family, and significant others about substance use disorders and how they effect the “3 B’s” (brain, body, and behavior), and also the availability of treatment options.

Linkage. One possible reason behind a relapse is the lack or loss of ties to a support group, recovery program, faith community, or family. After an assessment, help your patient establish links to specific support systems needed to foster recovery.

Anticipation. It is important to assess with the patient precipitating events that led to the relapse and anticipate warning signs. Anticipating future triggers (eg, stress, loss, relationship difficulties, etc.) will allow patients to be proactive in maintaining recovery.

Psychiatric. The presence of co-occurring psychiatric disorders is the expectation rather than the exception. After a patient has relapsed, we strongly emphasize reevaluating whether unaddressed mood, anxiety, or psychotic symptoms have contributed to the relapse.

Social. Relapse does not occur within a vacuum. Social issues clearly impact one’s ability to abstain from substances. A clinician who assesses a patient’s social milieu (eg, finances, friends, and employment) and social skills (eg, ability to communicate, ask for help, and assertively say no) likely will be able to identify key factors that led to relapse.

Empowerment. Resuming recovery is based on hope, cultivation of a healthy self-esteem, and sense of control over one’s life. After a relapse, strive to use a person-centered, strength-based approach that supports the patient’s commitment to change and self-determination.

Relapse is common during recovery from alcohol or substance abuse. It’s estimated that >90% of patients will experience a relapse with 1 year of initiating abstinence.¹ How clinicians approach relapse may make the difference between a prolonged relapse or a brief one, and whether the patient has multiple occurrences or infrequent “slips.” We use the mnemonic RELAPSE to teach our medical students and residents the key components involved in addressing and preventing relapse in our patients.

Reconnection. After a relapse, patients often feel shame and guilt. They may be hesitant to talk about it and may skip appointments. It is critical to reconnect with patients through a clinical posture that is welcoming, accepting, and nonjudgmental.

Education. When a patient relapses, you have the opportunity to educate the patient, family, and significant others about substance use disorders and how they effect the “3 B’s” (brain, body, and behavior), and also the availability of treatment options.

Linkage. One possible reason behind a relapse is the lack or loss of ties to a support group, recovery program, faith community, or family. After an assessment, help your patient establish links to specific support systems needed to foster recovery.

Anticipation. It is important to assess with the patient precipitating events that led to the relapse and anticipate warning signs. Anticipating future triggers (eg, stress, loss, relationship difficulties, etc.) will allow patients to be proactive in maintaining recovery.

Psychiatric. The presence of co-occurring psychiatric disorders is the expectation rather than the exception. After a patient has relapsed, we strongly emphasize reevaluating whether unaddressed mood, anxiety, or psychotic symptoms have contributed to the relapse.

Social. Relapse does not occur within a vacuum. Social issues clearly impact one’s ability to abstain from substances. A clinician who assesses a patient’s social milieu (eg, finances, friends, and employment) and social skills (eg, ability to communicate, ask for help, and assertively say no) likely will be able to identify key factors that led to relapse.

Empowerment. Resuming recovery is based on hope, cultivation of a healthy self-esteem, and sense of control over one’s life. After a relapse, strive to use a person-centered, strength-based approach that supports the patient’s commitment to change and self-determination.

Relapse is common during recovery from alcohol or substance abuse. It’s estimated that >90% of patients will experience a relapse with 1 year of initiating abstinence.¹ How clinicians approach relapse may make the difference between a prolonged relapse or a brief one, and whether the patient has multiple occurrences or infrequent “slips.” We use the mnemonic RELAPSE to teach our medical students and residents the key components involved in addressing and preventing relapse in our patients.

Reconnection. After a relapse, patients often feel shame and guilt. They may be hesitant to talk about it and may skip appointments. It is critical to reconnect with patients through a clinical posture that is welcoming, accepting, and nonjudgmental.

Education. When a patient relapses, you have the opportunity to educate the patient, family, and significant others about substance use disorders and how they effect the “3 B’s” (brain, body, and behavior), and also the availability of treatment options.

Linkage. One possible reason behind a relapse is the lack or loss of ties to a support group, recovery program, faith community, or family. After an assessment, help your patient establish links to specific support systems needed to foster recovery.

Anticipation. It is important to assess with the patient precipitating events that led to the relapse and anticipate warning signs. Anticipating future triggers (eg, stress, loss, relationship difficulties, etc.) will allow patients to be proactive in maintaining recovery.

Psychiatric. The presence of co-occurring psychiatric disorders is the expectation rather than the exception. After a patient has relapsed, we strongly emphasize reevaluating whether unaddressed mood, anxiety, or psychotic symptoms have contributed to the relapse.

Social. Relapse does not occur within a vacuum. Social issues clearly impact one’s ability to abstain from substances. A clinician who assesses a patient’s social milieu (eg, finances, friends, and employment) and social skills (eg, ability to communicate, ask for help, and assertively say no) likely will be able to identify key factors that led to relapse.

Empowerment. Resuming recovery is based on hope, cultivation of a healthy self-esteem, and sense of control over one’s life. After a relapse, strive to use a person-centered, strength-based approach that supports the patient’s commitment to change and self-determination.

Myths describe a legendary story and explain a model of behavior or natural event. For example, the story of Persephone’s abduction by Hades and subsequent return from the Underworld has described the changing of seasons and the cycle of growth and rebirth.

A clinical psychopharmacology practice that may—or may not—be evidence-based also can be considered a myth. We offer principles to help “bust” or prove this type of myth.

Factors to consider

When initially evaluating a specific pharmacologic practice, ask yourself:

• Is this an FDA-approved indication?
• Is this an evidence-based practice?
• Does the medication have a plausible pharmacologic mechanism in the context of its use?
• What is the source of the information that led to this prescribing practice?
• How many different treatments have you tried?
• What is the clinician’s and/or patient’s experience?

Ideally, prescribing practices are steeped in solid evidence. For myriad reasons, data regarding medication use in some psychiatric disorders are sparse. In these cases— or when evidence-based approaches to patient care are inadequate—prescribers can rely on only theoretical postulates and clinical experience.

Clinical experience differs among providers and within a practice, which renders it difficult to operationalize. A knowledge base derives from the accumulated day-to-day work with real world patients and should not be undermined. However, examining the extent to which your practice is related to experience and/or evidence-based information may help to avoid errors in medical decision-making,¹ including:

• availability bias: judging events by the ease to which examples come to mind
• confirmation bias: confirming what you expect to find
• anchoring: not thinking through multiple possibilities
• commission bias: tendency toward action vs inaction.

Re-examining a prescribing practice is not time-consuming. Techniques include:

1. Using a database such as Dynamed (www.ebscohost.com/dynamed) or UpToDate (www.uptodate.com) to obtain summarized information regarding levels of evidence. This can be done easily with the patient in the room.
2. Performing a quick PubMed or MED-LINE search and reviewing the list of journal articles, assessing quantity of information and quality of studies (ie, looking for reputable journals and studies with good research methodology, a large number of subjects, and independent funding).
3. Reviewing abstracts with relevant information, and reading full articles if compelling.
4. Searching specifically for pertinent reviews or meta-analyses. Many databases allow you to filter articles by type. After reading a review, examine the references, and pull articles for further reading if relevant.

‘Busting’ a psychopharmacology myth doesn’t preclude its use. However, in an era when evidence-based medicine is highlighted and treatments are developed on a regular basis, it pays to think twice when prescribing, and to review the literature routinely. When engaging in shared decision making with patients, it is valuable to summarize what exists—or doesn’t—as evidence in literature and differentiate it from clinical experience.

The myth of Persephone describes the cyclical nature of the harvest; crops grow from seeds, mature in sunlight, and are harvested, then recycled during winter to grow again. Similarly, a prescribing practice should be seeded in evidence, cultivated with clinical experience, and habitually re-examined.

Myths describe a legendary story and explain a model of behavior or natural event. For example, the story of Persephone’s abduction by Hades and subsequent return from the Underworld has described the changing of seasons and the cycle of growth and rebirth.

A clinical psychopharmacology practice that may—or may not—be evidence-based also can be considered a myth. We offer principles to help “bust” or prove this type of myth.

Factors to consider

When initially evaluating a specific pharmacologic practice, ask yourself:

• Is this an FDA-approved indication?
• Is this an evidence-based practice?
• Does the medication have a plausible pharmacologic mechanism in the context of its use?
• What is the source of the information that led to this prescribing practice?
• How many different treatments have you tried?
• What is the clinician’s and/or patient’s experience?

Ideally, prescribing practices are steeped in solid evidence. For myriad reasons, data regarding medication use in some psychiatric disorders are sparse. In these cases— or when evidence-based approaches to patient care are inadequate—prescribers can rely on only theoretical postulates and clinical experience.

Clinical experience differs among providers and within a practice, which renders it difficult to operationalize. A knowledge base derives from the accumulated day-to-day work with real world patients and should not be undermined. However, examining the extent to which your practice is related to experience and/or evidence-based information may help to avoid errors in medical decision-making,¹ including:

• availability bias: judging events by the ease to which examples come to mind
• confirmation bias: confirming what you expect to find
• anchoring: not thinking through multiple possibilities
• commission bias: tendency toward action vs inaction.

Re-examining a prescribing practice is not time-consuming. Techniques include:

1. Using a database such as Dynamed (www.ebscohost.com/dynamed) or UpToDate (www.uptodate.com) to obtain summarized information regarding levels of evidence. This can be done easily with the patient in the room.
2. Performing a quick PubMed or MED-LINE search and reviewing the list of journal articles, assessing quantity of information and quality of studies (ie, looking for reputable journals and studies with good research methodology, a large number of subjects, and independent funding).
3. Reviewing abstracts with relevant information, and reading full articles if compelling.
4. Searching specifically for pertinent reviews or meta-analyses. Many databases allow you to filter articles by type. After reading a review, examine the references, and pull articles for further reading if relevant.

‘Busting’ a psychopharmacology myth doesn’t preclude its use. However, in an era when evidence-based medicine is highlighted and treatments are developed on a regular basis, it pays to think twice when prescribing, and to review the literature routinely. When engaging in shared decision making with patients, it is valuable to summarize what exists—or doesn’t—as evidence in literature and differentiate it from clinical experience.

The myth of Persephone describes the cyclical nature of the harvest; crops grow from seeds, mature in sunlight, and are harvested, then recycled during winter to grow again. Similarly, a prescribing practice should be seeded in evidence, cultivated with clinical experience, and habitually re-examined.

Myths describe a legendary story and explain a model of behavior or natural event. For example, the story of Persephone’s abduction by Hades and subsequent return from the Underworld has described the changing of seasons and the cycle of growth and rebirth.

A clinical psychopharmacology practice that may—or may not—be evidence-based also can be considered a myth. We offer principles to help “bust” or prove this type of myth.

Factors to consider

When initially evaluating a specific pharmacologic practice, ask yourself:

• Is this an FDA-approved indication?
• Is this an evidence-based practice?
• Does the medication have a plausible pharmacologic mechanism in the context of its use?
• What is the source of the information that led to this prescribing practice?
• How many different treatments have you tried?
• What is the clinician’s and/or patient’s experience?

Ideally, prescribing practices are steeped in solid evidence. For myriad reasons, data regarding medication use in some psychiatric disorders are sparse. In these cases— or when evidence-based approaches to patient care are inadequate—prescribers can rely on only theoretical postulates and clinical experience.

Clinical experience differs among providers and within a practice, which renders it difficult to operationalize. A knowledge base derives from the accumulated day-to-day work with real world patients and should not be undermined. However, examining the extent to which your practice is related to experience and/or evidence-based information may help to avoid errors in medical decision-making,¹ including:

• availability bias: judging events by the ease to which examples come to mind
• confirmation bias: confirming what you expect to find
• anchoring: not thinking through multiple possibilities
• commission bias: tendency toward action vs inaction.

Re-examining a prescribing practice is not time-consuming. Techniques include:

1. Using a database such as Dynamed (www.ebscohost.com/dynamed) or UpToDate (www.uptodate.com) to obtain summarized information regarding levels of evidence. This can be done easily with the patient in the room.
2. Performing a quick PubMed or MED-LINE search and reviewing the list of journal articles, assessing quantity of information and quality of studies (ie, looking for reputable journals and studies with good research methodology, a large number of subjects, and independent funding).
3. Reviewing abstracts with relevant information, and reading full articles if compelling.
4. Searching specifically for pertinent reviews or meta-analyses. Many databases allow you to filter articles by type. After reading a review, examine the references, and pull articles for further reading if relevant.

‘Busting’ a psychopharmacology myth doesn’t preclude its use. However, in an era when evidence-based medicine is highlighted and treatments are developed on a regular basis, it pays to think twice when prescribing, and to review the literature routinely. When engaging in shared decision making with patients, it is valuable to summarize what exists—or doesn’t—as evidence in literature and differentiate it from clinical experience.

The myth of Persephone describes the cyclical nature of the harvest; crops grow from seeds, mature in sunlight, and are harvested, then recycled during winter to grow again. Similarly, a prescribing practice should be seeded in evidence, cultivated with clinical experience, and habitually re-examined.

As a specialty that deals with brain disorders, psychiatry is now much more integrated with other medical and surgical specialties than in the past. Psychiatry is no longer perceived as a ‘different’ discipline and has successfully embraced the medical model without abandoning its biopsychosocial principles.

But some chasms remain and several separations persist, impacting not only the image of the specialty but also psychiatrists and their mentally ill patients. Some issues need to be addressed before full integration can occur:

Geographic separation. Freestanding psychiatric hospitals completely detached from medical/surgical services perpetuate the old misconception that psychiatric disorders are different despite overwhelming scientific evidence that all mental disorders are medical brain disorders.

The same holds for outpatient care. Established about 50 years ago, community mental health centers (CMHCs) around the country operate separately from primary care clinics despite the high prevalence of general medical disorders among psychiatric patients, and the equally high prevalence of psychiatric disorders among primary care patients.

CMHCs perpetuate an old psychosocial model dominated by non-medical mental health professionals, although patients in those settings have severe brain disorders and need a comprehensive medical approach. Because function follows structure, this geographic separation inevitably contributes to the perception that psychiatric disorders are not really medical disorders but some kind of psychosocial maladaptiveness.

Financial separation. Psychiatric care has never been reimbursed on par with medical/surgical care, although all specialties, including psychiatry, diagnose and treat diseases of various body organs. The egregious injustice of this disparity (go ahead, call it discrimination) is truly shocking for the damage it has inflicted on tens of millions of psychiatric patients, their families, and their psychiatrists. Recently, parity has been pledged in federal laws, but remains a pipe dream for many, as insurance companies and businesses resist its implementation.

Organizational separation. The psychiatric/medical records of millions of patients with serious mental brain disorders are kept separate from their general medical records. This is universally true in CMHCs, which keep their own records, thus preventing collaborative care with primary care providers. This could lead to misdiagnosis, medical errors, duplicate lab tests, adverse drug-drug interactions, and lack of appropriate and timely primary care interventions. Some HMOs—where integrated care is a primary goal—still keep psychiatric records separately. The VA does a good job with unified records but access to psychiatric data is restricted. The intense confidentiality of psychiatric information compared with general medical information evokes a perception that psychiatric history and symptoms should not be accessed as is diabetes, hypertension, or cancer history. Could transparency be an antidote to the stigma of mental illness?

Cultural separation. Most people with serious psychiatric brain disorders receive care at CMHCs, where they are referred to as “clients” instead of “patients,” as though treating mental illness is a business transaction! No other medical specialty has abandoned the term “patient,” which immediately implies having a medical ailment that requires medical attention. Non-medical language contributes to an unnecessary separation from the rest of medicine.

Forensic separation. No other medical specialty has half of its patients in jails and prisons! Imagine if medical symptoms like coughing, wheezing, or vomiting lead to incarceration, as agitation or bizarre psychotic behavior frequently do. The criminalization of psychiatric disorders is an unconscionable travesty and a mark of shame on our country, which housed mentally ill individuals in state hospitals before the destructive tsunami of deinstitutionalization dismantled these facilities under the mantra of “least restrictive environment” and ironically replaced them with correctional facilities. The preponderance of legalistic intrusions into psychiatry inevitably spawned the booming subspecialty of forensic psychiatry. I don’t think there will ever be a forensic gastroenterologist or a forensic hematologist or a forensic oncologist.

So how do we eliminate those chasms and complete the full integration of psychiatry into the rest of medicine? It is not easy and it will take time, but a good start is to co-locate psychiatric care with primary care, unify medical records, achieve full insurance parity, and uphold the medical model with adjunctive psychosocial supports. A possible catalyst for this transformation would be for psychiatrists to regain their leadership roles in psychiatric health care and work under the rubric of psychiatry as a medical specialty.

As a specialty that deals with brain disorders, psychiatry is now much more integrated with other medical and surgical specialties than in the past. Psychiatry is no longer perceived as a ‘different’ discipline and has successfully embraced the medical model without abandoning its biopsychosocial principles.

But some chasms remain and several separations persist, impacting not only the image of the specialty but also psychiatrists and their mentally ill patients. Some issues need to be addressed before full integration can occur:

Geographic separation. Freestanding psychiatric hospitals completely detached from medical/surgical services perpetuate the old misconception that psychiatric disorders are different despite overwhelming scientific evidence that all mental disorders are medical brain disorders.

The same holds for outpatient care. Established about 50 years ago, community mental health centers (CMHCs) around the country operate separately from primary care clinics despite the high prevalence of general medical disorders among psychiatric patients, and the equally high prevalence of psychiatric disorders among primary care patients.

CMHCs perpetuate an old psychosocial model dominated by non-medical mental health professionals, although patients in those settings have severe brain disorders and need a comprehensive medical approach. Because function follows structure, this geographic separation inevitably contributes to the perception that psychiatric disorders are not really medical disorders but some kind of psychosocial maladaptiveness.

Financial separation. Psychiatric care has never been reimbursed on par with medical/surgical care, although all specialties, including psychiatry, diagnose and treat diseases of various body organs. The egregious injustice of this disparity (go ahead, call it discrimination) is truly shocking for the damage it has inflicted on tens of millions of psychiatric patients, their families, and their psychiatrists. Recently, parity has been pledged in federal laws, but remains a pipe dream for many, as insurance companies and businesses resist its implementation.

Organizational separation. The psychiatric/medical records of millions of patients with serious mental brain disorders are kept separate from their general medical records. This is universally true in CMHCs, which keep their own records, thus preventing collaborative care with primary care providers. This could lead to misdiagnosis, medical errors, duplicate lab tests, adverse drug-drug interactions, and lack of appropriate and timely primary care interventions. Some HMOs—where integrated care is a primary goal—still keep psychiatric records separately. The VA does a good job with unified records but access to psychiatric data is restricted. The intense confidentiality of psychiatric information compared with general medical information evokes a perception that psychiatric history and symptoms should not be accessed as is diabetes, hypertension, or cancer history. Could transparency be an antidote to the stigma of mental illness?

Cultural separation. Most people with serious psychiatric brain disorders receive care at CMHCs, where they are referred to as “clients” instead of “patients,” as though treating mental illness is a business transaction! No other medical specialty has abandoned the term “patient,” which immediately implies having a medical ailment that requires medical attention. Non-medical language contributes to an unnecessary separation from the rest of medicine.

Forensic separation. No other medical specialty has half of its patients in jails and prisons! Imagine if medical symptoms like coughing, wheezing, or vomiting lead to incarceration, as agitation or bizarre psychotic behavior frequently do. The criminalization of psychiatric disorders is an unconscionable travesty and a mark of shame on our country, which housed mentally ill individuals in state hospitals before the destructive tsunami of deinstitutionalization dismantled these facilities under the mantra of “least restrictive environment” and ironically replaced them with correctional facilities. The preponderance of legalistic intrusions into psychiatry inevitably spawned the booming subspecialty of forensic psychiatry. I don’t think there will ever be a forensic gastroenterologist or a forensic hematologist or a forensic oncologist.

So how do we eliminate those chasms and complete the full integration of psychiatry into the rest of medicine? It is not easy and it will take time, but a good start is to co-locate psychiatric care with primary care, unify medical records, achieve full insurance parity, and uphold the medical model with adjunctive psychosocial supports. A possible catalyst for this transformation would be for psychiatrists to regain their leadership roles in psychiatric health care and work under the rubric of psychiatry as a medical specialty.

As a specialty that deals with brain disorders, psychiatry is now much more integrated with other medical and surgical specialties than in the past. Psychiatry is no longer perceived as a ‘different’ discipline and has successfully embraced the medical model without abandoning its biopsychosocial principles.

But some chasms remain and several separations persist, impacting not only the image of the specialty but also psychiatrists and their mentally ill patients. Some issues need to be addressed before full integration can occur:

Geographic separation. Freestanding psychiatric hospitals completely detached from medical/surgical services perpetuate the old misconception that psychiatric disorders are different despite overwhelming scientific evidence that all mental disorders are medical brain disorders.

The same holds for outpatient care. Established about 50 years ago, community mental health centers (CMHCs) around the country operate separately from primary care clinics despite the high prevalence of general medical disorders among psychiatric patients, and the equally high prevalence of psychiatric disorders among primary care patients.

CMHCs perpetuate an old psychosocial model dominated by non-medical mental health professionals, although patients in those settings have severe brain disorders and need a comprehensive medical approach. Because function follows structure, this geographic separation inevitably contributes to the perception that psychiatric disorders are not really medical disorders but some kind of psychosocial maladaptiveness.

Financial separation. Psychiatric care has never been reimbursed on par with medical/surgical care, although all specialties, including psychiatry, diagnose and treat diseases of various body organs. The egregious injustice of this disparity (go ahead, call it discrimination) is truly shocking for the damage it has inflicted on tens of millions of psychiatric patients, their families, and their psychiatrists. Recently, parity has been pledged in federal laws, but remains a pipe dream for many, as insurance companies and businesses resist its implementation.

Organizational separation. The psychiatric/medical records of millions of patients with serious mental brain disorders are kept separate from their general medical records. This is universally true in CMHCs, which keep their own records, thus preventing collaborative care with primary care providers. This could lead to misdiagnosis, medical errors, duplicate lab tests, adverse drug-drug interactions, and lack of appropriate and timely primary care interventions. Some HMOs—where integrated care is a primary goal—still keep psychiatric records separately. The VA does a good job with unified records but access to psychiatric data is restricted. The intense confidentiality of psychiatric information compared with general medical information evokes a perception that psychiatric history and symptoms should not be accessed as is diabetes, hypertension, or cancer history. Could transparency be an antidote to the stigma of mental illness?

Cultural separation. Most people with serious psychiatric brain disorders receive care at CMHCs, where they are referred to as “clients” instead of “patients,” as though treating mental illness is a business transaction! No other medical specialty has abandoned the term “patient,” which immediately implies having a medical ailment that requires medical attention. Non-medical language contributes to an unnecessary separation from the rest of medicine.

Forensic separation. No other medical specialty has half of its patients in jails and prisons! Imagine if medical symptoms like coughing, wheezing, or vomiting lead to incarceration, as agitation or bizarre psychotic behavior frequently do. The criminalization of psychiatric disorders is an unconscionable travesty and a mark of shame on our country, which housed mentally ill individuals in state hospitals before the destructive tsunami of deinstitutionalization dismantled these facilities under the mantra of “least restrictive environment” and ironically replaced them with correctional facilities. The preponderance of legalistic intrusions into psychiatry inevitably spawned the booming subspecialty of forensic psychiatry. I don’t think there will ever be a forensic gastroenterologist or a forensic hematologist or a forensic oncologist.

So how do we eliminate those chasms and complete the full integration of psychiatry into the rest of medicine? It is not easy and it will take time, but a good start is to co-locate psychiatric care with primary care, unify medical records, achieve full insurance parity, and uphold the medical model with adjunctive psychosocial supports. A possible catalyst for this transformation would be for psychiatrists to regain their leadership roles in psychiatric health care and work under the rubric of psychiatry as a medical specialty.

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/schizophrenia-in-older-adults.html#comments

Ms. M, age 68, seeks treatment for stress and anxiety after her sister has a stroke. Ms. M has chronic paranoid schizophrenia, and her sister has been Ms. M’s primary support since the onset of illness in her late 20s. Ms. M lives in a supported housing community. Her last psychiatric hospitalization was 16 years ago; for the past 15 years she has been stable on haloperidol, 20 mg/d. Ms. M also takes diphenhydramine, 50 mg at bedtime, to help her sleep.

Ms. M is hypertensive but does not have diabetes, obesity, or metabolic syndrome. She has mild executive dysfunction and mild extrapyramidal symptoms (EPS) but no tardive dyskinesia (TD). There is no evidence of delusions or hallucinations, although Ms. M is mildly paranoid about her neighbors. In the last year, she has been experiencing tremors and has fallen twice.

The number of older adults (age ≥65) who developed schizophrenia before age 45 is expected to double in the next 2 decades; the 1-year prevalence of schizophrenia among older adults is approximately 0.6%.^1,2 This article reviews how positive, negative, and cognitive symptoms and social functioning change over decades and discusses strategies for reducing the impact of long-term antipsychotic use on neurologic and physical health. Although some patients experience schizophrenia onset later in life, in this article we focus on older adults who developed the illness before age 45.

Symptoms change with age

Positive symptoms of schizophrenia—hallucinations, delusions, and disorganized or catatonic behavior—do not “burn out” in most older adults.³ The severity of “day-to-day” psychotic symptoms appears reduced in patients with schizophrenia who have not had recent severe psychotic episodes. Aging-associated decrease in dopaminergic and other monoaminergic activities may explain this.

Some older adults experience sustained remission of positive symptoms and may no longer need antipsychotics.⁴ Factors that contribute to a better prognosis include:

• female sex
• developing the illness later in life (eg, fourth decade instead of second or third decade)
• being married
• obtaining appropriate treatment early in the illness.²

With treatment, positive symptoms can remit in 40% to 50% of older adults, especially those who have greater social support and fewer lifetime traumatic events.^3,5

Negative symptoms—flat affect, social withdrawal, and decreased motivation—may become worse in older adults with a history of poor functioning (especially institutionalized patients) as they age.^2,6 Changes in negative symptoms are more closely correlated with symptom chronicity, functional and cognitive impairment, soft neurologic signs such as impaired fine motor coordination, and institutionalization than with the patient’s age.⁷

Generalized cognitive deficits are ubiquitous in patients with schizophrenia and substantially impact community functioning.^1,8 Cognitive function may worsen in older schizophrenia patients with a history of poor functioning—especially institutionalized patients—as they age.⁹ Most older adults with schizophrenia who reside in the community have persistent, but generally not progressive, cognitive deficits. Low education levels, poor premorbid function, and more severe positive symptoms at baseline are associated with worse cognitive functioning at all ages.² Older adults with schizophrenia and TD have greater global cognitive deficits and greater deficits in learning than age-, education-, and subtype-matched schizophrenia patients without TD.¹

Differences and similarities in cognitive impairment in older adults with schizophrenia compared with those who have Alzheimer’s disease (AD) are listed in Table 1. The course of cognitive deficits appears to be the most sensitive measure for determining whether a patient with long-standing schizophrenia has developed concomitant AD. Individuals with AD experience a more precipitous and progressive decline in cognitive function compared with patients with schizophrenia. Neuropsychological testing is recommended to accurately diagnose AD in older schizophrenia patients as early as possible.

Table 1

Cognitive impairment: Schizophrenia vs Alzheimer’s disease

Depressive symptoms

More than two-fifths of older adults with schizophrenia show signs of clinical depression.¹⁰ Depression in this population is linked to positive symptoms, poor physical health, low income, and diminished network support. Routinely screen for depressive symptoms in older schizophrenia patients and institute prompt treatment as required. Assess these patients for suicide. Although suicide rates in schizophrenia patients decrease with age, they remain considerably higher than those of age-matched persons without schizophrenia.¹¹

Social functioning

Improvement or deterioration in social functioning is possible as patients with schizophrenia age.¹¹ Compared with age-matched patients in the general population and those with bipolar disorder, older adults with schizophrenia need more help with activities of daily living (eg, looking after the home, using public transportation).¹¹

Cognitive impairment seems to be the most important predictor of social functioning in patients with schizophrenia at any age. Impaired social functioning also is associated with negative symptoms and movement disorders. On community integration measures (how well the person lives, participates, and socializes in his or her community), older adults with schizophrenia do roughly half as well as their age-matched peers in the general community.³ Older schizophrenia patients’ social networks seem to be smaller than those of their age-matched peers,¹ but they may experience fewer discordant interactions, such as situations with high expressed emotions. Increased psychological resilience may help older adults better adapt to changes as they age (Box).^1,12

Box

A complex assessment

Older adults with schizophrenia have an increased prevalence of:

• obesity
• diabetes
• hyperlipidemia
• coronary artery disease
• myocardial infarction
• limited mobility
• illnesses related to smoking or substance abuse.^13,14

The severity of these conditions often is greater in older adults with schizophrenia compared with age-matched controls. Older adults with schizophrenia also have poorer access to and use of health care services and compliance with treatment regimens, and receive a lower quality of care. The incidence of physical health and neuropsychiatric problems increases with age and older adults with schizophrenia with poor functioning may be less able to recognize and report symptoms to health care providers.

Because these patients have complex health care concerns, we recommend using a checklist to help make routine visits thorough and identify and treat problems. Click here for a downloadable assessment checklist. Ideally, the initial assessment should use an interdisciplinary approach that includes the patient, family/knowledgeable informants, psychiatrist, psychiatric nurse practitioner/physician assistant, social worker, caseworker, chaplain (if appropriate), and a nurse. The initial assessment may take 2 to 3 visits to complete.

Adapting treatment

Older adults with schizophrenia can benefit from the psychopharmacologic and psychosocial interventions used for younger patients (Table 2).^15,16 However, you may need to adapt these treatments to accommodate cognitive impairment, medical comorbidities, or hearing and vision deficits. The most appropriate goal may not be recovery or rehabilitation, but making life more meaningful and satisfying for the patient and his or her family.

Pharmacotherapy. The 2009 schizophrenia Patient Outcomes Research Team (PORT) psychopharmacology treatment recommendations may be used for older adults.¹⁵ Most adverse effects of antipsychotics (except for dystonia) are more prevalent in older adults than in their younger counterparts. In general, second-generation antipsychotics (SGAs) are preferred over first-generation antipsychotics (FGAs) for treating positive symptoms in older patients because of SGAs’ lower risk of TD and EPS despite the increased risk of metabolic disorders.

Aripiprazole and ziprasidone are associated with significantly less risk of metabolic disorders and may be preferred in older adults who have diabetes, obesity, or hyperlipidemia. Aripiprazole has the lowest risk of QTc prolongation and may be preferred in patients who have prolonged QTc interval.¹⁵ Quetiapine and clozapine are associated with the lowest risk of EPS. Among SGAs, aripiprazole is associated with the lowest risk of prolactin elevation and sexual side effects and may be preferred in older adults who complain of sexual dysfunction or have osteoporosis.

Because rates of EPS and TDs may exceed 50% among older patients, many experts encourage clinicians to taper anti-psychotic dosages in patients with stable chronic symptoms. Tapering dosages may be critically important because EPS may affect functional performance more than positive or negative symptoms or duration of psychoses.

The severity of TD in older adults with schizophrenia may be masked because many patients receive high doses of FGAs. When a patient’s FGA dosage is reduced to manage EPS, subclinical TD may manifest for the first time, and existing TD may become noticeably worse. Consider clozapine for long-term management of older adults who have TD; however, burdens of its use—such as weekly blood draws and anticholinergic adverse effects—may limit its use in older adults.

Lowering the anticholinergic load by reducing the dosage of drugs with anti-cholinergic activity or discontinuing anti-cholinergic medications when possible is a key component of treating older adults with schizophrenia. Doing so may improve not only patients’ cognitive function but also their quality of life by reducing other anticholinergic adverse effects, such as constipation, blurred vision, and urinary retention.

Psychosocial interventions. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements may be followed for older adults. Recommended interventions include:

• assertive community treatment
• supported employment
• cognitive-behavioral therapy (CBT)
• family-based services
• token economy
• skills training.¹⁶

Social skills training with or without CBT can be successfully adapted for older adults. Such interventions can improve social functioning and everyday living skills. Environmental modifications—such as removing decorative mirrors from the home of a delusional patient who believes people are living in the walls—may alleviate distress.

In addition, social contact and structured activities such as group exercises may benefit older patients. Educate care-givers about ways they can work with older adults, such as distracting them or not directly challenging false beliefs. Comprehensive psychosocial interventions also can improve health care management skills.

Preliminary data indicate that CBT and skills training with role-plays, structured feedback, and homework assignments can improve quality of life of older adults with schizophrenia.^17,18 Functional Adaptation Skills Training focuses on medication management, social skills, communication skills, organization, planning, and financial management.¹⁹ Those who received this training showed improvement in their functional skills that persisted for at least 3 months after treatment ended.²⁰

Poor adherence to medication is common in older schizophrenia patients and has devastating consequences. Adherence problems are complex and often have multiple causes, which requires customized interventions that target specific causes. Patients who receive a combination of psychosocial treatment and antipsychotics are more likely to be compliant with their medication and less likely to relapse or be hospitalized.¹⁶

Addressing the social stigma associated with schizophrenia may help reduce the social isolation and loneliness that many older adults experience. Psychiatrists can help fight stigma by participating in community educational programs and encouraging patients’ families to become involved in support and advocacy organizations.

Table 2

Interventions for older adults with schizophrenia

CASE CONTINUED: Medication changes

Ms. M’s psychiatrist tells her that her problems with tremors and falls are most likely caused by haloperidol and recommends a slow dosage reduction and discontinuing diphenhydramine. Haloperidol is decreased to 10 mg/d for 1 month and then to 5 mg/d. Diphenhydramine is decreased to 25 mg at bedtime for 7 days and then stopped.

Ms. M declines physical therapy but agrees to participate in strength and balance training offered at the supported housing community 3 times a week for 4 weeks. Tremors resolve over the next month and Ms. M has not fallen since.

Ms. M complains of insomnia and is reluctant to further decrease haloperidol unless she is prescribed a different antipsychotic and given something to help her sleep. Ms. M is started on quetiapine, 25 mg/d at bedtime. Over 3 weeks, the dosage is increased to 100 mg/d. Ms. M tolerates quetiapine well and her sleep improves. Haloperidol is then decreased to 2.5 mg/d for 1 month and then discontinued. Ms. M also is offered supportive psychotherapy every 2 weeks to address her paranoia and stress. She continues to do well on quetiapine and supportive psychotherapy.

Related Resources

• Cohen CI, ed. Schizophrenia into later life: treatment, research, and policy. Arlington, VA: American Psychiatric Publishing, Inc; 2003.
• Mental health: a report of the Surgeon General. Chapter 5: other mental disorders in older adults; schizophrenia in late life. www.surgeongeneral.gov/library/mentalhealth/chapter5/sec5.html.

Drug Brand Names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Diphenhydramine • Sominex, Unisom, others
• Haloperidol • Haldol
• Quetiapine • Seroquel
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/schizophrenia-in-older-adults.html#comments

Ms. M, age 68, seeks treatment for stress and anxiety after her sister has a stroke. Ms. M has chronic paranoid schizophrenia, and her sister has been Ms. M’s primary support since the onset of illness in her late 20s. Ms. M lives in a supported housing community. Her last psychiatric hospitalization was 16 years ago; for the past 15 years she has been stable on haloperidol, 20 mg/d. Ms. M also takes diphenhydramine, 50 mg at bedtime, to help her sleep.

Ms. M is hypertensive but does not have diabetes, obesity, or metabolic syndrome. She has mild executive dysfunction and mild extrapyramidal symptoms (EPS) but no tardive dyskinesia (TD). There is no evidence of delusions or hallucinations, although Ms. M is mildly paranoid about her neighbors. In the last year, she has been experiencing tremors and has fallen twice.

The number of older adults (age ≥65) who developed schizophrenia before age 45 is expected to double in the next 2 decades; the 1-year prevalence of schizophrenia among older adults is approximately 0.6%.^1,2 This article reviews how positive, negative, and cognitive symptoms and social functioning change over decades and discusses strategies for reducing the impact of long-term antipsychotic use on neurologic and physical health. Although some patients experience schizophrenia onset later in life, in this article we focus on older adults who developed the illness before age 45.

Symptoms change with age

Positive symptoms of schizophrenia—hallucinations, delusions, and disorganized or catatonic behavior—do not “burn out” in most older adults.³ The severity of “day-to-day” psychotic symptoms appears reduced in patients with schizophrenia who have not had recent severe psychotic episodes. Aging-associated decrease in dopaminergic and other monoaminergic activities may explain this.

Some older adults experience sustained remission of positive symptoms and may no longer need antipsychotics.⁴ Factors that contribute to a better prognosis include:

• female sex
• developing the illness later in life (eg, fourth decade instead of second or third decade)
• being married
• obtaining appropriate treatment early in the illness.²

With treatment, positive symptoms can remit in 40% to 50% of older adults, especially those who have greater social support and fewer lifetime traumatic events.^3,5

Negative symptoms—flat affect, social withdrawal, and decreased motivation—may become worse in older adults with a history of poor functioning (especially institutionalized patients) as they age.^2,6 Changes in negative symptoms are more closely correlated with symptom chronicity, functional and cognitive impairment, soft neurologic signs such as impaired fine motor coordination, and institutionalization than with the patient’s age.⁷

Generalized cognitive deficits are ubiquitous in patients with schizophrenia and substantially impact community functioning.^1,8 Cognitive function may worsen in older schizophrenia patients with a history of poor functioning—especially institutionalized patients—as they age.⁹ Most older adults with schizophrenia who reside in the community have persistent, but generally not progressive, cognitive deficits. Low education levels, poor premorbid function, and more severe positive symptoms at baseline are associated with worse cognitive functioning at all ages.² Older adults with schizophrenia and TD have greater global cognitive deficits and greater deficits in learning than age-, education-, and subtype-matched schizophrenia patients without TD.¹

Differences and similarities in cognitive impairment in older adults with schizophrenia compared with those who have Alzheimer’s disease (AD) are listed in Table 1. The course of cognitive deficits appears to be the most sensitive measure for determining whether a patient with long-standing schizophrenia has developed concomitant AD. Individuals with AD experience a more precipitous and progressive decline in cognitive function compared with patients with schizophrenia. Neuropsychological testing is recommended to accurately diagnose AD in older schizophrenia patients as early as possible.

Table 1

Cognitive impairment: Schizophrenia vs Alzheimer’s disease

Depressive symptoms

More than two-fifths of older adults with schizophrenia show signs of clinical depression.¹⁰ Depression in this population is linked to positive symptoms, poor physical health, low income, and diminished network support. Routinely screen for depressive symptoms in older schizophrenia patients and institute prompt treatment as required. Assess these patients for suicide. Although suicide rates in schizophrenia patients decrease with age, they remain considerably higher than those of age-matched persons without schizophrenia.¹¹

Social functioning

Improvement or deterioration in social functioning is possible as patients with schizophrenia age.¹¹ Compared with age-matched patients in the general population and those with bipolar disorder, older adults with schizophrenia need more help with activities of daily living (eg, looking after the home, using public transportation).¹¹

Cognitive impairment seems to be the most important predictor of social functioning in patients with schizophrenia at any age. Impaired social functioning also is associated with negative symptoms and movement disorders. On community integration measures (how well the person lives, participates, and socializes in his or her community), older adults with schizophrenia do roughly half as well as their age-matched peers in the general community.³ Older schizophrenia patients’ social networks seem to be smaller than those of their age-matched peers,¹ but they may experience fewer discordant interactions, such as situations with high expressed emotions. Increased psychological resilience may help older adults better adapt to changes as they age (Box).^1,12

Box

A complex assessment

Older adults with schizophrenia have an increased prevalence of:

• obesity
• diabetes
• hyperlipidemia
• coronary artery disease
• myocardial infarction
• limited mobility
• illnesses related to smoking or substance abuse.^13,14

The severity of these conditions often is greater in older adults with schizophrenia compared with age-matched controls. Older adults with schizophrenia also have poorer access to and use of health care services and compliance with treatment regimens, and receive a lower quality of care. The incidence of physical health and neuropsychiatric problems increases with age and older adults with schizophrenia with poor functioning may be less able to recognize and report symptoms to health care providers.

Because these patients have complex health care concerns, we recommend using a checklist to help make routine visits thorough and identify and treat problems. Click here for a downloadable assessment checklist. Ideally, the initial assessment should use an interdisciplinary approach that includes the patient, family/knowledgeable informants, psychiatrist, psychiatric nurse practitioner/physician assistant, social worker, caseworker, chaplain (if appropriate), and a nurse. The initial assessment may take 2 to 3 visits to complete.

Adapting treatment

Older adults with schizophrenia can benefit from the psychopharmacologic and psychosocial interventions used for younger patients (Table 2).^15,16 However, you may need to adapt these treatments to accommodate cognitive impairment, medical comorbidities, or hearing and vision deficits. The most appropriate goal may not be recovery or rehabilitation, but making life more meaningful and satisfying for the patient and his or her family.

Pharmacotherapy. The 2009 schizophrenia Patient Outcomes Research Team (PORT) psychopharmacology treatment recommendations may be used for older adults.¹⁵ Most adverse effects of antipsychotics (except for dystonia) are more prevalent in older adults than in their younger counterparts. In general, second-generation antipsychotics (SGAs) are preferred over first-generation antipsychotics (FGAs) for treating positive symptoms in older patients because of SGAs’ lower risk of TD and EPS despite the increased risk of metabolic disorders.

Aripiprazole and ziprasidone are associated with significantly less risk of metabolic disorders and may be preferred in older adults who have diabetes, obesity, or hyperlipidemia. Aripiprazole has the lowest risk of QTc prolongation and may be preferred in patients who have prolonged QTc interval.¹⁵ Quetiapine and clozapine are associated with the lowest risk of EPS. Among SGAs, aripiprazole is associated with the lowest risk of prolactin elevation and sexual side effects and may be preferred in older adults who complain of sexual dysfunction or have osteoporosis.

Because rates of EPS and TDs may exceed 50% among older patients, many experts encourage clinicians to taper anti-psychotic dosages in patients with stable chronic symptoms. Tapering dosages may be critically important because EPS may affect functional performance more than positive or negative symptoms or duration of psychoses.

The severity of TD in older adults with schizophrenia may be masked because many patients receive high doses of FGAs. When a patient’s FGA dosage is reduced to manage EPS, subclinical TD may manifest for the first time, and existing TD may become noticeably worse. Consider clozapine for long-term management of older adults who have TD; however, burdens of its use—such as weekly blood draws and anticholinergic adverse effects—may limit its use in older adults.

Lowering the anticholinergic load by reducing the dosage of drugs with anti-cholinergic activity or discontinuing anti-cholinergic medications when possible is a key component of treating older adults with schizophrenia. Doing so may improve not only patients’ cognitive function but also their quality of life by reducing other anticholinergic adverse effects, such as constipation, blurred vision, and urinary retention.

Psychosocial interventions. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements may be followed for older adults. Recommended interventions include:

• assertive community treatment
• supported employment
• cognitive-behavioral therapy (CBT)
• family-based services
• token economy
• skills training.¹⁶

Social skills training with or without CBT can be successfully adapted for older adults. Such interventions can improve social functioning and everyday living skills. Environmental modifications—such as removing decorative mirrors from the home of a delusional patient who believes people are living in the walls—may alleviate distress.

In addition, social contact and structured activities such as group exercises may benefit older patients. Educate care-givers about ways they can work with older adults, such as distracting them or not directly challenging false beliefs. Comprehensive psychosocial interventions also can improve health care management skills.

Preliminary data indicate that CBT and skills training with role-plays, structured feedback, and homework assignments can improve quality of life of older adults with schizophrenia.^17,18 Functional Adaptation Skills Training focuses on medication management, social skills, communication skills, organization, planning, and financial management.¹⁹ Those who received this training showed improvement in their functional skills that persisted for at least 3 months after treatment ended.²⁰

Poor adherence to medication is common in older schizophrenia patients and has devastating consequences. Adherence problems are complex and often have multiple causes, which requires customized interventions that target specific causes. Patients who receive a combination of psychosocial treatment and antipsychotics are more likely to be compliant with their medication and less likely to relapse or be hospitalized.¹⁶

Addressing the social stigma associated with schizophrenia may help reduce the social isolation and loneliness that many older adults experience. Psychiatrists can help fight stigma by participating in community educational programs and encouraging patients’ families to become involved in support and advocacy organizations.

Table 2

Interventions for older adults with schizophrenia

CASE CONTINUED: Medication changes

Ms. M’s psychiatrist tells her that her problems with tremors and falls are most likely caused by haloperidol and recommends a slow dosage reduction and discontinuing diphenhydramine. Haloperidol is decreased to 10 mg/d for 1 month and then to 5 mg/d. Diphenhydramine is decreased to 25 mg at bedtime for 7 days and then stopped.

Ms. M declines physical therapy but agrees to participate in strength and balance training offered at the supported housing community 3 times a week for 4 weeks. Tremors resolve over the next month and Ms. M has not fallen since.

Ms. M complains of insomnia and is reluctant to further decrease haloperidol unless she is prescribed a different antipsychotic and given something to help her sleep. Ms. M is started on quetiapine, 25 mg/d at bedtime. Over 3 weeks, the dosage is increased to 100 mg/d. Ms. M tolerates quetiapine well and her sleep improves. Haloperidol is then decreased to 2.5 mg/d for 1 month and then discontinued. Ms. M also is offered supportive psychotherapy every 2 weeks to address her paranoia and stress. She continues to do well on quetiapine and supportive psychotherapy.

Related Resources

• Cohen CI, ed. Schizophrenia into later life: treatment, research, and policy. Arlington, VA: American Psychiatric Publishing, Inc; 2003.
• Mental health: a report of the Surgeon General. Chapter 5: other mental disorders in older adults; schizophrenia in late life. www.surgeongeneral.gov/library/mentalhealth/chapter5/sec5.html.

Drug Brand Names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Diphenhydramine • Sominex, Unisom, others
• Haloperidol • Haldol
• Quetiapine • Seroquel
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/schizophrenia-in-older-adults.html#comments

Ms. M, age 68, seeks treatment for stress and anxiety after her sister has a stroke. Ms. M has chronic paranoid schizophrenia, and her sister has been Ms. M’s primary support since the onset of illness in her late 20s. Ms. M lives in a supported housing community. Her last psychiatric hospitalization was 16 years ago; for the past 15 years she has been stable on haloperidol, 20 mg/d. Ms. M also takes diphenhydramine, 50 mg at bedtime, to help her sleep.

Ms. M is hypertensive but does not have diabetes, obesity, or metabolic syndrome. She has mild executive dysfunction and mild extrapyramidal symptoms (EPS) but no tardive dyskinesia (TD). There is no evidence of delusions or hallucinations, although Ms. M is mildly paranoid about her neighbors. In the last year, she has been experiencing tremors and has fallen twice.

The number of older adults (age ≥65) who developed schizophrenia before age 45 is expected to double in the next 2 decades; the 1-year prevalence of schizophrenia among older adults is approximately 0.6%.^1,2 This article reviews how positive, negative, and cognitive symptoms and social functioning change over decades and discusses strategies for reducing the impact of long-term antipsychotic use on neurologic and physical health. Although some patients experience schizophrenia onset later in life, in this article we focus on older adults who developed the illness before age 45.

Symptoms change with age

Positive symptoms of schizophrenia—hallucinations, delusions, and disorganized or catatonic behavior—do not “burn out” in most older adults.³ The severity of “day-to-day” psychotic symptoms appears reduced in patients with schizophrenia who have not had recent severe psychotic episodes. Aging-associated decrease in dopaminergic and other monoaminergic activities may explain this.

Some older adults experience sustained remission of positive symptoms and may no longer need antipsychotics.⁴ Factors that contribute to a better prognosis include:

• female sex
• developing the illness later in life (eg, fourth decade instead of second or third decade)
• being married
• obtaining appropriate treatment early in the illness.²

With treatment, positive symptoms can remit in 40% to 50% of older adults, especially those who have greater social support and fewer lifetime traumatic events.^3,5

Negative symptoms—flat affect, social withdrawal, and decreased motivation—may become worse in older adults with a history of poor functioning (especially institutionalized patients) as they age.^2,6 Changes in negative symptoms are more closely correlated with symptom chronicity, functional and cognitive impairment, soft neurologic signs such as impaired fine motor coordination, and institutionalization than with the patient’s age.⁷

Generalized cognitive deficits are ubiquitous in patients with schizophrenia and substantially impact community functioning.^1,8 Cognitive function may worsen in older schizophrenia patients with a history of poor functioning—especially institutionalized patients—as they age.⁹ Most older adults with schizophrenia who reside in the community have persistent, but generally not progressive, cognitive deficits. Low education levels, poor premorbid function, and more severe positive symptoms at baseline are associated with worse cognitive functioning at all ages.² Older adults with schizophrenia and TD have greater global cognitive deficits and greater deficits in learning than age-, education-, and subtype-matched schizophrenia patients without TD.¹

Differences and similarities in cognitive impairment in older adults with schizophrenia compared with those who have Alzheimer’s disease (AD) are listed in Table 1. The course of cognitive deficits appears to be the most sensitive measure for determining whether a patient with long-standing schizophrenia has developed concomitant AD. Individuals with AD experience a more precipitous and progressive decline in cognitive function compared with patients with schizophrenia. Neuropsychological testing is recommended to accurately diagnose AD in older schizophrenia patients as early as possible.

Table 1

Cognitive impairment: Schizophrenia vs Alzheimer’s disease

Depressive symptoms

More than two-fifths of older adults with schizophrenia show signs of clinical depression.¹⁰ Depression in this population is linked to positive symptoms, poor physical health, low income, and diminished network support. Routinely screen for depressive symptoms in older schizophrenia patients and institute prompt treatment as required. Assess these patients for suicide. Although suicide rates in schizophrenia patients decrease with age, they remain considerably higher than those of age-matched persons without schizophrenia.¹¹

Social functioning

Improvement or deterioration in social functioning is possible as patients with schizophrenia age.¹¹ Compared with age-matched patients in the general population and those with bipolar disorder, older adults with schizophrenia need more help with activities of daily living (eg, looking after the home, using public transportation).¹¹

Cognitive impairment seems to be the most important predictor of social functioning in patients with schizophrenia at any age. Impaired social functioning also is associated with negative symptoms and movement disorders. On community integration measures (how well the person lives, participates, and socializes in his or her community), older adults with schizophrenia do roughly half as well as their age-matched peers in the general community.³ Older schizophrenia patients’ social networks seem to be smaller than those of their age-matched peers,¹ but they may experience fewer discordant interactions, such as situations with high expressed emotions. Increased psychological resilience may help older adults better adapt to changes as they age (Box).^1,12

Box

A complex assessment

Older adults with schizophrenia have an increased prevalence of:

• obesity
• diabetes
• hyperlipidemia
• coronary artery disease
• myocardial infarction
• limited mobility
• illnesses related to smoking or substance abuse.^13,14

The severity of these conditions often is greater in older adults with schizophrenia compared with age-matched controls. Older adults with schizophrenia also have poorer access to and use of health care services and compliance with treatment regimens, and receive a lower quality of care. The incidence of physical health and neuropsychiatric problems increases with age and older adults with schizophrenia with poor functioning may be less able to recognize and report symptoms to health care providers.

Because these patients have complex health care concerns, we recommend using a checklist to help make routine visits thorough and identify and treat problems. Click here for a downloadable assessment checklist. Ideally, the initial assessment should use an interdisciplinary approach that includes the patient, family/knowledgeable informants, psychiatrist, psychiatric nurse practitioner/physician assistant, social worker, caseworker, chaplain (if appropriate), and a nurse. The initial assessment may take 2 to 3 visits to complete.

Adapting treatment

Older adults with schizophrenia can benefit from the psychopharmacologic and psychosocial interventions used for younger patients (Table 2).^15,16 However, you may need to adapt these treatments to accommodate cognitive impairment, medical comorbidities, or hearing and vision deficits. The most appropriate goal may not be recovery or rehabilitation, but making life more meaningful and satisfying for the patient and his or her family.

Pharmacotherapy. The 2009 schizophrenia Patient Outcomes Research Team (PORT) psychopharmacology treatment recommendations may be used for older adults.¹⁵ Most adverse effects of antipsychotics (except for dystonia) are more prevalent in older adults than in their younger counterparts. In general, second-generation antipsychotics (SGAs) are preferred over first-generation antipsychotics (FGAs) for treating positive symptoms in older patients because of SGAs’ lower risk of TD and EPS despite the increased risk of metabolic disorders.

Aripiprazole and ziprasidone are associated with significantly less risk of metabolic disorders and may be preferred in older adults who have diabetes, obesity, or hyperlipidemia. Aripiprazole has the lowest risk of QTc prolongation and may be preferred in patients who have prolonged QTc interval.¹⁵ Quetiapine and clozapine are associated with the lowest risk of EPS. Among SGAs, aripiprazole is associated with the lowest risk of prolactin elevation and sexual side effects and may be preferred in older adults who complain of sexual dysfunction or have osteoporosis.

Because rates of EPS and TDs may exceed 50% among older patients, many experts encourage clinicians to taper anti-psychotic dosages in patients with stable chronic symptoms. Tapering dosages may be critically important because EPS may affect functional performance more than positive or negative symptoms or duration of psychoses.

The severity of TD in older adults with schizophrenia may be masked because many patients receive high doses of FGAs. When a patient’s FGA dosage is reduced to manage EPS, subclinical TD may manifest for the first time, and existing TD may become noticeably worse. Consider clozapine for long-term management of older adults who have TD; however, burdens of its use—such as weekly blood draws and anticholinergic adverse effects—may limit its use in older adults.

Lowering the anticholinergic load by reducing the dosage of drugs with anti-cholinergic activity or discontinuing anti-cholinergic medications when possible is a key component of treating older adults with schizophrenia. Doing so may improve not only patients’ cognitive function but also their quality of life by reducing other anticholinergic adverse effects, such as constipation, blurred vision, and urinary retention.

Psychosocial interventions. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements may be followed for older adults. Recommended interventions include:

• assertive community treatment
• supported employment
• cognitive-behavioral therapy (CBT)
• family-based services
• token economy
• skills training.¹⁶

Social skills training with or without CBT can be successfully adapted for older adults. Such interventions can improve social functioning and everyday living skills. Environmental modifications—such as removing decorative mirrors from the home of a delusional patient who believes people are living in the walls—may alleviate distress.

In addition, social contact and structured activities such as group exercises may benefit older patients. Educate care-givers about ways they can work with older adults, such as distracting them or not directly challenging false beliefs. Comprehensive psychosocial interventions also can improve health care management skills.

Preliminary data indicate that CBT and skills training with role-plays, structured feedback, and homework assignments can improve quality of life of older adults with schizophrenia.^17,18 Functional Adaptation Skills Training focuses on medication management, social skills, communication skills, organization, planning, and financial management.¹⁹ Those who received this training showed improvement in their functional skills that persisted for at least 3 months after treatment ended.²⁰

Poor adherence to medication is common in older schizophrenia patients and has devastating consequences. Adherence problems are complex and often have multiple causes, which requires customized interventions that target specific causes. Patients who receive a combination of psychosocial treatment and antipsychotics are more likely to be compliant with their medication and less likely to relapse or be hospitalized.¹⁶

Addressing the social stigma associated with schizophrenia may help reduce the social isolation and loneliness that many older adults experience. Psychiatrists can help fight stigma by participating in community educational programs and encouraging patients’ families to become involved in support and advocacy organizations.

Table 2

Interventions for older adults with schizophrenia

CASE CONTINUED: Medication changes

Ms. M’s psychiatrist tells her that her problems with tremors and falls are most likely caused by haloperidol and recommends a slow dosage reduction and discontinuing diphenhydramine. Haloperidol is decreased to 10 mg/d for 1 month and then to 5 mg/d. Diphenhydramine is decreased to 25 mg at bedtime for 7 days and then stopped.

Ms. M declines physical therapy but agrees to participate in strength and balance training offered at the supported housing community 3 times a week for 4 weeks. Tremors resolve over the next month and Ms. M has not fallen since.

Ms. M complains of insomnia and is reluctant to further decrease haloperidol unless she is prescribed a different antipsychotic and given something to help her sleep. Ms. M is started on quetiapine, 25 mg/d at bedtime. Over 3 weeks, the dosage is increased to 100 mg/d. Ms. M tolerates quetiapine well and her sleep improves. Haloperidol is then decreased to 2.5 mg/d for 1 month and then discontinued. Ms. M also is offered supportive psychotherapy every 2 weeks to address her paranoia and stress. She continues to do well on quetiapine and supportive psychotherapy.

Related Resources

• Cohen CI, ed. Schizophrenia into later life: treatment, research, and policy. Arlington, VA: American Psychiatric Publishing, Inc; 2003.
• Mental health: a report of the Surgeon General. Chapter 5: other mental disorders in older adults; schizophrenia in late life. www.surgeongeneral.gov/library/mentalhealth/chapter5/sec5.html.

Drug Brand Names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Diphenhydramine • Sominex, Unisom, others
• Haloperidol • Haldol
• Quetiapine • Seroquel
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/vaccine-for-cocaine-addiction.html#comments

Unlike opioid or alcohol abuse, for cocaine dependence there are no FDA-approved pharmacotherapies, which leaves psychosocial treatment as the standard of care for the estimated 1.6 million individuals in the United States who abuse cocaine.¹ However, researchers are developing a novel way to help cocaine-dependent patients reduce their drug use. Therapy for addiction–cocaine addiction (TA-CD) is thought to curb cocaine use by engaging the body’s immune reaction and stopping cocaine molecules from reaching the brain, thereby reducing the drug’s pleasurable effects. One researcher working on this vaccine, Eugene Somoza, MD, PhD—the principal investigator of the Ohio Valley Node of the National Institute on Drug Abuse clinical trials network of 16 universities and treatment programs—discusses with Current Psychiatry Section Editor Robert M. Anthenelli, MD, how TA-CD works and how it might be used in clinical practice.

DR. ANTHENELLI: How is immunotherapy being applied to treating cocaine addiction and how does TA-CD work?

DR. SOMOZA: Our bodies have a very efficient immune system that can recognize foreign proteins and other complex molecules and develop specific antibodies against them that join irreversibly to these molecules to make them inactive. Immunotherapy usually is used to treat disorders that involve very complex molecules. Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier. The reinforcing properties of addictive agents depend on how fast they get into the brain. By slowing down or even stopping this process, you decrease the pleasurable effect individuals get from cocaine.

The cocaine vaccine that is being tested makes use of the B subunit of the cholera toxin molecule. It is highly immunogenic, and a recombinant of it is available in large quantities.² Cocaine molecules are connected to various areas of this complex cholera toxin subunit with covalent bonding. This makes the cocaine a larger target for an antibody response.

The interesting aspect of this process is that the vaccine acts outside of the brain. Other pharmacotherapies being tested, such as modafinil and disulfiram, target receptors or enzymes within the brain, which means that these 2 types of treatment would be synergistic. An early article on cocaine vaccines by Fox et al³ emphasized that this therapy is compatible with other treatments.

DR. ANTHENELLI: After receiving the vaccine, how long does it take for antibody levels to be high enough to produce a therapeutic effect?

DR. SOMOZA: Typically about 8 weeks.

DR. ANTHENELLI: Some trials have shown that patients display high variability in antibody levels. Only 38% of subjects in a 24-week, randomized, double-blind, placebo-controlled trial by Martell et al⁴ achieved high antibody levels (≥43 μ/mL). Are there ways to predict who will achieve the higher antibody titers and to increase the percentage of people who might develop the antibodies?

DR. SOMOZA: Right now there are not. In the Martell study, subjects’ antibody response curves—the increase and subsequent decrease in antibody concentration—were very different from individual to individual. We estimate that 40% of patients receiving the vaccine will develop ≥40 μ/mL of antibodies; this level is necessary for heavy cocaine users. However, not all patients take large amounts of cocaine, so we expect that even if a patient develops 30 μ/mL of antibodies, the amount of cocaine reaching the brain will be reduced— although the process may be slower—and using will not be as enticing.⁵

DR. ANTHENELLI: How long will the effects of TA-CD last, and how often will patients need to receive booster shots to keep antibody titers high?

DR. SOMOZA: The antibodies stay high for approximately 10 to 30 weeks, so you have to give boosters periodically. We need to carefully study if one can give a patient a booster every few months and, if so, how many booster shots would be required.

DR. ANTHENELLI: What are the known side effects of the vaccine?

DR. SOMOZA: In phase 1 and phase 2 studies, there haven’t been any problems at all.⁶ Theoretically, we could see some reaction at the injection site such as bruising or red or inflamed skin. In some cases with protein vaccines they’ve seen systemic reactions like fever. There’s also a risk of serum sickness, but this is theoretical based on other protein-based vaccines.⁷

DR. ANTHENELLI: Are there any data that address the safety of long-term TA-CD use?

DR. SOMOZA: We do not have any data on long-term use, but we know what happens over several months. When this project began 12 years ago, investigators worried that if the vaccine prevents cocaine from getting to the brain, cocaine-dependent individuals would just take more and more of the drug and suffer serious consequences. However, in preliminary studies, people have taken as much as 10 times their “normal” amount of cocaine with no adverse events. It looks like the vaccine may ameliorate some of cocaine’s effects on the heart. We’re certainly not encouraging study subjects to try to override the vaccine blockade, but these preliminary data at least minimize some of those concerns.

DR. ANTHENELLI: In clinical trials of TA-CD, during the 8-week ramp-up period where you’re waiting for patients’ antibody titers to get high enough to have a therapeutic effect, do trial participants receive other treatment?

DR. SOMOZA: Participants receive state-of-the-art cognitive-behavioral therapy (CBT) once a week. We do this to help patients look for triggers to cocaine use and how to handle them, but also to encourage them to stay in the study. It’s important that people who enroll in our trials are motivated to stop using. Many patients who have been using cocaine for years haven’t been able to own a house, get married, or even buy a car because all of their money is spent on cocaine. Eventually they decide it’s not a good idea to keep using forever. These are the participants we’d like to find.

There are other ways of increasing retention, such as rewarding patients for coming to appointments, providing urine for toxicology screens, or getting the boosters. We’re hoping contingency management will help keep patients in the trial.

How TA-CD will aid treatment

DR. ANTHENELLI: How do you envision TA-CD could be used in clinical practice?

DR. SOMOZA: It could become another tool in our armamentarium for treating cocaine dependence. Currently, there are no FDA-approved medications for cocaine dependence, although some pharmacologic treatments are being studied (Table).^8-13 When a patient comes in to be vaccinated, he or she also could receive other treatments if they are available, and the effect potentially would be additive. We would also use CBT because cocaine dependence is a very complex disorder. In CBT patients identify triggers that cause them to want to use and learn how to combat them and make better decisions.

DR. ANTHENELLI: Some research shows that TA-CD doesn’t stop cocaine use altogether but reduces use. Will that be a deterrent for clinicians who wish to help patients achieve absteinence?

DR. SOMOZA: That’s true about any medication we develop for addictions. I think it is magical thinking to say that you can give patients a pill and they will be abstinent for the rest of their lives. If you look at tobacco or alcohol, in practice abstinence is an end point that one has to approximate successively. In addition, permanent abstinence from cocaine is virtually impossible to measure. Because the half-life of benzoylecgonine (BE), the principle metabolite of cocaine, is 6 to 8 hours, this limits the effectiveness of urine toxicology screens in monitoring abstinence. Cocaine-dependent patients might not have used the drug the day before a urine toxicology screen. If a patient says he is abstaining from cocaine, it would be difficult to document it quantitatively without obtaining urine BE levels every day or every other day.

I think clinicians need to get used to the fact that we have to treat cocaine dependence in an incremental manner. A pharmacotherapy that would reduce use and hopefully limit the problems people are having as a result of cocaine use would be a positive step.

DR. ANTHENELLI: If TA-CD is found to be effective, what is the earliest it might come into clinical use?

DR. SOMOZA: I would speculate that it would be 7 to 10 years.

DR. ANTHENELLI: What other kinds of research are going on as far as vaccines for cocaine?

DR. SOMOZA: There is a strain of transgenic mice that when stimulated produce human, as well as mice, antibodies. At the University of Cincinnati, Andrew Norman, PhD, was able to immunize these mice and they generated human antibodies against cocaine (Box 1).^14,15 Then you’ll have vials of monoclonal antibodies that you can administer to your patient. However, this is still in early testing.

DR. ANTHENELLI: We’ve talked about immunotherapy and how it might work for the treatment of cocaine addiction. How might these types of vaccines be used for treating other substances of abuse?

DR. SOMOZA: Investigators are currently working on a vaccine for nicotine dependence (Box 2)^4,16-20 and there’s a vaccine being developed for methamphetamine,²¹ but it is not as advanced as cocaine. A similar methodology has been used for some time to treat digitalis overdose. There is no antidote for digitalis toxicity, so researchers have developed an antibody—digoxin immune fab—that attaches to the drug, which is then excreted through the kidneys. I fully expect that this methodology eventually will work for cocaine, meth-amphetamine, and nicotine dependence. My hunch is that producing human antibody in industrial quantities would be the most sensible way to eventually make this work.

Table

Pharmacotherapy for cocaine dependence: Most evidence is weak

Box 1

Box 2

Related Resource

• Martell BA, Mitchell E, Poling J, et al. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry. 2005;58(2):158-164.

Drug Brand Names

• Baclofen • Lioresal
• Digoxin • Lanoxin
• Digoxin immune fab • Digibind
• Disulfiram • Antabuse
• Modafinil • Provigil
• Ondansetron • Zofran
• Tiagabine • Gabitril

Disclosure

Dr. Anthenelli receives grant/research support from Eli Lilly and Company, Nabi Biopharmaceuticals, and Pfizer Inc., and is a consultant to Pfizer Inc.

Dr. Somoza receives grant/research support from the National Institute on Drug Abuse.

Drs. Norman and Ball receive grant/research support from the National Institutes of Health and the National Institute on Drug Abuse and are consultants to Vybion, Inc.

Box 3

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/vaccine-for-cocaine-addiction.html#comments

Unlike opioid or alcohol abuse, for cocaine dependence there are no FDA-approved pharmacotherapies, which leaves psychosocial treatment as the standard of care for the estimated 1.6 million individuals in the United States who abuse cocaine.¹ However, researchers are developing a novel way to help cocaine-dependent patients reduce their drug use. Therapy for addiction–cocaine addiction (TA-CD) is thought to curb cocaine use by engaging the body’s immune reaction and stopping cocaine molecules from reaching the brain, thereby reducing the drug’s pleasurable effects. One researcher working on this vaccine, Eugene Somoza, MD, PhD—the principal investigator of the Ohio Valley Node of the National Institute on Drug Abuse clinical trials network of 16 universities and treatment programs—discusses with Current Psychiatry Section Editor Robert M. Anthenelli, MD, how TA-CD works and how it might be used in clinical practice.

DR. ANTHENELLI: How is immunotherapy being applied to treating cocaine addiction and how does TA-CD work?

DR. SOMOZA: Our bodies have a very efficient immune system that can recognize foreign proteins and other complex molecules and develop specific antibodies against them that join irreversibly to these molecules to make them inactive. Immunotherapy usually is used to treat disorders that involve very complex molecules. Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier. The reinforcing properties of addictive agents depend on how fast they get into the brain. By slowing down or even stopping this process, you decrease the pleasurable effect individuals get from cocaine.

The cocaine vaccine that is being tested makes use of the B subunit of the cholera toxin molecule. It is highly immunogenic, and a recombinant of it is available in large quantities.² Cocaine molecules are connected to various areas of this complex cholera toxin subunit with covalent bonding. This makes the cocaine a larger target for an antibody response.

The interesting aspect of this process is that the vaccine acts outside of the brain. Other pharmacotherapies being tested, such as modafinil and disulfiram, target receptors or enzymes within the brain, which means that these 2 types of treatment would be synergistic. An early article on cocaine vaccines by Fox et al³ emphasized that this therapy is compatible with other treatments.

DR. ANTHENELLI: After receiving the vaccine, how long does it take for antibody levels to be high enough to produce a therapeutic effect?

DR. SOMOZA: Typically about 8 weeks.

DR. ANTHENELLI: Some trials have shown that patients display high variability in antibody levels. Only 38% of subjects in a 24-week, randomized, double-blind, placebo-controlled trial by Martell et al⁴ achieved high antibody levels (≥43 μ/mL). Are there ways to predict who will achieve the higher antibody titers and to increase the percentage of people who might develop the antibodies?

DR. SOMOZA: Right now there are not. In the Martell study, subjects’ antibody response curves—the increase and subsequent decrease in antibody concentration—were very different from individual to individual. We estimate that 40% of patients receiving the vaccine will develop ≥40 μ/mL of antibodies; this level is necessary for heavy cocaine users. However, not all patients take large amounts of cocaine, so we expect that even if a patient develops 30 μ/mL of antibodies, the amount of cocaine reaching the brain will be reduced— although the process may be slower—and using will not be as enticing.⁵

DR. ANTHENELLI: How long will the effects of TA-CD last, and how often will patients need to receive booster shots to keep antibody titers high?

DR. SOMOZA: The antibodies stay high for approximately 10 to 30 weeks, so you have to give boosters periodically. We need to carefully study if one can give a patient a booster every few months and, if so, how many booster shots would be required.

DR. ANTHENELLI: What are the known side effects of the vaccine?

DR. SOMOZA: In phase 1 and phase 2 studies, there haven’t been any problems at all.⁶ Theoretically, we could see some reaction at the injection site such as bruising or red or inflamed skin. In some cases with protein vaccines they’ve seen systemic reactions like fever. There’s also a risk of serum sickness, but this is theoretical based on other protein-based vaccines.⁷

DR. ANTHENELLI: Are there any data that address the safety of long-term TA-CD use?

DR. SOMOZA: We do not have any data on long-term use, but we know what happens over several months. When this project began 12 years ago, investigators worried that if the vaccine prevents cocaine from getting to the brain, cocaine-dependent individuals would just take more and more of the drug and suffer serious consequences. However, in preliminary studies, people have taken as much as 10 times their “normal” amount of cocaine with no adverse events. It looks like the vaccine may ameliorate some of cocaine’s effects on the heart. We’re certainly not encouraging study subjects to try to override the vaccine blockade, but these preliminary data at least minimize some of those concerns.

DR. ANTHENELLI: In clinical trials of TA-CD, during the 8-week ramp-up period where you’re waiting for patients’ antibody titers to get high enough to have a therapeutic effect, do trial participants receive other treatment?

DR. SOMOZA: Participants receive state-of-the-art cognitive-behavioral therapy (CBT) once a week. We do this to help patients look for triggers to cocaine use and how to handle them, but also to encourage them to stay in the study. It’s important that people who enroll in our trials are motivated to stop using. Many patients who have been using cocaine for years haven’t been able to own a house, get married, or even buy a car because all of their money is spent on cocaine. Eventually they decide it’s not a good idea to keep using forever. These are the participants we’d like to find.

There are other ways of increasing retention, such as rewarding patients for coming to appointments, providing urine for toxicology screens, or getting the boosters. We’re hoping contingency management will help keep patients in the trial.

How TA-CD will aid treatment

DR. ANTHENELLI: How do you envision TA-CD could be used in clinical practice?

DR. SOMOZA: It could become another tool in our armamentarium for treating cocaine dependence. Currently, there are no FDA-approved medications for cocaine dependence, although some pharmacologic treatments are being studied (Table).^8-13 When a patient comes in to be vaccinated, he or she also could receive other treatments if they are available, and the effect potentially would be additive. We would also use CBT because cocaine dependence is a very complex disorder. In CBT patients identify triggers that cause them to want to use and learn how to combat them and make better decisions.

DR. ANTHENELLI: Some research shows that TA-CD doesn’t stop cocaine use altogether but reduces use. Will that be a deterrent for clinicians who wish to help patients achieve absteinence?

DR. SOMOZA: That’s true about any medication we develop for addictions. I think it is magical thinking to say that you can give patients a pill and they will be abstinent for the rest of their lives. If you look at tobacco or alcohol, in practice abstinence is an end point that one has to approximate successively. In addition, permanent abstinence from cocaine is virtually impossible to measure. Because the half-life of benzoylecgonine (BE), the principle metabolite of cocaine, is 6 to 8 hours, this limits the effectiveness of urine toxicology screens in monitoring abstinence. Cocaine-dependent patients might not have used the drug the day before a urine toxicology screen. If a patient says he is abstaining from cocaine, it would be difficult to document it quantitatively without obtaining urine BE levels every day or every other day.

I think clinicians need to get used to the fact that we have to treat cocaine dependence in an incremental manner. A pharmacotherapy that would reduce use and hopefully limit the problems people are having as a result of cocaine use would be a positive step.

DR. ANTHENELLI: If TA-CD is found to be effective, what is the earliest it might come into clinical use?

DR. SOMOZA: I would speculate that it would be 7 to 10 years.

DR. ANTHENELLI: What other kinds of research are going on as far as vaccines for cocaine?

DR. SOMOZA: There is a strain of transgenic mice that when stimulated produce human, as well as mice, antibodies. At the University of Cincinnati, Andrew Norman, PhD, was able to immunize these mice and they generated human antibodies against cocaine (Box 1).^14,15 Then you’ll have vials of monoclonal antibodies that you can administer to your patient. However, this is still in early testing.

DR. ANTHENELLI: We’ve talked about immunotherapy and how it might work for the treatment of cocaine addiction. How might these types of vaccines be used for treating other substances of abuse?

DR. SOMOZA: Investigators are currently working on a vaccine for nicotine dependence (Box 2)^4,16-20 and there’s a vaccine being developed for methamphetamine,²¹ but it is not as advanced as cocaine. A similar methodology has been used for some time to treat digitalis overdose. There is no antidote for digitalis toxicity, so researchers have developed an antibody—digoxin immune fab—that attaches to the drug, which is then excreted through the kidneys. I fully expect that this methodology eventually will work for cocaine, meth-amphetamine, and nicotine dependence. My hunch is that producing human antibody in industrial quantities would be the most sensible way to eventually make this work.

Table

Pharmacotherapy for cocaine dependence: Most evidence is weak

Box 1

Box 2

Related Resource

• Martell BA, Mitchell E, Poling J, et al. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry. 2005;58(2):158-164.

Drug Brand Names

• Baclofen • Lioresal
• Digoxin • Lanoxin
• Digoxin immune fab • Digibind
• Disulfiram • Antabuse
• Modafinil • Provigil
• Ondansetron • Zofran
• Tiagabine • Gabitril

Disclosure

Dr. Anthenelli receives grant/research support from Eli Lilly and Company, Nabi Biopharmaceuticals, and Pfizer Inc., and is a consultant to Pfizer Inc.

Dr. Somoza receives grant/research support from the National Institute on Drug Abuse.

Drs. Norman and Ball receive grant/research support from the National Institutes of Health and the National Institute on Drug Abuse and are consultants to Vybion, Inc.

Box 3

Discuss this article at http://currentpsychiatry.blogspot.com/2010/09/vaccine-for-cocaine-addiction.html#comments

Unlike opioid or alcohol abuse, for cocaine dependence there are no FDA-approved pharmacotherapies, which leaves psychosocial treatment as the standard of care for the estimated 1.6 million individuals in the United States who abuse cocaine.¹ However, researchers are developing a novel way to help cocaine-dependent patients reduce their drug use. Therapy for addiction–cocaine addiction (TA-CD) is thought to curb cocaine use by engaging the body’s immune reaction and stopping cocaine molecules from reaching the brain, thereby reducing the drug’s pleasurable effects. One researcher working on this vaccine, Eugene Somoza, MD, PhD—the principal investigator of the Ohio Valley Node of the National Institute on Drug Abuse clinical trials network of 16 universities and treatment programs—discusses with Current Psychiatry Section Editor Robert M. Anthenelli, MD, how TA-CD works and how it might be used in clinical practice.

DR. ANTHENELLI: How is immunotherapy being applied to treating cocaine addiction and how does TA-CD work?

DR. SOMOZA: Our bodies have a very efficient immune system that can recognize foreign proteins and other complex molecules and develop specific antibodies against them that join irreversibly to these molecules to make them inactive. Immunotherapy usually is used to treat disorders that involve very complex molecules. Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier. The reinforcing properties of addictive agents depend on how fast they get into the brain. By slowing down or even stopping this process, you decrease the pleasurable effect individuals get from cocaine.

The cocaine vaccine that is being tested makes use of the B subunit of the cholera toxin molecule. It is highly immunogenic, and a recombinant of it is available in large quantities.² Cocaine molecules are connected to various areas of this complex cholera toxin subunit with covalent bonding. This makes the cocaine a larger target for an antibody response.

The interesting aspect of this process is that the vaccine acts outside of the brain. Other pharmacotherapies being tested, such as modafinil and disulfiram, target receptors or enzymes within the brain, which means that these 2 types of treatment would be synergistic. An early article on cocaine vaccines by Fox et al³ emphasized that this therapy is compatible with other treatments.

DR. ANTHENELLI: After receiving the vaccine, how long does it take for antibody levels to be high enough to produce a therapeutic effect?

DR. SOMOZA: Typically about 8 weeks.

DR. ANTHENELLI: Some trials have shown that patients display high variability in antibody levels. Only 38% of subjects in a 24-week, randomized, double-blind, placebo-controlled trial by Martell et al⁴ achieved high antibody levels (≥43 μ/mL). Are there ways to predict who will achieve the higher antibody titers and to increase the percentage of people who might develop the antibodies?

DR. SOMOZA: Right now there are not. In the Martell study, subjects’ antibody response curves—the increase and subsequent decrease in antibody concentration—were very different from individual to individual. We estimate that 40% of patients receiving the vaccine will develop ≥40 μ/mL of antibodies; this level is necessary for heavy cocaine users. However, not all patients take large amounts of cocaine, so we expect that even if a patient develops 30 μ/mL of antibodies, the amount of cocaine reaching the brain will be reduced— although the process may be slower—and using will not be as enticing.⁵

DR. ANTHENELLI: How long will the effects of TA-CD last, and how often will patients need to receive booster shots to keep antibody titers high?

DR. SOMOZA: The antibodies stay high for approximately 10 to 30 weeks, so you have to give boosters periodically. We need to carefully study if one can give a patient a booster every few months and, if so, how many booster shots would be required.

DR. ANTHENELLI: What are the known side effects of the vaccine?

DR. SOMOZA: In phase 1 and phase 2 studies, there haven’t been any problems at all.⁶ Theoretically, we could see some reaction at the injection site such as bruising or red or inflamed skin. In some cases with protein vaccines they’ve seen systemic reactions like fever. There’s also a risk of serum sickness, but this is theoretical based on other protein-based vaccines.⁷

DR. ANTHENELLI: Are there any data that address the safety of long-term TA-CD use?

DR. SOMOZA: We do not have any data on long-term use, but we know what happens over several months. When this project began 12 years ago, investigators worried that if the vaccine prevents cocaine from getting to the brain, cocaine-dependent individuals would just take more and more of the drug and suffer serious consequences. However, in preliminary studies, people have taken as much as 10 times their “normal” amount of cocaine with no adverse events. It looks like the vaccine may ameliorate some of cocaine’s effects on the heart. We’re certainly not encouraging study subjects to try to override the vaccine blockade, but these preliminary data at least minimize some of those concerns.

DR. ANTHENELLI: In clinical trials of TA-CD, during the 8-week ramp-up period where you’re waiting for patients’ antibody titers to get high enough to have a therapeutic effect, do trial participants receive other treatment?

DR. SOMOZA: Participants receive state-of-the-art cognitive-behavioral therapy (CBT) once a week. We do this to help patients look for triggers to cocaine use and how to handle them, but also to encourage them to stay in the study. It’s important that people who enroll in our trials are motivated to stop using. Many patients who have been using cocaine for years haven’t been able to own a house, get married, or even buy a car because all of their money is spent on cocaine. Eventually they decide it’s not a good idea to keep using forever. These are the participants we’d like to find.

There are other ways of increasing retention, such as rewarding patients for coming to appointments, providing urine for toxicology screens, or getting the boosters. We’re hoping contingency management will help keep patients in the trial.

How TA-CD will aid treatment

DR. ANTHENELLI: How do you envision TA-CD could be used in clinical practice?

DR. SOMOZA: It could become another tool in our armamentarium for treating cocaine dependence. Currently, there are no FDA-approved medications for cocaine dependence, although some pharmacologic treatments are being studied (Table).^8-13 When a patient comes in to be vaccinated, he or she also could receive other treatments if they are available, and the effect potentially would be additive. We would also use CBT because cocaine dependence is a very complex disorder. In CBT patients identify triggers that cause them to want to use and learn how to combat them and make better decisions.

DR. ANTHENELLI: Some research shows that TA-CD doesn’t stop cocaine use altogether but reduces use. Will that be a deterrent for clinicians who wish to help patients achieve absteinence?

DR. SOMOZA: That’s true about any medication we develop for addictions. I think it is magical thinking to say that you can give patients a pill and they will be abstinent for the rest of their lives. If you look at tobacco or alcohol, in practice abstinence is an end point that one has to approximate successively. In addition, permanent abstinence from cocaine is virtually impossible to measure. Because the half-life of benzoylecgonine (BE), the principle metabolite of cocaine, is 6 to 8 hours, this limits the effectiveness of urine toxicology screens in monitoring abstinence. Cocaine-dependent patients might not have used the drug the day before a urine toxicology screen. If a patient says he is abstaining from cocaine, it would be difficult to document it quantitatively without obtaining urine BE levels every day or every other day.

I think clinicians need to get used to the fact that we have to treat cocaine dependence in an incremental manner. A pharmacotherapy that would reduce use and hopefully limit the problems people are having as a result of cocaine use would be a positive step.

DR. ANTHENELLI: If TA-CD is found to be effective, what is the earliest it might come into clinical use?

DR. SOMOZA: I would speculate that it would be 7 to 10 years.

DR. ANTHENELLI: What other kinds of research are going on as far as vaccines for cocaine?

DR. SOMOZA: There is a strain of transgenic mice that when stimulated produce human, as well as mice, antibodies. At the University of Cincinnati, Andrew Norman, PhD, was able to immunize these mice and they generated human antibodies against cocaine (Box 1).^14,15 Then you’ll have vials of monoclonal antibodies that you can administer to your patient. However, this is still in early testing.

DR. ANTHENELLI: We’ve talked about immunotherapy and how it might work for the treatment of cocaine addiction. How might these types of vaccines be used for treating other substances of abuse?

DR. SOMOZA: Investigators are currently working on a vaccine for nicotine dependence (Box 2)^4,16-20 and there’s a vaccine being developed for methamphetamine,²¹ but it is not as advanced as cocaine. A similar methodology has been used for some time to treat digitalis overdose. There is no antidote for digitalis toxicity, so researchers have developed an antibody—digoxin immune fab—that attaches to the drug, which is then excreted through the kidneys. I fully expect that this methodology eventually will work for cocaine, meth-amphetamine, and nicotine dependence. My hunch is that producing human antibody in industrial quantities would be the most sensible way to eventually make this work.

Table

Pharmacotherapy for cocaine dependence: Most evidence is weak

Box 1

Box 2

Related Resource

• Martell BA, Mitchell E, Poling J, et al. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry. 2005;58(2):158-164.

Drug Brand Names

• Baclofen • Lioresal
• Digoxin • Lanoxin
• Digoxin immune fab • Digibind
• Disulfiram • Antabuse
• Modafinil • Provigil
• Ondansetron • Zofran
• Tiagabine • Gabitril

Disclosure

Dr. Anthenelli receives grant/research support from Eli Lilly and Company, Nabi Biopharmaceuticals, and Pfizer Inc., and is a consultant to Pfizer Inc.

Dr. Somoza receives grant/research support from the National Institute on Drug Abuse.

Drs. Norman and Ball receive grant/research support from the National Institutes of Health and the National Institute on Drug Abuse and are consultants to Vybion, Inc.

Box 3

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

Presenting patients to supervisors in a cogent fashion appears to be a dying (or already dead) art among psychiatric residents. Trainees often approach the oral patient presentation as simply a routine necessity rather than a core professional skill that reflects their ability to synthesize and relay clinical information. In this article we offer suggestions on how to reclaim this lost art.

Tell a story. Think of your presentation as a story about the patient. A story has a beginning, middle, and end; in this case, the order is present illness, psychiatric history, medical history, social history, family history, examination, laboratory data, diagnostic impression, treatment plan, and prognosis. Do not intermingle these elements into a free-associative stream of consciousness or a tale of how and in what order you obtained the information. It is the doctor’s—not the patient’s—responsibility to be a good historian.¹

Define the ‘leading edge.’ For an inpatient, the leading edge might be the symptoms that led to hospitalization. For an outpatient, it is not unusual for the present illness to go back many years, which is where the presentation should begin. Resist the temptation to start more recently because to do so often leaves the listener wondering—when did this begin, and how does it fit into the bigger picture?

Respect your listeners. You want to leave your audience with a clear picture of who your patient is. Presenting a patient should call to mind the saying, “If I’d had more time, I would have written a shorter letter.” It takes more time and effort to fashion a succinct presentation than to produce a rambling narrative with extraneous material; it requires synthesis and judgment to determine what to leave in and what to leave out. George Murray, MD, a consultation psychiatrist and our mentor, is fond of saying, “Do you know how to bore your audience? Tell them everything.” Respect your listeners’ time and credit their intelligence. Your presentation should stimulate questions, not preempt them by being overly inclusive or exhausting all of your allotted time.

Do not rehash the history when presenting the assessment. The assessment is what you think about the history and examination data—how you put it all together to make sense of it diagnostically so you can approach treatment in an organized way. It is not the time to recapitulate what you should have summarized in the earlier part of your discourse. The diagnostic impression is where you can show off how you think as a physician. It is where you can shine.

Presenting patients to supervisors in a cogent fashion appears to be a dying (or already dead) art among psychiatric residents. Trainees often approach the oral patient presentation as simply a routine necessity rather than a core professional skill that reflects their ability to synthesize and relay clinical information. In this article we offer suggestions on how to reclaim this lost art.

Tell a story. Think of your presentation as a story about the patient. A story has a beginning, middle, and end; in this case, the order is present illness, psychiatric history, medical history, social history, family history, examination, laboratory data, diagnostic impression, treatment plan, and prognosis. Do not intermingle these elements into a free-associative stream of consciousness or a tale of how and in what order you obtained the information. It is the doctor’s—not the patient’s—responsibility to be a good historian.¹

Define the ‘leading edge.’ For an inpatient, the leading edge might be the symptoms that led to hospitalization. For an outpatient, it is not unusual for the present illness to go back many years, which is where the presentation should begin. Resist the temptation to start more recently because to do so often leaves the listener wondering—when did this begin, and how does it fit into the bigger picture?

Respect your listeners. You want to leave your audience with a clear picture of who your patient is. Presenting a patient should call to mind the saying, “If I’d had more time, I would have written a shorter letter.” It takes more time and effort to fashion a succinct presentation than to produce a rambling narrative with extraneous material; it requires synthesis and judgment to determine what to leave in and what to leave out. George Murray, MD, a consultation psychiatrist and our mentor, is fond of saying, “Do you know how to bore your audience? Tell them everything.” Respect your listeners’ time and credit their intelligence. Your presentation should stimulate questions, not preempt them by being overly inclusive or exhausting all of your allotted time.

Do not rehash the history when presenting the assessment. The assessment is what you think about the history and examination data—how you put it all together to make sense of it diagnostically so you can approach treatment in an organized way. It is not the time to recapitulate what you should have summarized in the earlier part of your discourse. The diagnostic impression is where you can show off how you think as a physician. It is where you can shine.

Presenting patients to supervisors in a cogent fashion appears to be a dying (or already dead) art among psychiatric residents. Trainees often approach the oral patient presentation as simply a routine necessity rather than a core professional skill that reflects their ability to synthesize and relay clinical information. In this article we offer suggestions on how to reclaim this lost art.

Tell a story. Think of your presentation as a story about the patient. A story has a beginning, middle, and end; in this case, the order is present illness, psychiatric history, medical history, social history, family history, examination, laboratory data, diagnostic impression, treatment plan, and prognosis. Do not intermingle these elements into a free-associative stream of consciousness or a tale of how and in what order you obtained the information. It is the doctor’s—not the patient’s—responsibility to be a good historian.¹

Define the ‘leading edge.’ For an inpatient, the leading edge might be the symptoms that led to hospitalization. For an outpatient, it is not unusual for the present illness to go back many years, which is where the presentation should begin. Resist the temptation to start more recently because to do so often leaves the listener wondering—when did this begin, and how does it fit into the bigger picture?

Respect your listeners. You want to leave your audience with a clear picture of who your patient is. Presenting a patient should call to mind the saying, “If I’d had more time, I would have written a shorter letter.” It takes more time and effort to fashion a succinct presentation than to produce a rambling narrative with extraneous material; it requires synthesis and judgment to determine what to leave in and what to leave out. George Murray, MD, a consultation psychiatrist and our mentor, is fond of saying, “Do you know how to bore your audience? Tell them everything.” Respect your listeners’ time and credit their intelligence. Your presentation should stimulate questions, not preempt them by being overly inclusive or exhausting all of your allotted time.

Do not rehash the history when presenting the assessment. The assessment is what you think about the history and examination data—how you put it all together to make sense of it diagnostically so you can approach treatment in an organized way. It is not the time to recapitulate what you should have summarized in the earlier part of your discourse. The diagnostic impression is where you can show off how you think as a physician. It is where you can shine.