Treating Bipolar Disorder in Primary Care: Diagnosis, Pharmacology, and Management.

Bipolar disorder is a chronic mental illness associated with early mortality, elevated risk of comorbid cardiovascular disease, enormous burden of disability, and large societal costs. Patients often seek treatment for symptoms of bipolar disorder in the primary care setting but are frequently misdiagnosed. This article provides primary care providers with an evidence-based approach to the screening, diagnosis, and pharmacological management of bipolar disorder. Guidance is also provided for helping patients connect with higher levels of specialty psychiatric care when clinically indicated.

A Retrospective Multicenter Evaluation of Clozapine Use in Pediatric Patients Admitted for Acute Psychiatric Hospitalization.

OBJECTIVES: Clozapine is the drug of choice for treatment-resistant schizophrenia. While pediatric clozapine use is not contraindicated, the literature describing its clinical application is limited. The primary objective of this study was to assess the use of clozapine in a child and adolescent population by characterizing the documented safety and clinical benefits of the medication. METHODS: A multicenter retrospective study at sites in the United States and Australia included children and adolescents admitted to a psychiatric unit who were administered at least one dose of clozapine. Information related to demographics, patient history, past treatments, clozapine, and adverse events was collected. RESULTS: Eighty-two patients from eight sites were included in this study. Patients were predominantly clozapine naive (76.8%), and most had a discharge diagnosis of a primary psychotic disorder (61%) or bipolar disorder (25.6%). Four clozapine discontinuations occurred during hospitalization due to severe neutropenia, ileus, need for diagnostic clarification, and significant psychomotor retardation. The remainder (n = 78) were discharged on a mean clozapine dose of 218.1 ± 142.2 mg. Sedation (26.8%) and sialorrhea (17.1%) were the most common documented adverse events. The mean number of previously trialed antipsychotics before clozapine was 3.5 ± 1.4 (range 1-10). Improvement with clozapine was documented as significant (31.7%), moderate (32.9%), minimal (12.2%), no improvement (2.4%), and not described (20.7%). CONCLUSIONS: In this cohort, 95% of pediatric patients admitted with or started on clozapine during an acute psychiatric hospitalization were discharged on the medication. The high incidence of adverse events should reinforce to clinicians the need for vigilant monitoring. Pediatric guidelines recommend clozapine for refractory schizophrenia but stress the critical need to ensure an accurate diagnosis. Limited data exist for the use of clozapine in pediatric patients with other diagnoses.

Organizational Characteristics of Veterans Affairs Clinics With High and Low Utilization of Clozapine.

OBJECTIVE: Twenty to thirty percent of patients with schizophrenia experience treatment resistance. Clozapine is the only medication proven effective for treatment-resistant schizophrenia. However, in most settings less than 25% of patients with treatment-resistant schizophrenia receive clozapine. This study was conducted to identify facilitators of and barriers to clozapine use to inform development of interventions to maximize appropriate clozapine utilization. METHODS: Seventy semistructured phone interviews were conducted with key informants of clozapine processes at U.S. Department of Veterans Affairs medical centers in various U.S. regions, including urban and rural areas, with high (N=5) and low (N=5) rates of clozapine utilization. Interviewees included members of mental health leadership, psychiatrists, clinical pharmacists, and advanced practice nurses. Interviews were analyzed by using an emergent thematic strategy to identify barriers and facilitators related to clozapine prescribing. RESULTS: High utilization was associated with integration of nonphysician psychiatric providers and clear organizational processes and infrastructure for treatment of severe mental illness, for example, use of clozapine clinics and mental health intensive case management. Low utilization was associated with a lack of champions to support clozapine processes and with limited-capacity care systems. Obstacles identified at both high- and low-utilization sites included complex, time-consuming paperwork; reliance on a few individuals to facilitate processes; and issues related to transportation for patients living far from care facilities. CONCLUSIONS: Implementation efforts to organize, streamline, and simplify clozapine processes; development of a multidisciplinary clozapine clinic; increased capacity of existing clinics; and provision of transportation are reasonable targets to increase clozapine utilization.

The Business Case for Expanded Clozapine Utilization.

OBJECTIVE: In most settings, less than 25% of patients with treatment-resistant schizophrenia receive clozapine, the only medication proven effective for treatment-resistant schizophrenia. Therefore, a business case analysis was conducted to assess whether increasing clozapine utilization for treatment-resistant schizophrenia in a health care system would result in direct health care cost savings. METHODS: Veterans with treatment-resistant schizophrenia who were treated in the Veterans Health Administration (VHA) were studied. Treatment response, suicides, adverse drug reactions (and associated mortality), and effects on inpatient hospitalization related to clozapine were derived from a systematic review of published studies. A one-factor sensitivity analysis and a probabilistic sensitivity analysis (PSA) with Monte Carlo simulation were conducted to calculate the cost-benefits of increased clozapine utilization. RESULTS: Despite monitoring costs, in the base case analysis, the VHA would save $22,444 per veteran with treatment-resistant schizophrenia over the first year of clozapine therapy, primarily from 18.6 fewer inpatient days per patient. If current utilization was doubled, and 50% of those veterans continued clozapine treatment for one year, VHA would save an estimated $80 million. Cost savings were most sensitive to the proportion of treatment-resistant patients who received clozapine, decrease in inpatient days, cost of inpatient stays, clozapine response rate, and number of patients with treatment-resistant schizophrenia. In the PSA, initiation of clozapine for all VHA patients with treatment-resistant schizophrenia who were not currently treated with clozapine would save at least $290 million in 95% of simulations. CONCLUSIONS: Increased clozapine utilization would result in net cost savings for the VHA.

Brain-derived neurotrophic factor and schizophrenia.

Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of schizophrenia. However, for many patients, drugs that alter dopaminergic function do not consistently lead to resolution of the symptoms of schizophrenia. Thus, there is an increased interest in pathophysiologic processes that result in altered neurodevelopment and plasticity associated with schizophrenia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis, synaptic plasticity, cognition, and neurotransmission. Genetic polymorphism, expression, and function of BDNF have been implicated in psychiatric diseases, including schizophrenia. This review discusses BDNF, its role in neurologic processes, and the evidence implicating BDNF in schizophrenia.

Pharmacologic management of bipolar disorder in a Medicare Advantage population.

OBJECTIVE: The purpose of this study was to examine patterns of pharmacotherapy for beneficiaries in a high-risk Medicare Advantage program who were diagnosed with bipolar disorder. METHODS: This was a cross-sectional study of 2338 Medicare Advantage beneficiaries diagnosed with bipolar disorder. Pharmacotherapy treatment was assessed via receipt of (1) a mood stabilizer or antipsychotic or both (i.e., guideline concordant bipolar care) and (2) unopposed antidepressant (i.e., without prescription of a mood stabilizer or an antipsychotic). Logistic regression was used to examine correlates of bipolar disorder care. RESULTS: Among those younger than 65 years of age (n = 1395), 54% received guideline concordant therapy and 29% received unopposed antidepressant therapy. Among those 65 years and older (n = 943), 40% received guideline concordant therapy and 33% received unopposed antidepressant therapy. CONCLUSION: Overall, about half of beneficiaries in this Medicare Advantage plan received guideline concordant pharmacotherapy for bipolar disorder, while approximately one-third received an unopposed antidepressant prescription. Antipsychotic medications accounted for most of the monotherapy observed. This study identifies opportunities for further improvements in the pharmacotherapy of bipolar disorder in high-risk Medicare patients.

Infection and inflammation leading to clozapine toxicity and intensive care: a case series.

OBJECTIVE: To describe 3 cases of clozapine toxicity associated with infectious and/or inflammatory processes. CASE SUMMARIES: Three patients stable on clozapine therapy prior to a medical hospital admission developed clozapine toxicity. It was suspected that an acute infectious and/or inflammatory process in each patient was related to abrupt mental status changes, onset of sialorrhea, myoclonus, and/or need for ventilatory support. Investigations of altered mental status did not reveal alternative causes and presentations were not consistent with neuroleptic malignant syndrome, other acute neurologic complications, or psychiatric decompensation. All patients improved after clozapine dose reductions allowing for transfer from intensive care units. Using the Naranjo ADR Probability Scale for each case, a probable relation between clozapine toxicity and the infectious and/or inflammatory process was determined. DISCUSSION: Clozapine toxicity may manifest with multiple symptoms, including sedation, sialorrhea, and hypotension. In addition to overdose and drug interactions; infection and/or inflammation may precipitate clozapine toxicity. This may be related to cytokine-mediated inhibition of cytochrome P450 1A2. The likelihood of toxicity via this mechanism has not been well characterized, thus careful monitoring is required for medically ill patients receiving clozapine. Clozapine is extensively bound to the acute phase reactant, α-1 acid glycoprotein, which may unpredictably protect against clinical toxicity. C-reactive protein has also been investigated to relate clozapine toxicity to infection and/or inflammation. CONCLUSION: Clozapine toxicity developed in 3 patients admitted to a medical setting suspected to be related to infection and/or inflammation. Clinicians should be aware of this potential adverse drug event with clozapine.

Psychotropics and sudden cardiac death.

Over the past two decades there has been a large increase in the number of patients prescribed psychotropic medications. Many of these agents are associated with QTc prolongation which is considered a marker for increased risk of sudden cardiac death due to malignant arrhythmias such as Torsades de pointes (TdP). Psychotropics rarely lead to sudden death in healthy individuals on a single QTc prolonging medication. However, factors such polypharmacy, recent initiation of a QTc prolonging medication, bradycardia, electrolyte abnormalities and preexisting arrhythmias increase the likelihood of psychotropic-induced sudden cardiac death. Therefore, clinicians must recognize which psychotropics and risk factors are associated with increased risk in order to minimize the risks of psychotropic QTc prolongation.

Antipsychotic prescribing pathways, polypharmacy, and clozapine use in treatment of schizophrenia.

OBJECTIVE: To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. METHODS: Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher's exact test. RESULTS: Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%-2%). CONCLUSIONS: Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials.

The use of omega-3 fatty acids in mental illness.

PURPOSE: This article will summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of mental illness. BACKGROUND: Omega-3 fatty acids are involved in many physiologic processes. Since they cannot be made de novo in the body, they are considered essential nutrients. As the Western diet evolved, dietary intake of fatty acids has shifted to increased omega-6 fatty acids and decreased omega-3 fatty acids intake. These changes have been correlated with numerous differences in prevalence and course of mental illnesses. METHODS: A MEDLINE search from 1966 to December 2010 was completed to identify studies comparing changes in symptoms, functioning, other outcomes, and/or side effects in patients treated with omega-3 fatty acids for mental illness. The studies were reviewed and reported by specific psychiatric disorder studied. CONCLUSIONS: Omega-3 fatty acids play a role in many biologic functions. Epidemiologic data implicate omega-3 fatty acid deficiencies in many mental illnesses. Data are most robust for omega-3 fatty acids' role in affective disorders. However, data are conflicting, negative, or absent for most mental illnesses.

Development and delivery of a quality improvement program to reduce antipsychotic polytherapy.

BACKGROUND: Although antipsychotic polytherapy is considered appropriate in limited circumstances (e.g., during a brief "cross-titration" period when switching medications), its increasing prevalence indicates use beyond this limited scope. Despite absence of support in the medical literature and higher costs, antipsychotic polytherapy is common in the treatment of schizophrenia and related disorders. The highest utilization of antipsychotic polytherapy occurs on psychiatric inpatient units, and in 2008, the Joint Commission released the first set of 7 hospital-based inpatient psychiatric services (HBIPS) core measures, 2 of which assess antipsychotic polytherapy at time of discharge. OBJECTIVE: To describe the effect on antipsychotic polytherapy at time of discharge of a 2-part quality improvement program composed of educational seminars and prescriber-specific feedback provided to 11 psychiatrists in 4 acute inpatient psychiatric units in 2 hospitals. METHODS: In a regional academic health care system, we determined the prevalence of antipsychotic monotherapy and polytherapy at time of discharge for all patients discharged on standing antipsychotic medications during 3 periods: (a) a 3-month baseline period (August 2006 through October 2006); (b) in July 2007, after delivery of 4 educational luncheon seminars to 11 psychiatrists from November 2006 through June 2007; and (c) in June 2008, following the provision of monthly prescriber-specific audit feedback from August 2007 through June 2008. To prepare nurses for the change and address possible safety concerns, an educational module was delivered to the psychiatric nursing staff at "best practice" day lectures held in the first quarter of 2007. General themes in the educational presentations included literature-based reviews of (a) safety and efficacy of antipsychotic polytherapy, (b) medical risks of antipsychotic medications, (c) specific versus nonspecific effects of these medications, and (d) effectiveness of first- versus second-generation antipsychotic medications. The prescriber-specific audit feedback was provided in paper form and masked the identity of the other prescribers. The chief of service reviewed audit feedback individually with each psychiatrist on a quarterly basis. The primary outcome measure was the percentage of patients prescribed 2 or more antipsychotics at discharge. A secondary outcome measure was the percentage of patients prescribed 3 or more antipsychotics at discharge. Differences in the primary outcome measure, comparing (a) July 2007 with the baseline period and (b) June 2008 with July 2007, were analyzed using Fisher's Exact tests. The Cochran-Armitage test for trend was used to assess the relationship between the primary outcome measure and the extent of the intervention, measured as the 3 time periods. For the secondary outcome measure, the Goodman-Kruskal gamma test for ordered categorical data was calculated to examine the association between the the proportion of patients receiving 1, 2, or 3 or more antipsychotics at discharge and the 3 time periods. RESULTS: The percentage of patients prescribed 2 or more antipsychotics at discharge declined from 33.9% at baseline (132 of 389 patients), to 21.8% after delivery of the educational modules (44 of 202 patients, P = 0.002), and to 12.2% after audit feedback (18 of 147 patients, P = 0.023; Cochran-Armitage test for trend P < 0.001). When antipsychotic use was classified as 1, 2, or 3 or more antipsychotic medications, more extensive intervention was associated with decreased combination use (Goodman- Kruskal gamma = 0.39, P < 0.001). In the baseline period, 5.9% of patients were prescribed 3 or more antipsychotics at discharge. Following completion of the educational and audit components, respectively, the proportion of patients prescribed 3 or more antipsychotics declined to 2.5% and then to 0.0%. CONCLUSION: Educational modules presented to psychiatrists and nurses in group settings were associated with a decrease in the rate of prescribing 2 or more antipsychotics at discharge from acute psychiatric inpatient units. Addition of monthly audit feedback provided to psychiatrists was associated with further decreases.

When is antipsychotic polypharmacy supported by research evidence? Implications for QI.

BACKGROUND: Concurrent use of multiple standing antipsychotics (antipsychotic polypharmacy) is increasingly common among both inpatients and outpatients. Although this has often been cited as a potential quality-of-care problem, reviews of research evidence on antipsychotic polypharmacy have not distinguished between appropriate versus inappropriate use. METHODS: A MEDLINE search from 1966 to December 2007 was completed to identify studies comparing changes in symptoms, functioning, and/or side effects between patients treated with multiple antipsychotics and patients treated with a single antipsychotic. The studies were reviewed in two groups on the basis of whether prescribing was concordant with guideline recommendations for multiple-antipsychotic use. RESULTS: A review of the literature, including three randomized controlled trials, found no support for the use of antipsychotic polypharmacy in patients without an established history of treatment resistance to multiple trials of monotherapy. In patients with a history of treatment resistance to multiple monotherapy trials, limited data support antipsychotic polypharmacy, but positive outcomes were primarily found in studies of clozapine augmented with a second-generation antipsychotic. DISCUSSION: Research evidence is consistent with the goal of avoiding antipsychotic polypharmacy in patients who lack guideline-recommended indications for its use. The Joint Commission is implementing a core measure set for Hospital-Based Inpatient Psychiatric Services. Two of the measures address antipsychotic polypharmacy. The first measure assesses the overall rate. The second measure determines whether clinically appropriate justification has been documented supporting the use of more than one antipsychotic medication.

Antidepressants use in pediatric populations.

In October of 2003, the FDA issued a public health warning stating that preliminary evidence showed selective serotonin re-uptake inhibitors (SSRIs) and related antidepressants might be associated with excess reports of suicidality. In 2004, the FDA convened a committee of neuropsychiatric and pediatric subcommittee members and expert consultants to evaluate the safety of antidepressants in children and adolescents. The committee reviewed a meta-analysis of antidepressant use in pediatric patients and concluded that there was a causal link between pediatric antidepressant use and suicidality. In response, the FDA mandated that a 'black box' warning be added to the prescribing and promotional information for all antidepressants. The warning specifically states 'antidepressants increase the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders'. Interestingly, the FDA tempered the warning with the following statement: 'Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide'. Therefore, in effect, the FDA has warned that both untreated depression and treatments for depression lead to suicidality. Now, 4 years later, the repercussions of the black box warning are becoming evident.

Duloxetine: a dual serotonin-norepinephrine reuptake inhibitor for treatment of major depressive disorder.

The burden of mental illness has been underestimated worldwide. Depression was the fourth leading cause of disease burden in the world in 1990 and is projected to be the second leading cause of disability by 2020. It is a leading cause of morbidity and mortality in the United States, costing billions of dollars annually in direct and indirect medical costs and losses in productivity. Patients with major depressive disorder (MDD) may experience both psychological and medical complaints, including somatic sensations or pain. Some antidepressants have been shown to treat chronic pain syndromes, but despite the variety of antidepressants available in the United States, only 65-70% of patients respond to initial antidepressant treatment. Treatments are limited by delayed onset of antidepressant effects, side effects, partial response, and treatment resistance. Duloxetine, approved by the U.S. Food and Drug Administration for the treatment of MDD, is a reuptake inhibitor at serotonergic and noradrenergic neurons and appears to have low affinity for other neurotransmitter systems. In clinical trials, duloxetine was effective for the treatment of MDD and was well tolerated. Further study is needed to compare its efficacy with that of other antidepressants, to clarify effects on somatic symptoms, and to assess potential adverse cardiovascular and sexual side effects. Duloxetine is also approved for the management of diabetic peripheral neuropathic pain and is under investigation for the treatment of stress urinary incontinence in women.

Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans.

STUDY OBJECTIVE: To determine if S-adenosyl-L-methionine (SAMe), a widely used dietary supplement with antidepressant properties, is significantly bioavailable, and whether toxic methylated compounds are produced with oral SAMe administration in humans. Serum homocysteine levels were also measured since alterations in these levels have been theorized in association with SAMe. DESIGN: Unblinded pharmacokinetic trial. SUBJECTS: Fifteen healthy volunteers. SETTING: Clinical research unit in a psychiatric hospital. INTERVENTION: Subjects received oral SAMe for 4 weeks; the dosage was titrated over 5 days to 1600 mg/day. Serum levels of SAMe, toxic methylated compounds (methanol, formaldehyde, and formic acid), and homocysteine were measured at baseline and at weeks 2 and 4. At baseline, a structured clinical interview for axis I disorders (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was completed to assess for any undiagnosed psychiatric disorders. Mood was rated at baseline and at weeks 2 and 4 using the Zung Depression Rating Scale, Young Mania Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression Scale, and the Global Assessment of Function Scale. MEASUREMENTS AND MAIN RESULTS: After oral administration, SAMe levels were significantly elevated. Slight, likely insignificant, elevations in serum formaldehyde levels were detected in three subjects. No subject exhibited elevated homocysteine levels during SAMe treatment. One subject developed a transient mixed manic state with suicidal ideation within 2 weeks of starting SAMe; she recovered fully within 3 days of discontinuing the compound. CONCLUSION: Oral dosages of 1600 mg/day of SAMe appear to be significantly bioavailable and nontoxic, at least regarding toxic methylated metabolites and homocysteine. However, the risk of mania in vulnerable individuals remains a serious concern.

Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits.

OBJECTIVE: Since use of multiple drugs to treat psychiatric patients is increasing, and research on this practice is rare, the authors carried out a retrospective case-control study of multiple versus single antipsychotic treatment in psychiatric inpatients. METHOD: Inpatient treatment groups receiving either antipsychotic monotherapy or polytherapy were matched in terms of age, sex, diagnostic category, and admission clinical ratings (Global Assessment of Functioning [GAF] and Clinical Global Impression [CGI]), which yielded 70 subject pairs. They were compared in terms of total chlorpromazine-equivalent daily dose, changes in total daily dose, length of hospitalization, incidence of adverse effects, and changes in clinical ratings (CGI, GAF, Positive and Negative Syndrome Scale score) between admission and discharge. RESULTS: Initial doses were closely similar at admission for both treatment groups, but the median total final antipsychotic dose was 78% higher for those receiving antipsychotic polytherapy versus monotherapy. Also, median length of stay in the hospital was 55% (8.5 days) longer, and risk of adverse effects was 56% higher with polytherapy, whereas clinical improvement scores were similar (within 11%) for both treatments. CONCLUSIONS: Short-term treatment with multiple antipsychotics was associated with major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit. These findings require further testing in controlled prospective studies.