Depot antipsychotics: Where do we stand?

BACKGROUND: Nonadherence to medication is a major problem for patients with schizophrenia. To counter this problem, pharmaceutical companies began developing depot antipsychotics. Although there are currently 5 first-generation and 6 second-generation depot antipsychotics available worldwide, many physicians are still reluctant to use this category of drug initially. This review provides the latest information about the use of depot antipsychotics in schizophrenia treatment as well as several studies in support of depot antipsychotic use as first-line treatment for patients with schizophrenia. METHODS: A systematic review of 4 milestone schizophrenia studies was performed to provide an aggregate analysis of the history and use of depot antipsychotics. Results and findings from several clinical trials--the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), European First Episode Schizophrenia Trial (EUFEST), A Comparison of Long-Acting Injectable Medications for Schizophrenia (ACLAIMS), and Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE)--were summarized to provide more information on the development and evolution of depot antipsychotics, common factors that contribute to nonadherence, and guidelines for each long-acting injectable currently available. RESULTS: The CATIE schizophrenia study revealed a 74% rate of discontinuation of oral antipsychotics within 6 months of use. Similar findings from the EUFEST study indicated that 42% of participants discontinued oral medications after 12 months of use. The ACLAIMS study reported no statistically significant difference in efficacy failure rate between haloperidol decanoate and paliperidone palmitate. The PRIDE study found that first hospitalization or arrest was 43% higher among patients in the oral antipsychotic group vs the depot group during the study. CONCLUSIONS: This review provides clinical evidence to support the use of depot formulations as first-line treatment for patients with schizophrenia, which may improve adherence and thereby lower risk of relapse, suicide, rehospitalization, and incarceration.

Frontotemporal dementia mimicking bipolar disorder.

Frontotemporal dementia is a cause of behavioral disturbance that usually appears in individuals between 45 and 65 years of age. The authors present the case of a 65-year-old patient that illustrates how frontotemporal dementia can be misdiagnosed based on a behavioral pattern that suggests the presence of a primary mood disorder. Early accurate diagnosis of frontotemporal dementia and subsequent supportive measures can allow patients and families to make important decisions about business and legal affairs and how to spend remaining leisure time in the most meaningful and enjoyable way possible.

Effects of switching from olanzapine, quetiapine, and risperidone to aripiprazole on 10-year coronary heart disease risk and metabolic syndrome status: results from a randomized controlled trial.

PURPOSE: This study examined the clinical significance of switching from olanzapine, quetiapine, or risperidone to aripiprazole by examining changes in predicted risk of cardiovascular disease (CVD) according to the Framingham Risk Score (FRS) and metabolic syndrome status. FRS estimates 10-year risk of "hard" coronary heart disease (CHD) outcomes (myocardial infarction and coronary death) while metabolic syndrome is associated with increased risk of CVD, stroke, and diabetes mellitus. METHOD: Changes in FRS and metabolic syndrome status were compared between patients with BMI ≥ 27 and non-HDL-C ≥ 130 mg/dL randomly assigned to stay on stable current treatment (olanzapine, quetiapine, or risperidone) or switch to treatment with aripiprazole with 24 weeks of follow-up. All study participants were enrolled in a behavioral program that promoted healthy diet and exercise. RESULTS: The pre-specified analyses included 89 switchers and 98 stayers who had post-baseline measurements needed to assess changes. Least squares mean estimates of 10-year CHD risk decreased more for the switch (from 7.0% to 5.2%) than the stay group (from 7.4% to 6.4%) (p = 0.0429). The odds ratio for having metabolic syndrome (stay vs. switch) at the last observation was 1.748 (95% CI 0.919, 3.324, p = 0.0885). CONCLUSION: Switching from olanzapine, quetiapine, or risperidone to aripiprazole was associated with larger reductions in predicted 10-year risk of CHD than the behavioral program alone. The advantage of switching on metabolic syndrome was not statistically significant. The benefits of switching must be balanced against its risks, which in this study included more discontinuations of the study treatment but no significant increase in symptoms or hospitalizations.

Rational use of multiple medications in medicine and psychiatry: a dimensional perspective.

The authors propose a definition for rational multiple medication use (MMU). They then discuss how levels of diagnostic sophistication, ranging from symptomatic to syndromic to pathophysiologic to pathoetiologic, affect the ability to use multiple medications rationally. Based on this concept of diagnostic sophistication, MMU can be conceptualized dimensionally. Thus, MMU ranges from highly evolved and substantially evidence-validated approaches based on an understanding of the pathophysiological and pathoetiological nature of a disease (e.g., anti-retroviral treatment for HIV, multi-modal treatment of various malignancies), to those based on an understanding of the pathophysiology of an illness (e.g., various treatment combinations used to treat Parkinson's disease), to less evolved or less evidence-based medication combinations based on a syndromic diagnosis (e.g., such as are often used to treat bipolar disorder). By better understanding the principles involved in rational MMU, clinicians can optimize the treatment they provide their patients. (Journal of Psychiatric Practice 2013;19:54-61).

A case of psychosis after use of a detoxification kit and a review of techniques, risks, and regulations associated with the subversion of urine drug tests.

CONTEXT: The practice of drug testing in the workplace has been adopted for US federal government employees, and many state and local governments as well as private businesses have followed suit. However, a parallel industry dedicated to subverting the results of urine drug testing has emerged with little or no regulation. EVIDENCE ACQUISITION: First, the case of a 19-year-old man who developed psychosis after the use of a detoxification kit is presented. Second, a review of the existing literature on the techniques, risks, and regulations associated with the use of drug tampering kits is provided. PubMed, Cochrane Database, and Google Scholar were searched using the keywords UDS, urine toxicology, pass the drug test, and clean UA, with no restrictions on publication date. Case reports, letters to the editor, and original research and review articles in multiple languages were reviewed, as were federal regulations and acts on the topic. The search yielded 4,082 results, of which 49 articles were selected for relevance. Some articles were later omitted as they had cited the original article and had nothing new to offer. RESULTS: Three commonly used tampering techniques are in vivo adulteration, urine substitution, and in vitro adulteration. Review of the literature regarding the risks involved with use of tampering kits yielded no results. In 1986, an executive order was issued requiring all federal employees to refrain from illicit drug use, and the 1988 Drug-Free Workplace Act precipitated the Substance Abuse and Mental Health Services Administration guidelines and their subsequent revisions. Recently, many states have made regulatory efforts to bring drug test defrauding under the ambit of law. CONCLUSIONS: Clinicians need to be aware of the tampering techniques and the possibility of false-negative urine drug tests. Cognizance of inherent risks involved with using these techniques including psychiatric and/or medical complications is also warranted. The manufacture, sale, and use of these products have little or no regulation by state or federal authorities, making them potentially dangerous and imposing new challenges in testing for abused drugs. The extent of use of these products and techniques is not known at this time and is an area that warrants further research.

The adjunctive use of metformin to treat or prevent atypical antipsychotic-induced weight gain: a review.

Patients with schizophrenia have a greater incidence of being overweight or obese compared with the general population. Such individuals are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidemia, and other metabolic derangements. As a result, frequent monitoring of weight and other metabolic parameters is recommended. In addition, several pharmacologic strategies to help prevent or reduce SGA-induced weight gain have been proposed. Despite this, clinicians often struggle to manage obesity and metabolic issues in such patients. Metformin has attracted attention as a potential treatment option because it is thought to result in weight reduction and improved glycemic control in obese patients with and without type 2 diabetes mellitus. This article focuses on relevant pharmacologic aspects of metformin and reviews currently available evidence on the use of metformin as an augmentation agent for the treatment or prevention of SGA-induced weight gain.

Mania possibly induced by desvenlafaxine.

A case is presented of the occurrence of an episode of mania apparently induced by desvenlafaxine, in a patient with a history of major depressive disorder and no apparent history of previous mania or hypo-mania. To our knowledge, this is the first such documented case with this new antidepressant. The discussion focuses on the concept of the bipolar spectrum, and how to view patients who have only become manic while taking antidepressants.

Duloxetine for the treatment of generalized anxiety disorder: a review.

Approximately 16 million people in the United States suffer from anxiety disorders alone, while another 12 million experience both anxiety and at least one other psychiatric condition. Generalized anxiety disorder (GAD) has lifetime prevalence rates between 5% and 6%. Treatment of GAD is aimed primarily at symptom reduction. Duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI), received Food and Drug Administration (FDA) approval for the treatment of GAD in 2007. This article reviews the pharmacologic profile and seminal clinical trials associated with the FDA indication of duloxetine for GAD. A literature search performed using PubMed with the keywords "duloxetine", "gad", "generalized anxiety disorder", and "venlafaxine XR" yielded 27 articles. We also focused on papers that pooled data from these seminal studies. Data on file from Eli Lilly were also reviewed, including data from the Eli Lilly website. Based on this search, duloxetine was found to be an FDA-approved treatment option for GAD that has been studied in several double-blind, placebo-controlled clinical trials. This review of duloxetine will help physicians to interpret clinical studies properly and also help them to make an informed decision about which patients are the most appropriate candidates for a trial of duloxetine.

Can hypnosis differentiate epileptic from nonepileptic events in the video/EEG monitoring unit? Data from a pilot study.

OBJECTIVE: An estimated 24% of patients referred to epilepsy clinics actually have nonepileptic seizures. Various procedures have been used to precipitate nonepileptic events. The goal of this study was to use hypnosis in seizure provocation and differentiation between epileptic and nonepileptic seizure events. METHODS: Fifty study participants were enrolled from the Via Christi Comprehensive Epilepsy Center's video/electroencephalography unit. Patients underwent the Hypnotic Induction Profile (HIP) to assess susceptibility to hypnosis. After completion of the HIP, participants underwent hypnosis by a physician trained to do so. They received a hypnotic suggestion to have a seizure. All seizure-like events were classified as either an epileptic, nonepileptic, or undetermined event based on whether or not the patient had abnormal EEG activity during the event. RESULTS: Of the 50 participants enrolled, 3 withdrew consent, resulting in 47 participants. Seven (15%) participants failed to have an event of any type and were classified as undetermined. Sixteen (34%) participants were classified as having epileptic seizure events, and 24 (51%) participants had nonepileptic events. Most participants were Caucasian (87%), female (57%), and unemployed (55%). HIP scores ranged from 0 to 10. Participants classified with nonepileptic scores had higher mean HIP scores (8.08, SD 2.483) than those diagnosed with epileptic seizures [5.94, SD 3.492, t(25)=2.126, P=0.044]. The sensitivity of eliciting a nonepileptic event during hypnosis was only 0.46, but the specificity was 0.88. CONCLUSION: Hypnosis may be considered as a method of seizure provocation. Events provoked by hypnotic suggestion were more likely than not to be nonepileptic events. However, the current study has moderate specificity and poor sensitivity. Seizures could not be induced in patients who did not also have spontaneous seizures. Additional methodologies for seizure provocation need to be explored.

Diurnal mood variation in outpatients with major depressive disorder.

BACKGROUND: Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features of major depressive disorder (MDD) according to the Diagnostic and Statistical Manual. This report used data from the sequenced treatment alternatives to relieve depression study to determine whether DMV was associated with treatment outcome to citalopram. METHODS: Two thousand eight hundred and seventy-five outpatients with nonpsychotic MDD were evaluated during a 14-week trial of the selective serotonin reuptake inhibitor citalopram. Participants were divided into three groups: those with "classic" DMV (early morning worsening), those with any form of DMV (morning, afternoon, or evening worsening), and those with no DMV. Participants with classic DMV and those with any form of DMV were compared to those with no DMV in terms of baseline sociodemographic and clinical characteristics, treatment outcomes, and treatment features. RESULTS: Minor baseline clinical characteristics and treatment feature differences were found between participants with and without DMV. Participants with classic morning DMV had slightly higher response rates than those without DMV. However, no differences were found in response or remission between either group of participants with DMV and those with no DMV. CONCLUSION: DMV does not appear to be associated with a unique prominent pattern of response to selective serotonin reuptake inhibitor treatment in patients with depression, and does not appear to be a serotonergically modulated process. Further evaluation is necessary to determine if this relationship holds true for dopaminergic and noradrenergic antidepressant agents, such as dual-acting agents or antidepressant medication combinations.

Response to a selective serotonin reuptake inhibitor (citalopram) in major depressive disorder with melancholic features: a STAR*D report.

OBJECTIVE: This study examined demographic and clinical correlates of DSM-IV major depressive disorder with melancholic features and assessed whether melancholic features were predictive of response to a selective serotonin reuptake inhibitor antidepressant. METHOD: Participants with major depressive disorder (N = 2875) at primary and specialty care sites who received the first step treatment with citalopram in the Sequenced Treatment Alternatives to Relieve Depression study were included. Patients were enrolled between July 2001 and April 2004. Melancholic features were ascribed by previously developed algorithms of telephone interview ratings prior to treatment. Demographics, clinical features, and treatment response were compared between those with and without melancholic features. RESULTS: The 23.5% of participants with melancholic features were characterized by higher severity scores, greater rates of previous suicide attempts and ratings of current suicidal risk, and more concurrent psychiatric comorbidity. Unadjusted remission rates for those with melancholic features were statistically significantly reduced in absolute terms by up to 8.4% compared to those without melancholic features, which is a 24.1% decrease in relative chance of remission (p < .0001). Following adjustments for between-group baseline differences, remission rates were no longer different. CONCLUSION: Melancholic features are associated with a significantly reduced remission rate with an SSRI. This effect appears to be accounted for by demographic and clinical features associated with melancholic features. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT0021528.

Challenging the established diagnosis in psychiatric practice: is it worth it?

A major source of clinical errors is inaccurate diagnosis. The authors stress the importance of a thorough work-up in establishing a reliable diagnosis and the need to challenge and correct erroneous diagnoses to avoid inadequate response, reduced adherence to treatment, medication errors, increased healthcare costs, unnecessary hospitalization, and other adverse outcomes. Four case reports are presented to illustrate common sources of psychiatric misdiagnosis: effects of switching several psychotropic agents simultaneously, confounding effects of systemic illness and/or substance abuse, poor communication among clinicians and between clinicians and patients, and excessive reliance on the expertise of specialists. In reviewing the cases, the authors focus on "red flags," such as lack of response to the current medication regimen despite adherence to treatment, that may be helpful in identifying diagnostic errors.

Diurnal mood variation in outpatients with major depressive disorder: implications for DSM-V from an analysis of the Sequenced Treatment Alternatives to Relieve Depression Study data.

OBJECTIVE: Diurnal mood variation (DMV) with early morning worsening is considered a classic symptom of melancholic features in The Diagnostic and Statistical Manual of Mental Disorders (DSM) as well as The International Classification of Diseases (ICD) criteria for somatic major depressive disorder (MDD). Using the unique opportunity afforded by the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study data, we examined whether DMV with afternoon or evening worsening, in addition to classic early morning worsening, was related to other symptom constructs to determine whether the exclusive reliance on morning worsening is justified in defining melancholic features. METHOD: Baseline demographic and clinical characteristics, as well as depressive symptoms, including DMV, were evaluated in 3744 outpatients with nonpsychotic MDD enrolled in the STAR*D study. RESULTS: DMV in at least one of the time periods was reported by 22.4% (N = 837) of the sample. Only 3.3% (N = 28) of these 837 patients with DMV attributed it to environmental factors. Of the 809 participants (96.7%) with DMV unrelated to environmental events, only 31.9% (N = 258) reported morning worsening, while 19.5% (N = 158) and 48.6% (N = 393) reported afternoon and evening worsening, respectively. Minimal distinctions in demographic characteristics, clinical features, and depressive symptoms were found between participants with morning worsening and those with either afternoon or evening worsening. More importantly, other melancholic symptom features were associated with DMV regardless of time of worsening. CONCLUSION: DMV was meaningfully related to other melancholia criteria regardless of when the DMV occurred. If replicated, these findings suggest that DMV as a component of melancholic features might be expanded to include any DMV, not simply early morning worsening.

Coadministration of nefazodone and desipramine: a pharmacokinetic interaction study.

OBJECTIVE: To determine the potential for pharmacokinetic interaction between nefazodone (NFZ), and desipramine (DMI). METHOD: A single center, open-label, multiple-dose, parallel-group pharmacokinetic trial conducted in 28 healthy male and female subjects. Group A received DMI 50 mg/day for 2 days followed by DMI 75 mg/day for the next 17 days. On Days 10-14, subjects also received 100 mg NFZ twice daily, and during Days 15-19, the NFZ dose was increased to 150 mg twice daily. Group B received 100 mg NFZ twice daily for 5 days followed by 150 mg NFZ twice daily for the next 14 days. On Days 11-12, subjects also received 50 mg DMI and during Days 13-19, the DMI dose was increased to 75 mg daily. Serial blood samples were collected for Group A and Group B. Plasma concentrations of NFZ and its metabolites, mCPP, hydroxynefazodone (OH-NFZ), and triazoledione, DMI, and the DMI metabolite, 2-hydroxydesipramine (2-OH-DMI) were determined. RESULTS: Pharmacokinetic analysis demonstrated that the addition of NFZ to DMI did not result in any significant changes in the AUC(0-12), Cmax, or tmax of either DMI or 2-OH-DMI. Addition of DMI to NFZ resulted in statistically significant increases of 40% in the AUC(0-12) and 42% in the Cmax of mCPP. A significant decrease in the AUC(0-12) (19%) of OH-NFZ also was observed. The increase in mCPP may be attributable to inhibition of mCPP metabolism by DMI. CONCLUSION: Overall, the combined administration of DMI and NFZ appeared to be safe and well tolerated in both treatment groups.