Olanzapine/samidorphan combination consistently mitigates weight gain across various subgroups of patients.

OBJECTIVE: A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2. METHODS: The multicenter, randomized, double-blind ENLIGHTEN-2 study (NCT02694328) included outpatients aged 18-55 years with a diagnosis of schizophrenia based on DSM-5 criteria, a body mass index (BMI) of 18 to 30 kg/m2, and stable body weight (self-reported change ≤5% for ≥3 months before study entry). Patients were randomized 1:1 to receive OLZ/SAM or olanzapine for 24 weeks. Co-primary endpoints (previously reported) were percent change in body weight and proportion of patients with at least 10% weight gain from baseline at week 24. Prespecified exploratory subgroup analyses by sex, age, self-reported race, and baseline BMI were conducted. RESULTS: At week 24, treatment with OLZ/SAM resulted in numerically less percent weight gain than with olanzapine across all subgroups evaluated. The proportion of patients with at least 10% weight gain was smaller in each subgroup treated with OLZ/SAM vs olanzapine. CONCLUSION: In these exploratory subgroup analyses from the ENLIGHTEN-2 study, weight-mitigating effects of OLZ/SAM vs olanzapine were observed consistently across patient subgroups and were in line with results from the overall study population.

Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Weight gain and comorbidities associated with oral second-generation antipsychotics: analysis of real-world data for patients with schizophrenia or bipolar I disorder.

BACKGROUND: Many second-generation antipsychotics (SGAs) are associated with weight gain and cardiometabolic effects. Antipsychotic-associated weight gain is linked to treatment interruptions, potentially increasing risk of relapse and hospitalization. This retrospective study assessed clinically significant weight gain (CSWG), treatment interruptions, and development of cardiometabolic conditions in patients with schizophrenia (SZ) or bipolar I disorder (BD-I) following initiation of oral SGAs with moderate to high weight gain risk. METHODS: Patients with no prior use of moderate to high weight gain risk oral SGAs were identified from patient-level medical/pharmacy claims and electronic medical records (January 2013-February 2020; OM1 Real-World Data Cloud). Those with ≥ 1 weight measurement in both the 12 months preceding and 3 months after SGA initiation (index date) were analyzed for continuous changes in weight, CSWG (≥ 7% and ≥ 10% increases from baseline), treatment interruptions (switches/discontinuations), and development of cardiometabolic conditions. RESULTS: Median follow-up times in the SZ (n = 8174) and BD-I (n = 9142) cohorts were 153.4 and 159.4 weeks, respectively; 45.5% and 50.7% were obese at baseline. Mean (SD) percent weight increase during treatment was 3.3% (7.2) and 3.7% (7.0) for patients with SZ and BD-I, respectively, and was highest for underweight/normal weight patients (SZ: 4.8% [8.1]; BD-I: 5.5% [8.7]). More than 96% had treatment interruptions during follow-up, primarily discontinuations. CSWG and treatment interruptions occurred within a median of 13 and 14 weeks after treatment initiation, respectively. Of patients with CSWG and treatment interruptions, approximately 75% did not return to baseline weight during follow-up. Among those without baseline cardiometabolic conditions, 14.7% and 11.3% of patients with SZ or BD-I, respectively, developed ≥ 1 condition over 12 months post-index. Incidence was generally highest among those who were overweight/obese at baseline and those who experienced CSWG. CONCLUSIONS: In this analysis of real-world data, both weight gain and treatment interruptions occurred early in treatment for patients with SZ or BD-I. Treatment-associated weight gain persisted despite switching or discontinuing index treatment. Additionally, cardiometabolic morbidity increased within 12 months of treatment initiation. Patients with SZ or BD-I are at greater risk than the general population for cardiometabolic conditions; weight gain associated with SGAs may exacerbate these health risks.

A survey of personnel and services offered in 32 outpatient US clozapine clinics.

BACKGROUND: Clozapine clinics can facilitate greater access to clozapine, but there is a paucity of data on their structure in the US. METHODS: A 23-item survey was administered to participants recruited from the SMI Adviser Clozapine Center of Excellence listserv to understand characteristics of clozapine clinics. RESULTS: Clozapine clinics (N = 32) had a median caseload of 45 (IQR = 21-88) patients and utilized a median of 5 (IQR = 4-6) interdisciplinary roles. The most common roles included psychiatrists (100%), pharmacists (65.6%), nurses (65.6%), psychiatric nurse practitioners (53.1%), and case managers (53.1%). The majority of clinics outreached to patients who were overdue for labs (78.1%) and had access to on-site phlebotomy (62.5%). Less than half had on call services (46.9%). CONCLUSIONS: In this first systematic description of clozapine clinics in the US, there was variation in the size, staffing, and services offered. These findings may serve as a window into configurations of clozapine teams.

Monitoring and improving antipsychotic adherence in outpatient forensic diversion programs.

Outpatient diversion programs present an opportunity for severely mentally ill defendants to receive psychiatric treatment and have alleged offenses dismissed by the court. Moreover, the successful completion of pretrial diversion is associated with fewer post-program arrest and jail days. The target patient population for such programs is typically people with schizophrenia spectrum disorders, but the care of such patients in outpatient settings presents challenges for monitoring treatment fidelity, specifically antipsychotic adherence, as low adherence rates are associated with increased rates of recidivism. Presented here is a review of evidence-based strategies that must be employed to track antipsychotic adherence in outpatient diversion programs, including pill counts, use of long-acting injectable antipsychotics, and determination of plasma antipsychotic levels to assess adherence and the adequacy of antipsychotic treatment. Antipsychotic therapy remains the foundation of schizophrenia treatment, but only through the use of all available modalities can clinicians maximize the odds that schizophrenia patients in pretrial diversion maintain psychiatric stability and successfully complete mental health court mandates.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus.

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Converting oral to long-acting injectable antipsychotics: a guide for the perplexed.

There has been increasing recognition that antipsychotic nonadherence is common across all stages of schizophrenia, starting from the first episode. Moreover, numerous meta-analyses of the existing literature indicate superiority of long-acting injectable (LAI) over oral antipsychotics when one adjusts for the greater illness severity and duration among patients in LAI antipsychotic trials. The increasing availability of LAI antipsychotic options has raised interest in converting patients from oral medication; however, the successful transition from oral to the comparable LAI antipsychotic requires an understanding of the current extent of antipsychotic exposure, the kinetics of the LAI preparation, and the expected plasma levels achieved by the LAI formulation. The purpose of this article is to provide, in a concise format, the essential information for converting patients to the LAI forms of haloperidol, fluphenazine, risperidone, paliperidone, olanzapine, and aripiprazole from the comparable oral medication, and how the use of plasma antipsychotic levels can be invaluable for this process.

Augmentation of phenelzine with aripiprazole and quetiapine in a treatment-resistant patient with psychotic unipolar depression: case report and literature review.

Irreversible monoamine oxidase inhibitor (MAOI) antidepressants have significant efficacy in treatment-resistant unipolar depression, but in some instances patients may not achieve remission. Among the adjunctive and augmentation strategies, certain second-generation antipsychotics (SGAs) have approval for inadequate responders to antidepressant therapy, including aripiprazole, brexpiprazole, and quetiapine, with lurasidone and the olanzapine/fluoxetine combination indicated for bipolar depression. Clinicians may eschew SGA options in part due to the limited literature on SGA-MAOI combinations, with only one published case involving aripiprazole, and none for olanzapine, lurasidone, or brexpiprazole. In addition to the limited publication history on SGA-MAOI treatment, clinicians may also be deterred by uncertainty regarding SGA mechanisms and the risk of serotonin syndrome or other adverse outcomes. This paper describes the case of a 54-year-old male with a history of psychotic unipolar depression treated with a combination of phenelzine, aripiprazole, and quetiapine, and reviews the 12 published cases of SGA-MAOI combination therapy with a focus on the pharmacological basis for serotonin syndrome, and the SGA mechanisms that should not be associated with a risk for this syndrome.