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.

Weight changes before and after lurasidone treatment: a real-world analysis using electronic health records.

BACKGROUND: Severe and persistent mental illnesses, such as schizophrenia and bipolar disorder, are associated with increased risk of obesity compared to the general population. While the association of lurasidone and lower risk of weight gain has been established in short and longer-term clinical trial settings, information about lurasidone's association with weight gain in usual clinical care is limited. This analysis of usual clinical care evaluated weight changes associated with lurasidone treatment in patients with schizophrenia or bipolar disorder. METHODS: A retrospective, longitudinal analysis was conducted using de-identified electronic health records from the Humedica database for patients who initiated lurasidone monotherapy between February 2011 and November 2013. Weight data were analyzed using longitudinal mixed-effects models to estimate the impact of lurasidone on patient weight trajectories over time. Patients' weight data (kg) were tracked for 12-months prior to and up to 12-months following lurasidone initiation. Stratified analyses were conducted based on prior use of second-generation antipsychotics with medium/high risk (clozapine, olanzapine, quetiapine, or risperidone) versus low risk (aripiprazole, ziprasidone, first-generation antipsychotics, or no prior antipsychotics) for weight gain. RESULTS: Among the 439 included patients, the mean age was 42.2 years, and 69.7% were female. The average duration of lurasidone treatment across all patients was 55.2 days and follow-up duration after the index date was 225.1 days. The estimated impact of lurasidone on weight was - 0.77 kg at the end of the 1-year follow-up. Patients who had received a prior second-generation antipsychotic with medium/high risk for weight gain were estimated to lose an average of 1.68 kg at the end of the 1-year follow-up. CONCLUSIONS: Lurasidone was associated with a reduction in weight at 1 year following its initiation in patients with schizophrenia or bipolar disorder. Stratified analyses indicated that weight reduction was more pronounced among patients who had received second-generation antipsychotics associated with a higher risk of weight gain prior to lurasidone treatment. These findings are consistent with the results of prior short- and long-term prospective studies and suggest that lurasidone is associated with low risk for weight gain in patients with schizophrenia or bipolar disorder.

Forgotten but not gone: new developments in the understanding and treatment of tardive dyskinesia.

The broad use of atypical antipsychotics was expected to dramatically reduce the prevalence and incidence of tardive dyskinesia (TD), but data show that TD remains an important challenge due the persistent nature of its symptoms and resistance to numerous treatment modalities, including antipsychotic discontinuation. Recent insights on genetic risk factors and new concepts surrounding pathophysiology have spurred interest in the possibility of targeted treatment for TD. As will be reviewed in this article, the number of evidence-based strategies for TD treatment is small: only clonazepam, amantadine, ginkgo biloba extract, and the vesicular monoamine transporter 2 (VMAT2) inhibitor tetrabenazine have compelling data. Using new insights into the metabolism of tetrabenazine and the properties of its active metabolites, 2 modifications of tetrabenazine have been synthesized to improve the kinetic profile, and are currently involved in double-blind placebo controlled studies aimed at U.S. Food and Drug Administration (FDA) regulatory approval. The possible availability of these new agents, deuterated tetrabenazine and valbenazine, significantly widens the range of treatment choices for patients with TD. For clinicians with patients at risk for TD due to dopamine antagonist exposure, experience has shown that the problem of TD will be an ongoing issue in modern psychiatry, and that an appreciation of new developments in the pathophysiology of, risk factors for, and treatment of TD is crucial to managing this condition.

A rational approach to employing high plasma levels of antipsychotics for violence associated with schizophrenia: case vignettes.

Forensic psychiatric settings contain a high prevalence of treatment-resistant violent schizophrenia patients. Clozapine therapy has the most robust data for the management of violence in patients with schizophrenia, but for those who cannot tolerate or refuse clozapine, high-dose antipsychotic treatment to high achieve high plasma levels remains a viable option despite limited evidence for efficacy in controlled trials. This article enumerates rational guidelines for employing high plasma level strategies, emphasizing the appropriate interpretation of, and reaction to high plasma antipsychotic levels in these treatment resistant patients, and the need to push treatment to the limits of tolerability or clinical response.

An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.

Understanding depot antipsychotics: an illustrated guide to kinetics.

Long-acting injectable (LAI) antipsychotics can have considerable advantages over oral medications for the management of patients with schizophrenia. Despite the high prevalence of treatment nonadherence with oral pharmacotherapy, LAI antipsychotics are significantly underutilized in this patient population. The availability of newer LAI antipsychotic preparations combined with a resurgent interest in the use of typical antipsychotics has rekindled awareness of the value of LAI medications. This article is intended to provide a visual understanding of the various kinetic profiles of LAI antipsychotics to facilitate initiation and greater use of these agents.

"Meta-guidelines" for the management of patients with schizophrenia.

Guidelines for treating various conditions can be helpful in setting practice standards, but the presence of several sets of guidelines from different countries, experts, and settings, written at different times, can also create confusion. Here we provide a "guideline of guidelines" for the treatment of schizophrenia, or "meta-guidelines, which not only reconcile the various existing standards but also update them to include the use of several newer agents, most of which were marketed following the publication of existing standards.

Making sense of norclozapine levels: 3 clinical axioms.

Laboratories commonly provide norclozapine concentrations when a plasma clozapine level is requested, but the appropriate use of this information for the treatment of individuals with schizophrenia is not always clear. Particularly vexing is the fact that norclozapine possesses pharmacological properties that are distinct from its parent compound and which contribute to clozapine's efficacy signal, yet the literature focuses primarily on the association of clozapine levels with symptomatic improvement. The purpose of this brief article is to highlight findings with respect to the need to track norclozapine levels, or the ratio of clozapine/norclozapine plasma levels, to optimize efficacy among inadequate responders to clozapine treatment. In addition, there will be a discussion of the specific type of information provided by the clozapine/norclozapine ratio on clozapine's clearance, and how this ratio is sometimes misinterpreted. There is clinical value from to be derived from norclozapine levels and the clozapine/norclozapine ratio for schizophrenia management, and the principles governing use of this information will be distilled into 3 succinct axioms to aid clinicians in managing their clozapine-treated patients with schizophrenia.

Increased Metabolic Potential, Efficacy, and Safety of Emerging Treatments in Schizophrenia.

Patients with schizophrenia experience a broad range of detrimental health outcomes resulting from illness severity, heterogeneity of disease, lifestyle behaviors, and adverse effects of antipsychotics. Because of these various factors, patients with schizophrenia have a much higher risk of cardiometabolic abnormalities than people without psychiatric illness. Although exposure to many antipsychotics increases cardiometabolic risk factors, mortality is higher in patients who are not treated versus those who are treated with antipsychotics. This indicates both direct and indirect benefits of adequately treated illness, as well as the need for beneficial medications that result in fewer cardiometabolic risk factors and comorbidities. The aim of the current narrative review was to outline the association between cardiometabolic dysfunction and schizophrenia, as well as discuss the confluence of factors that increase cardiometabolic risk in this patient population. An increased understanding of the pathophysiology of schizophrenia has guided discovery of novel treatments that do not directly target dopamine and that not only do not add, but may potentially minimize relevant cardiometabolic burden for these patients. Key discoveries that have advanced the understanding of the neural circuitry and pathophysiology of schizophrenia now provide possible pathways toward the development of new and effective treatments that may mitigate the risk of metabolic dysfunction in these patients. Novel targets and preclinical and clinical data on emerging treatments, such as glycine transport inhibitors, nicotinic and muscarinic receptor agonists, and trace amine-associated receptor-1 agonists, offer promise toward relevant therapeutic advancements. Numerous areas of investigation currently exist with the potential to considerably progress our knowledge and treatment of schizophrenia.