Objective: Addressing negative symptoms of schizophrenia can be a treatment challenge. This 56-week post hoc analysis examined effects of combined olanzapine and samidorphan (OLZ/SAM) on negative symptoms. Methods: Adults with acute schizophrenia who received 4 weeks of OLZ/SAM, olanzapine, or placebo and initiated a subsequent 52-week open-label OLZ/SAM extension study (conducted 1/2016-6/2018) were included. Data were pooled across lead-in study (conducted 12/2015- 6/2017) treatment arms. Negative symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS) Marder Negative Factor score. Changes from baseline were evaluated overall, in patients with prominent negative symptoms (defined as baseline Marder Negative Factor score ≥24), and in patients with predominant negative symptoms/low positive symptoms (baseline Marder Negative Factor score ≥24 and PANSS Mohr Positive Factor score ≤19). Results: Patients (n=281) had mean (SD) PANSS Total and Marder Negative Factor scores of 101.7 (11.1) and 25.2 (4.6), respectively, at baseline. Least squares (LS) mean (SE) change from baseline in Marder Negative Factor score at week 56 was -8.2 (0.35). Among patients with prominent negative symptoms (baseline mean, 27.8; n=186), LS mean (SE) change in Marder Negative Factor score was -9.6 (0.44) at week 56. Similar improvement at week 56 was observed for patients with predominant negative symptoms (n=48; LS mean [SE] change, -8.9 [0.78]). Conclusion: In this 56-week post hoc analysis of patients initially experiencing an acute exacerbation of schizophrenia, OLZ/SAM was associated with significant and durable improvement in negative symptoms of schizophrenia, overall and among both patients with prominent and predominant negative symptoms. Trial Registration: ClinicalTrials.gov identifiers NCT02634346 (https:// clinicaltrials.gov/study/NCT02634346) and NCT02669758 (https://clinicaltrials. gov/study/NCT02669758).

Objective: To evaluate weight change with a combination of olanzapine and samidorphan (OLZ/SAM) versus olanzapine by pooling data across clinical studies. Methods: This study was an individual patient data (IPD) meta-analysis of clinical trial data. Data Sources and Study Selection: EMBASE, MEDLINE, and PsycInfo were searched for randomized clinical trials (≥12 weeks) in adults with schizophrenia or bipolar I disorder in which weight change from baseline was the primary or secondary end point. Search results were reviewed for eligible studies. Participants: Patients receiving daily OLZ/SAM (olanzapine 5-20 mg + samidorphan 10 mg) or olanzapine (5-20 mg) who underwent ≥1 postbaseline weight assessment by week 12 were included. Outcomes: The primary outcome was percent change in body weight at week 12. Secondary outcomes were proportions of patients with ≥7% or ≥10% weight gain from baseline at week 12. Results: Overall, 1063 patients from 3 studies conducted between June 2013 and December 2021 were analyzed. At week 12, OLZ/SAM treatment was associated with a lower least squares mean (LSM) percent change in body weight from baseline (3.68%) vs olanzapine (5.43%) (LSM [SE] difference=-1.75% [.41]; 95% CI, -2.55 to -0.94). Fewer patients treated with OLZ/SAM gained ≥7% (23.9% vs 34.6%; odds ratio [OR] = 0.58; 95% CI, 0.043-0.79) or ≥10% (13.7% vs 20.4%; OR = 0.60; 95% CI, 0.42-0.88) of their baseline body weight at week 12. Conclusion: In this IPD meta-analysis, OLZ/SAM treatment was associated with less weight gain and reduced risk of reaching ≥7% or ≥10% gain in body weight versus olanzapine over 12 weeks.

Objective: Evaluate long-term safety, tolerability, and durability of the effect of olanzapine/samidorphan (0LZ/SAM) for up to 4 years in patients with schizophrenia, schizophreniform disorder, or bipolar I disorder (BD-I). Methods: This phase 3, multicenter, open-label, long-term extension (conducted June 2017 -September 2023) assessed 0LZ/SAM in patients completing the ENLIGHTEN clinical program. Patients received >= 2-4 years of additional treatment. Safety assessments included adverse event (AE) incidences and changes from baseline in body weight, waist circumference, and lipid/glycemic parameters. The durability of the effect was assessed using the Clinical Global Impressions -Severity (CGI-S) scale. Results: Of 524 patients enrolled, 523 received >= 1 dose of 0LZ/SAM. Of these, 460 (88%) patients had schizophrenia, 15 (3%) had schizophreniform disorder, and 48 (9%) had BD-I. Mean (SD) age was 35.1 (12.2) years. Mean (SD) 0LZ/SAM exposure was 652.4 (454.8) days. Of 451 patients eligible for 2 years of treatment, 242 (53.7%) received it; of 335 patients eligible for 4 years, 109 (32.5%) received it. The most common AEs were weight increased (9.8%), headache (7.1%), anxiety (6.1%), insomnia (5.9%), somnolence (5.9%), nausea (5.7%), and weight decreased (5.7%). At 2 years, mean (SD) body weight change was 0.84 (6.84) kg; waist circumference change was -0.56 (6.24) cm. At 4 years, mean (SD) body weight change was 2.65 (8.12) kg; waist circumference change was 1.37 (8.65) cm. Changes in lipid/glycemic parameters were minimal. CGI-S scores remained stable. Conclusion: 0LZ/SAM maintained symptom control with a long-term safety profile over 4 years consistent with that of prior studies.

This review article describes why and how aripiprazole was formulated as aripiprazole lauroxil (AL), an extended-release antipsychotic agent that is delivered via a long-acting injectable formulation, and the clinical trials investigating its use. AL was formulated as an inactive prodrug of aripiprazole using LinkeRx® technology to provide a prolonged-release antipsychotic with predictable dissolution over time. The resulting AL pharmacokinetic profile is characterized by a long half-life and little peak-to-trough aripiprazole concentration variability across dosing intervals of every 1 month, every 6 weeks, and every 2 months. The prodrug technology was further refined to develop an AL initiation formulation with a somewhat faster release of aripiprazole, eliminating the need for a 21-day oral aripiprazole supplementation period. With this initiation formulation, AL treatment can be started in 1 day. Key AL characteristics, including pharmacokinetic profile and efficacy, safety, and tolerability data, are presented. In addition to the efficacy and safety established in clinical trials of oral aripiprazole, a placebo-controlled 12-week pivotal study investigated AL 441 mg and 882 mg monthly regimens in patients with acutely exacerbated schizophrenia and provided efficacy and safety information that led to US Food and Drug Administration approval in 2015. Thereafter, studies established the long-term safety profile and durability of the AL treatment effect. The 25-week, active-controlled ALPINE study evaluated the feasibility and effectiveness of AL 1064 mg every 2 months, initiated using the 1-day AL initiation regimen, without further oral supplementation beyond day 1, in patients hospitalized for acutely exacerbated schizophrenia with subsequent transition to outpatient care. In short-term and long-term studies, AL was generally well tolerated at initiation and during acute and maintenance treatment. Pharmacokinetic, efficacy, and safety characteristics support the use of AL across inpatient and outpatient treatment settings.

IntroductionQualitative research methods can be used to obtain a deeper understanding of patient experience by collecting information in the patients’ own words about their encounters, perspectives, and feelings. In this study, patients with schizophrenia were interviewed to capture their voice and to complement the quantitative data typically obtained in clinical trials.MethodsSemi-structured exit interviews were conducted with 41 patients who completed or prematurely discontinued from a phase 3, open-label trial (NCT02873208). The interview guide included open-ended questions on current and prior disease burden, symptoms, quality of life, and treatment experiences. Steps taken to reduce interview stress and secure the validity of data included interviewer sensitivity training specific to mental health conditions and schizophrenia, use of in-person interviews whenever possible and use of videoconferencing for remote interviews to promote trust and comfort, and working closely with clinical site staff to identify patient eligibility and willingness to participate. Transcripts based on audio recordings were content coded and analyzed using thematic analysis; a post-hoc quantitative content analysis was conducted.ResultsPatients reported that the symptoms of schizophrenia negatively impacted their work, relationships, self-esteem, emotional health, and daily activities. Most patients had positive experiences with medications that alleviated hallucinations, depression, and anxiety. However, side effects of medications were associated with negative impacts on physical, emotional, behavioral, and cognitive health. Lack of energy/drowsiness, weight gain, mood changes, and involuntary movements were the most common side effects reported with the use of antipsychotic medications. Patients reported unmet treatment needs related to better symptom control and to improved social and physical functioning.ConclusionCollection of qualitative information within a schizophrenia clinical development process provides value and insights into patients’ views on burden of illness, experiences with previous medications, and experiences following participation in a clinical trial and can inform design for future studies.

Abstract 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.

Objective: Patients with early-phase schizophrenia or bipolar I disorder (BD-I) are at greater risk for antipsychotic-associated weight gain. This 12-week, randomized, double-blind study conducted between June 2017 and December 2021 evaluated weight effects of combination olanzapine and samidorphan (OLZ/SAM) versus olanzapine in early-phase illness.Methods: Young adults (16-39 years) with DSM-5 schizophrenia, schizophreniform disorder, or BD-I, < 4 years since symptom onset, body mass index < 30 kg/m2, and < 24 weeks' cumulative antipsychotic exposure were randomized to OLZ/SAM (5-20/10 mg/d) or olanzapine (5-20 mg/d). Primary endpoint was percent change from baseline body weight at week 12. Secondary endpoints, tested hierarchically, were proportions of patients with ≥ 10% or ≥ 7% weight gain, waist circumference change, and Clinical Global Impressions-Severity (CGI-S) change.Results: Of 428 patients (OLZ/SAM, n = 213; olanzapine, n = 215), 408 had ≥ 1 postbaseline weight assessment and were analyzed. Percent weight change was significantly lower with OLZ/SAM versus olanzapine (4.91% vs 6.77%; least-squares mean [LSM] [SE] difference, -1.87% [0.75]; P = .012). Although fewer patients treated with OLZ/SAM had ≥ 10% weight gain, the difference was not statistically significant versus olanzapine (21.9% vs 30.4%, respectively; OR = 0.64; 95% CI = 0.39 to 1.05); hierarchical testing precluded further statistical evaluation of secondary endpoints. Proportions of patients with ≥ 7% weight gain (33.1% vs 44.8%; OR = 0.61, 95% CI = 0.39 to 0.94) and waist circumference change (2.99 vs 3.90 cm; LSM [SE] difference, -0.92 cm [0.58]; 95% CI = -2.06 to 0.22) favored OLZ/SAM. LSM (SE) CGI-S change with OLZ/SAM was -0.82 (0.06). OLZ/SAM and olanzapine had similar safety profiles, including small, similar metabolic parameter changes.Conclusions: In patients with early-phase schizophrenia, schizophreniform disorder, or BD-I, OLZ/SAM treatment resulted in less weight gain versus olanzapine.Trial Registration: ClinicalTrials.gov identifier: NCT03187769.

Dear Editor:A recent systematic review by Laguado and Saklad highlighted the importance of addressing olanzapine-associated weight gain.1 While highly efficacious, olanzapine use has been limited by its propensity to cause significant weight gain. The authors considered the role of opioid antagonists in this setting by reviewing efficacy and safety data from the clinical development program of combination olanzapine and samidorphan (OLZ/SAM), concluding in part that samidorphan effectively mitigates olanzapine-associated weight gain. We provide comments on the authors' methodology, as their conclusions may underestimate weight gain mitigation with OLZ/SAM.We suggest that a more precise estimate of OLZ/SAM's weight mitigation benefit would be obtained by (1) analyzing separately the studies that were of sufficient duration to detect differences in weight gain from those that were not, and (2) weighting these study results before calculating the mitigating effect of OLZ/SAM on olanzapine-associated weight gain.Trials by Martin et al, Correll et al, and Kahn et al were of adequate duration (12, 24, and 12 weeks, respectively) to evaluate the targeted differences in treatment-associated weight gain between OLZ/SAM and olanzapine.2-4 In each of these studies, weight gain trajectories for OLZ/SAM and olanzapine were initially similar but then diverged between 4 and 6 weeks of treatment, after which weight gain plateaued in OLZ/SAM-treated patients but continued to increase over time in olanzapine-treated patients. Silverman et al and Potkin et al conducted 3-week and 4-week studies, respectively, that were not of suitable duration to use in calculations of the weight mitigation benefit of OLZ/SAM.5,6Additionally, to obtain a more precise estimate of OLZ/SAM's weight mitigation benefit, the results should be weighted by the sample size of each study. Aggregating outcomes of different studies without considering differences in sample sizes can lead to inaccurate estimates of an intervention's magnitude of effect7,8 that are avoided by using accepted weighting procedures.7Furthermore, in discerning the true weight mitigation benefit of OLZ/SAM, only studies combining 10 mg of samidorphan with olanzapine are of relevance, as 10 mg is the only dose approved by the United States Food and Drug Administration for use in OLZ/SAM. Last, the description of the number needed to harm (NNH) may be misinterpreted by readers as harm associated with the use of OLZ/SAM because the authors did not present NNH as a negative value. By convention, the use of either a negative NNH or the number needed to treat (NNT), rather than NNH, would communicate more clearly the treatment benefit (ie, the weight-mitigating effect of treatment with OLZ/SAM compared with olanzapine).Given these considerations and based on studies that were of sufficient duration and designed to evaluate weight gain in patients with serious mental illness, OLZ/SAM's weight mitigation benefit versus olanzapine ranged from −1.33 to −1.9 kg in trials lasting 12 to 24 weeks2-4; however, the benefit may be greater over longer treatment durations because weight gain plateaus with OLZ/SAM treatment but continues to increase with olanzapine treatment.In summary, the methodologies used by the authors may have underestimated the weight-mitigating effect of OLZ/SAM on olanzapine-associated weight gain.1 To assess the magnitude of this effect accurately, only studies of duration sufficient for assessing this outcome should be included, results of included studies should be weighted, and estimates of effect size should be calculated. Finally, while olanzapine-associated weight gain tends to continue over the long-term, results from open-label studies suggest that weight gain stabilizes during long-term OLZ/SAM treatment.9,10 Further characterizing the weight gain mitigation effect provided by OLZ/SAM versus olanzapine during treatment courses longer than 6 months' duration may be beneficial to clinicians and to patients, many of whom require long-term and continuous antipsychotic treatment.11

Abstract Background Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population. Methods PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5. Results Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42–8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05–12.65) vs 5.51 (4.73–6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration. Conclusions In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

AbstractBackground and HypothesesWeight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine.Study DesignThis phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids.ResultsAfter 24 weeks’ treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, −2.63 mm Hg; 95% CI: −4.78, −0.47), diastolic blood pressure (LSM difference, −0.75 mm Hg; 95% CI: −2.31, 0.80), and BMI (LSM difference, −0.65 kg/m2; 95% CI: −1.01, −0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia.ConclusionsOLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.

Background.How can psychiatrists best provide care in complex, sometimes overwhelming disasters? COVID-19 strained every aspect of health care to the breaking point, from finances to pharmaceutical supply lines. We can expect more challenges to prescribing in the future, as shown by recent hurricanes in Puerto Rico, fires in California, and ice storms in Texas. When medications become scarce or inaccessible, then clinicians need to make difficult prescribing decisions. We suggest that a culture of deprescribing, a systematic approach to reducing or simplifying medications, could be applied to awide variety of crises. Deprescribing is defined as the planned reduction of medications to improve patient health or to reduce side effects (see deprescribing.org). It has been used to reduce polypharmacy in geriatric and other complex populations. It provides evidence-based guidance for phasing out many classes of medications. It is part of the larger program to reduce waste in health care and to make pharmacy more rational. Disasters and resource scarcity, however, require a different approach. In contrast to routine care focused on individual patients, crisis standards of care (CSC) shift the clinical focus to the community. Instead of deprescribing guidelines for individual clinicians, CSC deprescribing would be national policies addressing shortages of important medications. We did a scoping review looking for studies of deprescribing in a crisis. Methods/Results. We extracted 1340 references in Google Scholar 2016 to 2021 using (deprescribing) AND (disaster OR crisis OR climate OR pandemic OR supply lines ). A scan of texts found 160 references matching our criteria, and only 19 of them addressed deprescribing as a strategy to strengthen health systems or providers in an emergency. Most of those were related to scarce supplies during COVID, and a few addressed the carbon impact of medications. We also reviewed related literatures on medication supply chain vulnerabilities, WHO Essential Medicines, and healthcare rationing. Implications.Deprescribing gained attention during the COVID pandemic, responding to both disrupted supply lines and improving patient safety.Writers concerned with climate change support deprescribing to reduce the carbon impact ofmedications. Deprescribing as crisis policy could help streamline national stockpiles, supply chains, and manufacturing. Education could make deprescribing second nature for clinicians, potentially decreasing stress and increasing flexibility in future emergencies. Barriers to deprescribing generally include cultural inertia, industry lobbyists, education, and malpractice fears. In a crisis, deprescribing guidelines could provide clinicians with confidence and flexibility while conserving scarce resources. Research is needed to evaluate deprescribing guidelines for crises, especially ensuring equity in how they reduce polypharmacy and save money. Funding. No funding Dose Patterns for Long-Term Deutetrabenazine Treatment in Patients With Tardive Dyskinesia by Baseline AIMS Item 8 Score Hadas Barkay, PhD, Stacy Finkbeiner, PhD, Amanda Wilhelm, PhD, Jessica Alexander, PhD, Nayla Chaijale, PhD and Mark Forrest Gordon, MD Teva Pharmaceuticals, Netanya, Israel, and Teva Pharmaceuticals, West Ches-

Abstract Background A combination of olanzapine and samidorphan (OLZ/SAM) that provides the efficacy of olanzapine while mitigating weight gain was recently approved by the FDA for the treatment of schizophrenia and bipolar I disorder. To improve communication of the OLZ/SAM benefit-risk profile, a structured framework was utilized. Methods The Benefit-Risk Action Team framework was used to evaluate OLZ/SAM, with analyses completed for each pivotal study. ENLIGHTEN-1 evaluated antipsychotic efficacy and safety. ENLIGHTEN-2 evaluated the weight profile of OLZ/SAM vs olanzapine. Benefit-risk outcomes were selected based on study outcome parameters, known risks of olanzapine and samidorphan, and public health importance. A subset of opioid antagonist risks was not assessed due to clinical trial exclusions; however, they were factored into the overall evaluation. Risk differences and confidence intervals were analyzed. Results In ENLIGHTEN-1, OLZ/SAM had a lower risk of psychiatric discontinuation and nonresponse to treatment compared with placebo; higher risks of hyperprolactinemia, weight gain (≥7%), sedation, and worsening of fasting triglycerides and glucose, and no difference for fasting total and LDL cholesterol, neutropenia, orthostatic hypotension, and movement disorders. In ENLIGHTEN-2, OLZ/SAM had reduced risks of weight gain and waist circumference increase compared to olanzapine along with similar risks of relapse and psychiatric discontinuation and no difference in metabolic worsening, neutropenia, hyperprolactinemia, orthostatic hypotension, sedation, and movement disorders. Discussion Based on this assessment, OLZ/SAM has comparable efficacy and a safety profile consistent with olanzapine, with reduced weight gain. A structured approach to assessing the benefit-risk profile of a product facilitates transparent evaluation and communication. Funding Alkermes, Inc.

Among patients with schizophrenia (SZ) and bipolar I disorder (BD-I) treated with second-generation antipsychotics (SGAs), clinically-significant weight gain (CSWG) and treatment interruptions (TIs) are challenges that may result in morbidity/mortality.CSWG and TIs were assessed among patients who initiated oral SGAs of moderate-to-high weight gain risk (no exposure to index SGAs/first-generation antipsychotics for =12 months) using medical records/claims (OM1 Data Cloud; January 2013-February 2020). Outcomes included CSWG (=7% increase in baseline weight) and TIs (switches [to SGAs of low weight gain risk/long-acting injectables] or discontinuations [no SGAs for >30 days]). Descriptive analyses included proportions of patients with CSWG and TIs, and median time to these outcomes.Approximately three-quarters of patients were overweight/obese at baseline (SZ: N=8,174; BD-I: N=9,142). Within 3 months of SGA initiation, 12% of all patients experienced CSWG. For patients on treatment with index SGAs for >6 months (SZ: 29%; BD-I: 27%), 28% (SZ) and 30% (BD-I) experienced CSWG during follow-up. Median time to CSWG was 14 weeks. CSWG results were numerically similar among patients with SZ and BD-I.Over 96% of patients had TIs during follow-up (median time of 12 [SZ] and 13 [BD-I] weeks). Among patients with CSWG and subsequent TIs and weight measurements, 74% did not return to baseline weight after interrupting treatment; the remainder returned to baseline weight with median times of 38 (SZ) and 39 (BD-I) weeks. Results suggest that most patients with CSWG do not return to baseline weight after stopping treatment with oral SGAs of moderate-to-high weight gain risk.Funding. Alkermes, Inc.

AbstractObjectivesOlanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.MethodsThe OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.ResultsOLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.ConclusionData across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.FundingAlkermes, Inc.

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine's unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.

[This corrects the article DOI: 10.2147/NDT.S313840.].