Remitted psychotic depression (MDDPsy) has heterogeneity of outcome. The study's aims were to identify subgroups of persons with remitted MDDPsy with distinct trajectories of depression severity during continuation treatment and to detect predictors of membership to the worsening trajectory.

One hundred and twenty-six persons aged 18–85 years participated in a 36-week randomized placebo-controlled trial (RCT) that examined the clinical effects of continuing olanzapine once an episode of MDDPsy had remitted with sertraline plus olanzapine. Latent class mixed modeling was used to identify subgroups of participants with distinct trajectories of depression severity during the RCT. Machine learning was used to predict membership to the trajectories based on participant pre-trajectory characteristics.

Seventy-one (56.3%) participants belonged to a subgroup with a stable trajectory of depression scores and 55 (43.7%) belonged to a subgroup with a worsening trajectory. A random forest model with high prediction accuracy (AUC of 0.812) found that the strongest predictors of membership to the worsening subgroup were residual depression symptoms at onset of remission, followed by anxiety score at RCT baseline and age of onset of the first lifetime depressive episode. In a logistic regression model that examined depression score at onset of remission as the only predictor variable, the AUC (0.778) was close to that of the machine learning model.

Residual depression at onset of remission has high accuracy in predicting membership to worsening outcome of remitted MDDPsy. Research is needed to determine how best to optimize the outcome of psychotic MDDPsy with residual symptoms.

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.

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.

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.

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.

Clinically significant weight gain (CSWG) is associated with increased morbidity and mortality. This study describes CSWG and comorbidities observed in patients with bipolar I disorder (BD-I) and schizophrenia (SZ) after initiating select second-generation antipsychotics (SGAs).

Percent change in weight, CSWG (=7% weight increase), and incident comorbidities within 12 months of treatment were assessed among patients initiating oral SGAs of moderate-to-high weight gain risk using medical records/claims (OM1 Real-World Data Cloud; January 2013-February 2020). Oral SGAs included clozapine (SZ), iloperidone (SZ), paliperidone (SZ), olanzapine, olanzapine/fluoxetine (BD-I), quetiapine, and risperidone. Outcomes were stratified by baseline body mass index and reported descriptively.

Among patients with BD-I (N = 9142) and SZ (N = 8174), approximately three-quarters were overweight/obese at baseline. During treatment (mean duration = 30 weeks), average percent weight increase was 3.7% (BD-I) and 3.3% (SZ). Average percent weight increase was highest for underweight/normal weight patients (BD-I = 5.5%; SZ = 4.8%), followed by overweight (BD-I = 3.8%; SZ = 3.4%) and obese patients (BD-I = 2.7%; SZ = 2.3%). Within 3 months of treatment, 12% of all patients experienced CSWG. A total of 11.3% (BD-I) and 14.7% (SZ) of patients developed coronary artery disease, hypertension, dyslipidemia, or type 2 diabetes within 12 months of treatment; development of comorbidities was highest among overweight/obese patients and those with CSWG.

Patients who were underweight/normal weight at baseline had the greatest percent change in weight during treatment. Increased comorbidities were observed within 12 months of treatment, specifically among overweight/obese patients and those with CSWG. The magnitude of weight gain and development of comorbidities were similar for patients with BD-I and SZ.

Alkermes, Inc.