Trial of SAGE-217 in Patients with Major Depressive Disorder.

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. FINDINGS: This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference -12·2, 95% CI -20·77 to -3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). INTERPRETATION: In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. FUNDING: Sage Therapeutics, Inc.

Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.

BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.

A prospective study of cannabis use as a risk factor for non-adherence and treatment dropout in first-episode schizophrenia.

INTRODUCTION: Although several studies have reported on cannabis use and adherence for first episode of psychosis patients, the findings remain unclear as to whether cannabis use is a risk factor for poor adherence in young people with first-episode schizophrenia. This study was designed to follow patients' use of cannabis and adherence in a naturalistic setting during the first 12 months of treatment. It examines whether cannabis use is a risk factor for two distinct types of non-adherence: non-adherence to medication and treatment dropout. METHODS: Participants were 112 first-episode schizophrenia patients of diverse backgrounds at two community hospitals, enrolled in a study of differential effectiveness of two second-generation antipsychotic medications. Multiple indicators were used to assess cannabis use and adherence to medication. Patients were encouraged to continue in the study even after periods of treatment refusal or change from study to standardized medication. Study hypotheses were tested using Cox proportional hazards models with cannabis use as a time-varying covariate. RESULTS: After 12 months, 23 had dropped out and 37 had at some point been non-adherent to medication. Of 34 participants who used cannabis during treatment, 32 had a prior diagnosis of cannabis abuse/dependence and 30 were male. Independently of age, race, socioeconomic status, gender, site, and medication assignment, cannabis use significantly increased hazard of non-adherence by a factor of 2.4 (p<.001) and hazard of dropout by a factor of 6.4 (p=.034). CONCLUSION: Results indicate that cannabis use is a risk factor for non-adherence to medication and dropout from treatment. Treatment for first-episode schizophrenia may be more effective if providers address the issue of cannabis use with patients throughout the early years of treatment, especially for those with existing cannabis abuse/dependence.

Volumetric and shape analysis of the thalamus in first-episode schizophrenia.

Thalamic abnormalities have been implicated in the pathogenesis of schizophrenia, although the majority of studies used chronic samples treated extensively with antipsychotics. Moreover, the clinical and neuropsychological correlates of these abnormalities remain largely unknown. Using high-resolution MR imaging and novel methods for shape analysis, we investigated thalamic subregions in 35 (25 M/10 F) first-episode schizophrenia patients compared with 33 (23 M/10 F) healthy volunteers. The right and left thalami were traced bilaterally on coronal brain slices and volumes were compared between groups. In addition, regional abnormalities were identified by comparing distances, measured from homologous thalamic surface points to the central core of each individual's surface model, between groups in 3D space. Patients had significantly less total thalamic volume compared with healthy volunteers. Statistical mapping demonstrated most pronounced shape abnormalities in the pulvinar; however, estimated false discovery rates in these regions were sizable. Smaller thalamus volume was significantly correlated with worse overall neuropsychological functioning and specific deficits were observed in the language, motor, and executive domains. There were no significant associations between thalamus volume and positive or negative symptoms. Our findings suggest that thalamic abnormalities are evident at the onset of a first episode of schizophrenia prior to extensive pharmacologic intervention and that these abnormalities have neuropsychological correlates.