Michael E. Thase

Importance: Few pharmacotherapies are approved for treatment-resistant depression, and many patients do not achieve remission following treatment with those therapies. Objective: To examine the efficacy and safety of single-day treatment with a synthetic formulation of inhaled mebufotenin (GH001) vs placebo in patients with treatment-resistant depression. Design, Setting, and Participants: This was a 7-day, randomized, double-blind, placebo-controlled phase 2b trial with a 6-month open-label extension phase conducted at 16 sites in Europe from May 2023 to March 2025. Adult patients aged 18 to 64 years with treatment-resistant depression, defined as nonresponse to 2 to 5 oral antidepressant treatments, with current episode duration of up to 2 years were included. Of 128 assessed for eligibility, 81 were randomized and completed the placebo-controlled period of the trial. Interventions: Patients were randomly assigned 1:1 to receive an individualized dosing regimen of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo individualized dosing regimen on a single day (day 1). Main Outcomes and Measures: The primary efficacy end point was the change from baseline to day 8 in Montgomery-Åsberg Depression Rating Scale total score (range, 0-60; higher scores indicate greater severity of depression), comparing GH001 with placebo. Secondary end points included remission (Montgomery-Åsberg Depression Rating Scale score ≤10) at day 8. Results: Among the 81 patients randomized to GH001 (n = 40) or placebo (n = 41), the mean (SD) age was 41.6 (11.4) years and 43.9 (10.9) years and 24 (60.0%) and 22 (53.7%) were female, respectively. Change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 was significantly greater for GH001 vs placebo (least squares mean difference [SE], −15.5 [1.7]; P < .001; effect size, −2.0). Day 8 remission rates were 23/40 (57.5%) with GH001 and 0/41 (0%) with placebo. No severe or serious adverse events were reported in the placebo-controlled period. Conclusions and Relevance: In this study, an individualized dosing regimen of inhaled GH001 resulted in significant improvements in depression symptoms relative to placebo and was well tolerated, supporting its potential as a novel, rapid-acting treatment for treatment-resistant depression. Trial Registration: ClinicalTrials.gov Identifier: NCT05800860

The selective serotonin reuptake inhibitors (SSRI) are widely considered to be the first choice for antidepressant therapy. There is evidence from inpatient studies dating to 1986, however, suggesting that the tricyclic antidepressant clomipramine, which inhibits reuptake of both serotonin and norepinephrine, may have greater efficacy than some SSRIs for severe depression. There is controversy whether the newer, better tolerated, and safer serotonin norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and—in some countries—milnacipran and desvenlafaxine) are more efficacious than SSRIs. In addressing this controversy, this article first focuses on the limitations of randomized controlled trials (RCTs), including the factors that limit their sensitivity to detect differences between active antidepressants, and meta-analysis to examine results of large sets of RCTs. Next, the results of RCTs and meta-analyses are reviewed. Although few individual studies report significant differences, meta-analyses consistently suggest that venlafaxine may have greater efficacy than the SSRIs as a class. The magnitude of this advantage is modest (i.e., differences in remission rates of 5–10%) and no advantage has been demonstrated versus escitalopram. The advantage for duloxetine versus selected SSRIs is limited to patients with more severe depression and the RCTs are flawed by use of minimum therapeutic doses of SSRIs. No evidence of an advantage is found in RCTs of milnacipran versus SSRIs. Even a modest difference in antidepressant efficacy—if sustained—may have important public health implications for the common, disabling condition of depression. Nevertheless, differences in tolerability and cost also must be considered when choosing therapies.

One of the several pressing unmet needs in the pharmacotherapy of MDD is development of drugs with novel mechanisms of action that can effectively treat depressed patients who do not respond to first- and second-line antidepressants. The value of identifying such a medication would be enhanced if it were also generally well-tolerated and addressed depressive symptoms that are less responsive to SSRIs or SNRIs, such as insomnia or anxiety. This narrative review summarizes the investigation of a novel class of medications originally developed to treat insomnia, the Orexin Receptor Antagonists (ORAs), as adjunctive treatments for depressed patients who have been able to tolerate but who do not obtain an adequate response to standard antidepressants. Although it is likely that the currently approved Dual Orexin Receptor Antagonists (DORAs)—suvorexant, lemborexant and daridorexant—are safe and useful options for concomitant therapy of insomnia in antidepressant-treated patients, these medications have not been approved for this indication. Moreover, DORAs have not been extensively studied as adjunctive therapies for MDD. By contrast, the investigational ORA seltorexant, which is a selective Orexin 2 receptor antagonist, has shown significant antidepressant effects in Phase 2 and Phase 3 trials. Although at least one more unequivocally positive pivotal study will be needed to garner FDA approval for clinical use in the United States, this drug shows promise as a novel and well-tolerated option for patients with difficult to treat depressive episodes.

Health care providers found the Rapid Mood Screener, a new bipolar I disorder screening tool, to be superior to the widely used Mood Disorder Questionnaire in sensitivity/specificity, brevity, practicality, and easy scoring.