This Year In Major Depressive Disorder

FDA Approves First At-Home Brain Stimulation Device for Treatment of Depression

The US Food and Drug Administration (FDA) has approved Flow Neuroscience’s FL-100, the first at-home brain stimulation device for treating major depressive disorder in adults, based on results from the Empower phase 2 study showing significant symptom remission and improvement. The wearable headset delivers transcranial direct current stimulation to the dorsolateral prefrontal cortex over a typical 12-week course and can be used alone or with other treatments for moderate to severe depression.

FDA Clears Investigational New Drug Application for TNX-102 SL for Treatment of Major Depressive Disorder

The FDA has cleared the Investigational New Drug application for TNX-102 SL, allowing Tonix Pharmaceuticals to begin clinical development of this sublingual cyclobenzaprine formulation as a treatment for major depressive disorder in adults. The planned phase 2 HORIZON study will be a 6-week, randomized, double-blind, placebo-controlled trial enrolling about 360 patients across ~30 U.S. sites to evaluate efficacy and measures including depression severity and sleep disturbance. TNX-102 SL is designed to target sleep disruptions often associated with depression and has shown promising signals in prior studies, with generally low incidence of side effects common to traditional antidepressants

FDA Clears Deep Transcranial Magnetic Stimulation for Adolescents With MDD

The FDA has granted a label expansion for BrainsWay’s Deep transcranial magnetic stimulation system as an adjunct therapy for adolescents aged 15–21 with major depressive disorder, extending its previous indication for ages 22–86. This clearance was based on real-world evidence from over 1100 adolescent patients showing significant improvements in depressive and anxiety symptoms with a safety profile consistent with adult use.

A “Surprise” Miss: NBI-1070770 for Major Depressive Disorder Fails in Phase 2 Study

Neurocrine Biosciences announced that its investigational antidepressant NBI-1070770 failed to meet the primary endpoint in a phase 2 trial for major depressive disorder, showing no significant improvement in depressive symptoms compared to placebo in adults who had an inadequate response to prior treatment. The study enrolled 73 participants and evaluated changes in depression severity but did not demonstrate efficacy, although the drug was generally well tolerated. Neurocrine said it will continue analyzing the data to understand the results and determine next steps for the compound.

New Positive Phase 2 Data on Osavampator for Major Depressive Disorder

A phase 2 SAVITRI study found that osavampator (NBI-1065845), an investigational AMPA receptor positive allosteric modulator, produced statistically significant and clinically meaningful reductions in depression severity compared with placebo in adults with major depressive disorder who had an inadequate response to prior antidepressants, meeting both primary (Day 28) and secondary (Day 56) endpoints. The 1 mg dose showed significant improvement and remission rates, while the 3 mg dose showed favorable but not statistically significant results, and the drug was generally well tolerated with no serious adverse events. Based on these positive outcomes, Neurocrine Biosciences plans to continue evaluating the 1 mg daily dosing in ongoing Phase 3 studies.

Time to Care About Apathy: A Practical Guide for General Psychiatrists

Authors emphasize that apathy—a marked reduction in goal-directed behavior and emotional engagement—is distinct from depression and is common yet often overlooked in psychiatric and neurologic settings, especially among older adults with cognitive impairment. It outlines 3 neurobiologically based apathy subtypes (executive, emotional, and initiation) and provides practical guidance on using validated screening tools and tailored pharmacological and behavioral interventions to improve outcomes.

Positive Results of Analysis of Esketamine Nasal Spray on Emotional Blunting in Patients With Treatment-Resistant Depression

A post hoc analysis of a phase 4 study found that esketamine nasal spray was associated with significant improvements in emotional blunting in adults with treatment-resistant depression compared with placebo, based on composite items from the MADRS and PHQ-9. Improvements were observed as early as day 2 and persisted through day 28 for both the 56-mg and 84-mg doses, alongside overall antidepressant effects. The authors note that findings are exploratory because the measures used were not specifically validated to assess emotional blunting, and adverse effects such as nausea and dissociation were reported.

Treatment Resistance: It’s Complicated

Treatment resistance in depression is a complex, multilevel phenomenon influenced by biological factors, illness severity, comorbidities, treatment adherence, and psychosocial stressors, and it lacks a universally accepted definition. The article highlights challenges in distinguishing true treatment resistance from pseudo-resistance due to inadequate dosing, duration, or comorbid conditions, and it discusses strategies to optimize initial treatments before labeling a patient as treatment resistant. It also emphasizes the importance of comprehensive assessment, use of evidence-based therapeutic options, and individualized care to improve outcomes in those with difficult-to-treat depressive disorders.