Major depressive disorder affects about 8% of U.S. adults in a given year. Standard treatment includes antidepressants like SSRIs and SNRIs, therapy, and sometimes combinations of both. For severe or treatment-resistant depression, options include esketamine nasal spray, transcranial magnetic stimulation, and electroconvulsive therapy.
What's actually going on in research
Trials are testing fast-acting drugs that work differently from SSRIs, including psychedelics like psilocybin and MDMA-assisted therapy, new glutamate-targeting medications, anti-inflammatory approaches, and digital therapeutics. Researchers are also studying biomarkers to predict which treatments will work for which patients, addressing the trial-and-error nature of current care.
Psychedelic-assisted therapy
Psilocybin combined with therapy has shown rapid antidepressant effects in Phase 2 trials, with some people responding within days rather than weeks. Multiple companies are now testing single-dose and repeated-dose protocols in large Phase 3 studies.
Glutamate modulators
Beyond esketamine, which acts on NMDA receptors, researchers are testing other glutamate-pathway drugs including AMPA receptor modulators. These aim for rapid relief without the dissociative effects of ketamine.
Inflammation-targeted treatments
Some depression appears linked to immune system activation. Trials are testing anti-inflammatory drugs and approaches that target specific inflammatory markers in people whose depression hasn't responded to standard medications.
What to know before you search
Eligibility typically depends on depression severity measured by standard scales, number of prior medication trials, current episode duration, and whether certain symptoms like suicidal thoughts are present or excluded.
What types of trials are currently open
- Medication trials — Testing new antidepressants with novel mechanisms, often comparing them to placebo or existing medications. Some studies focus on people who haven't responded to prior treatments.
- Psychedelic therapy trials — Testing psilocybin, MDMA, or other psychedelics combined with structured therapy sessions, typically with a single dose or small number of doses.
- Device-based trials — Studies of transcranial magnetic stimulation, vagus nerve stimulation, and other non-medication approaches for treatment-resistant depression.
- Digital therapeutic trials — Testing app-based therapy, online interventions, and digital tools that deliver cognitive behavioral therapy or other evidence-based approaches.
- Biomarker studies — Following people with depression to identify blood tests, brain imaging patterns, or genetic markers that predict treatment response.
Recently added Major Depressive Disorder trials
A Study to Evaluate the Safety and Efficacy of ALKS 7290 as an Adjunctive Therapy to Antidepressants in Adult Participants With Major Depressive Disorder
The purpose of this study is to assess the efficacy, safety and tolerability of ALKS 7290 following oral administration in adult participants with Major Depressive Disorder.
Understanding the Neural Underpinnings of Risk-Taking Behavior in Psychiatric Disease
The purpose of this study is to understand how the orbitofrontal cortex (OFC), a region at the front of the brain, guides decisions about whether to pursue a possible reward when doing so also carries a risk of loss, and how this process is altered in depression. People with depression are often less motivated by rewards and more sensitive to potential losses, leading them to avoid situations that others would approach. The OFC is thought to play a central role in these "approach or avoid" decisions, but how it normally does so, and what goes wrong in depression, is not well understood. This study asks two questions: (1) How does activity in different parts of the OFC signal the decision to approach or avoid? (2) Does this activity differ in people with depression in a way that explains a bias toward avoidance? We hypothesize that the medial OFC (toward the middle of the brain) signals approach, the lateral OFC (toward the side of the brain) signals avoidance, and that in depression the medial OFC signal is weakened, tipping decisions toward avoidance. Participants are adults who are hospitalized with stereo-EEG (sEEG) electrodes already placed in the brain by their medical team, either to locate the source of seizures in epilepsy or as part of a separate clinical trial for treatment-resistant depression. The electrodes are placed for clinical reasons only, not for this study. During their hospital stay, participants complete a short, game-like computer task (about 20 minutes per session) in which they repeatedly choose whether to approach or avoid options that offer different chances of reward and loss. Their choices and reaction times are recorded along with brain activity from the existing electrodes, and participants rate their mood before each session. The researchers will compare OFC activity during approach versus avoid decisions, use mathematical models of decision-making to measure how strongly each participant weighs rewards and losses, and compare participants with and without depression. No drugs, devices, or brain stimulation are given as part of this study. The findings are intended to guide the development of more targeted brain-stimulation treatments for treatment-resistant depression.
Find Major Depressive Disorder trials matched specifically to you
Answer 3 quick questions and we'll show you trials that fit your situation.