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
Study on iTBS Regulating the Reward Circuit Function to Improve Anhedonia in Depression
The goal of this clinical trial is to learn if the proposed intermittent theta burst stimulation (iTBS) protocol can effectively improve anhedonia symptoms in depressed patients. The stimulation targets in our protocol include (1) dual-target stimulation at the left dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). (2) single-target stimulation at the left DLPFC. The main questions it aims to answer are: * Whether iTBS of dual-target stimulation (left DLPFC and OFC) can improve the symptoms of anhedonia and better than single-target stimulation at the left DLPFC? * Whether iTBS of the dual targets of left DLPFC and OFC can improve the symptoms of anhedonia by correcting the abnormal functional connectivity of DLPFC-NAc and OFC-sgACC, regulating the functional abnormalities of NAc and sgACC, and indirectly repairing the overall dysfunction of the reward circuit. * Researchers will compare dual-target stimulation to single-target stimulation and sham dual-target stimulation (a dedicated sham coil is utilized which produces an identical audible click and physical sensation) to see if the proposed iTBS protocol works to treat anhedonia. Participants will: * Take 6 sessions of dual-target iTBS or single-target iTBS every day, for 5 consecutive days. * Visit our hospital at 1 week, 4 weeks, and 8weeks after the iTBS treatment completion, for clinical evaluation and brain image examination.
Receive nutritionist-designed groceries for 6 months to improve mood
This randomized controlled trial will test whether providing medically tailored groceries for 6 months can improve depressive symptoms among adults with depression and food insecurity. The intervention under study is a 6-month, medically tailored grocery program provided by the Boston-based non-profit organization, Community Servings. Food boxes are mailed to participants' homes every two weeks and are designed by a registered dietitian nutritionists to support an individuals' health needs. Participants may also attend optional nutritional counseling sessions. In this randomized clinical trial, 300 adults with depression and food insecurity will be assigned to one of two groups. The intervention group will receive medically tailored grocery boxes delivered to their home every two weeks for six months (13 boxes total), along with nutritional counseling support. The comparison group will receive usual medical care plus a $30 monthly grocery gift card for six months to be used to purchase any products of their choice. Participants will be recruited from UMass Memorial Health and health centers associated with Community Care Cooperative (C3) in the greater Worcester area in Massachusetts.The main goal of the study is to determine whether the grocery program reduces symptoms of depression. The study will also examine effects on anxiety, food insecurity, diet quality, and healthcare use.
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