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Home/Research/Placebo/Treatment-Resistant Depression (TRD)

Placebo for Treatment-Resistant Depression (TRD)

17 papers and 103 clinical trials exploring placebo as a treatment for treatment-resistant depression (trd).

CompoundComparator / Control

Placebo

Placebo is the most widely referenced comparator in psychedelic clinical research, appearing in over 500 trials. Understanding how placebos are designed, administered, and interpreted is essential to evaluating the evidence base for psychedelic-assisted therapies — and one of the field’s most contested methodological challenges.

Full Placebo profile
Indication30% of individuals with depression experience treatment-resistant depression.

Treatment-Resistant Depression (TRD)

Research into psychedelics as a treatment for Treatment-Resistant Depression (TRD) is advancing rapidly, with compounds like psilocybin showing particular promise. Approximately 30% of depression sufferers experience TRD, which reflects a significant unmet need in mental health treatment.

Full Treatment-Resistant Depression (TRD) profile

Academic Research

17 papers
Open Accessindividual

Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial

This naturalistic follow-up of a Phase IIb randomised active placebo-controlled trial (n=144) found that one or two 25 mg doses of psilocybin with psychotherapy were linked to sustained reductions in depression symptoms in treatment-resistant major depression (TRD) at six and twelve months. Benefits were similar across groups, while restarting antidepressant medication during follow-up was associated with worse scores.

Published
May 27, 2026
Journal
Psychotherapy and Psychosomatics
Authors
Mertens, L. J., Betzler, F., Brand, M., Evens, R., Jungaberle, A., Jungaberle, H., Kärtner, L., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Harder, H., Kirchen, N., Kulakova, E., Kunz, L. C., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Koslowski, M., Gründer, G.
Open Accessindividual

Efficacy and Safety of Psilocybin in Treatment-Resistant Major Depression: The EPISODE Randomized Clinical Trial

In this triple‑blind, active placebo‑controlled randomised trial (n=144) of adults with treatment‑resistant depression, two 25 mg doses of psilocybin plus adjunct psychotherapy produced clinically meaningful reductions in depressive symptoms on exploratory secondary measures but did not significantly improve the pre‑second‑dose HAMD17 response rate versus nicotinamide.

Published
March 18, 2026
Journal
JAMA Psychiatry
Authors
Mertens, L. J., Koslowski, M., Betzler, F., Brand, M., Evens, R., Kärtner, L., Jungaberle, A., Jungaberle, H., Majić, T., Schmitz, C. N., Ströhle, A., Scharf, D., Spangemacher, M., Wolff, M., Assadi, Z., Bahri, S., Becher, L., Färber, L. V., Kirchen, N., Kulakova, E., Kunz, L., Meijer, A., Rohrmoser, B., Wellek, S., Berger, M. M., Gründer, G.
Open Accessindividual

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

This single-blind placebo-controlled study (n=40) investigated the neural and behavioral effects of acute ketamine in healthy participants. Results revealed robust inter-individual variability in both neural and behavioral responses to ketamine, with data-driven individual symptom variation mapping onto distinct neural gradients. These findings emphasize the need to consider individual variation in response to ketamine and suggest potential implications for developing precise pharmacological biomarkers in psychiatry.

Published
April 17, 2024
Journal
eLife
Authors
Moujaes, F., Lisa, J., Rahmati, M., Burt, J. B., Schleifer, C., Adkinson, B. D., Savic, A., Santamauro, N., Tamayo, Z., Diehl, C., Kolobaric, A., Flynn, M., Rieser, N., Fonteneau, C., Camarro, T., Xu, J., Cho, Y., Repovs, G., Fineberg, S. K., Morgan, P. T., Seifritz, E., Vollenweider, F. X., Krystal, J. H., Murray, J. D., Preller, K. H., Anticevic, A., Vollenweider
Paywallmeta

Rapidity of Symptom Improvement With Intranasal Esketamine for Major Depressive Disorder: A Systematic Review and Meta-Analysis

This meta-analysis (s=8, n=1437) compared the effect of intranasal esketamine to placebo (both in combination with standard antidepressants) as a treatment for major depressive disorder (MDD). It was found that intranasal esketamine, in combination with the standard treatment, did effectively reduce depression severity when compared to the placebo, with higher doses having a longer-lasting effect.

Published
December 1, 2022
Journal
Journal of Clinical Psychiatry
Authors
Hock, R. S., Feeney, A., Iovieno, N., Murrough, J. W., Sanjay, ;., Mathew, J., Iosifescu, D. V., Fava, M., Jha, M. K., Papakostas, G. I.
Open Accessindividual

Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability

This post hoc analysis of two Phase III double-blind studies assessed the effects of baseline irritability on clinical outcomes in participants with treatment-resistant depression (TRD) (n=560) treated with intranasal ketamine (esketamine) plus an oral antidepressant (ESK + AD). ESK + AD improved symptoms of depression regardless of baseline irritability level and increased odds of achieving a response in all participants.

Published
October 20, 2022
Journal
Journal of Affective Disorders
Authors
Jha, M. K., Williamson, D. J., Magharehabed, G., Turkoz, I., Daly, E. J., Trivedi, M. H.
Open Accessindividual

Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

This double-blind placebo-controlled between-subjects study (n=23) tested the antidepressant efficacy of inhaled nitrous oxide (50% N2O|50% O2 versus 100% O2) in patients diagnosed with major depression (MDD). Across multiple treatment sessions administered across a period of 4 weeks, there were significant reductions in depressive symptoms in the acute response to treatment and accumulatively across sessions.

Published
September 1, 2021
Journal
brazilian Journal of Psychiatry
Authors
Guimarães, M. C., Guimarães, T. M., Hallak, J. E., Abrão, J., Machado-de-Sousa, J. P.

Clinical Trials

103 trials
Not yet recruitingPhase II

Ketamine With Dialectical Behavioural Therapy (DBT) for Suicidality in Individuals With Treatment-Resistant Depression and Borderline Personality Disorder (KET-DBT)

This Phase II randomised, quadruple-masked trial (n=120) will study adults aged 18 to 70 years with borderline personality disorder, treatment-resistant major depressive disorder or bipolar disorder, and suicidal ideation, evaluating whether intravenous ketamine plus dialectical behavioural therapy (DBT) reduces suicidal ideation more rapidly and robustly than midazolam plus DBT. The main purpose is to assess change in suicidal ideation severity from baseline to Day 35 using the Modified Scale for Suicidal Ideation (MSSI). All participants will receive DBT for 6 months, starting before the infusions, with weekly individual sessions and the addition of weekly group sessions from Week 5. The experimental arm will receive six intravenous ketamine infusions over 1 month: the first two at 0.5 mg/kg over 40 minutes, infusions 3 and 4 flexibly dosed at 0.5 mg/kg to 0.75 mg/kg, and infusions 5 and 6 flexibly dosed at 0.5 mg/kg to 0.85 mg/kg. The comparator arm will receive six intravenous midazolam infusions over the same period: the first two at 0.02 mg/kg over 40 minutes, infusions 3 and 4 at 0.02 mg/kg to 0.03 mg/kg, and infusions 5 and 6 at 0.2 mg/kg to 0.035 mg/kg. Participants will also complete hospital visits, remote follow-up by call or videocall, and a range of mood, cognitive and behavioural assessments.

Started
June 1, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT07569198
RecruitingPhase NA

Coaching as an Adjunct to Ketamine Therapy for Treatment-Resistant Depression

This non-randomised, single-group interventional trial (n=20) will assess the feasibility and acceptability of adding psychedelic integration coaching to ongoing maintenance ketamine treatment in adults with treatment-resistant depression (TRD). The study will enrol participants already receiving maintenance intravenous ketamine or intranasal esketamine at Massachusetts General Hospital and aims to explore whether coaching can support symptom improvement and personal growth alongside existing treatment. Participants will receive 12 weekly, 50-minute one-on-one coaching sessions delivered via Zoom by trained psychedelic integration coaches. The coaching is non-clinical, collaborative and participant-directed. Over the 3-month coaching period, and again at a 1-month follow-up, participants will attend monthly study visits with brief remote assessments by a study clinician and self-report questionnaires, with visits taking about 1 to 2 hours depending on the time point. The primary outcomes are feasibility and acceptability from enrolment through Month 3.

Started
April 1, 2026
Type
interventional
Blinding
none
Randomized
No
Registry ID
NCT07563868
Not yet recruitingPhase NA

Neural Mechanisms of Ketamine Antidepressant Treatment 2.0: Exploring how ketamine affects the brain function in people with difficult-to-treat depression.

This is a randomised, quadruple‑blind, placebo‑controlled mechanistic clinical trial enrolling 90 participants (60 adults with major depressive disorder, including treatment‑resistant cases, and 30 healthy controls) at the Royal Melbourne Hospital, Australia, with recruitment from February 2026 and completion expected December 2027. Participants receive a single subcutaneous administration of ketamine 0.75 mg/kg versus placebo (0.9% saline). The primary outcome is change in habenula activity measured using ultra‑high‑field 7T MRI at baseline and 24–48 hours after dosing, designed to probe rapid neural mechanisms underlying ketamine’s antidepressant effects. Secondary outcomes assess clinical and behavioural effects using the Montgomery–Åsberg Depression Rating Scale (MADRS), QIDS‑C, Snaith–Hamilton Pleasure Scale (SHAPS), GAD‑7, and objective activity monitoring by actigraphy. The protocol includes healthy controls to facilitate mechanistic comparisons between clinical and non‑clinical neural responses. The study phase is not specified in the available data. The quadruple‑blind design and saline comparator aim to isolate drug‑specific neural changes and early clinical signal following a single subcutaneous ketamine exposure in treatment‑resistant and broader MDD populations.

Started
February 2, 2026
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
ACTRN12625001087448
RecruitingPhase NA

Virtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant Depression

This interventional trial (n=30) will evaluate the efficacy and tolerability of a virtual reality-based mindfulness intervention combined with intranasal esketamine treatment compared to esketamine treatment alone in patients with treatment-resistant major depressive disorder (TRD). Participants will be randomly assigned to receive either the combined treatment (esketamine plus mindfulness) or standard esketamine treatment as usual, with the primary aim of assessing reductions in depressive symptoms. During the 4-week induction phase, both groups will receive intranasal esketamine, with the experimental group also participating in a 10-minute virtual reality mindfulness session prior to each treatment. Following this, the maintenance phase will last from weeks 5 to 30, with participants continuing esketamine administration once weekly for four weeks, followed by biweekly sessions. Key outcome measures will include changes in depressive symptom severity, inflammatory blood parameters, tolerability, and the duration of remission, with assessments conducted at baseline, the end of the induction phase, and at 30 and 54 weeks post-treatment.

Started
September 18, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
NCT07422519
RecruitingPhase III

Ketamine Augmentation of ECT in Treatment-Resistant Depression (Ketamina)

Phase III double-blind, randomised, placebo-controlled trial (n=30) testing IV ketamine 0.5 mg/kg given during ECT sessions 2, 4 and 6 in hospitalised adults with treatment-resistant MDD.

Started
July 10, 2025
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT07088380
CompletedPhase NA

Electroconvulsive Therapy Versus Intravenous Ketamine in Treatment-Resistant Major Depressive Disorder

This randomised, open-label, parallel-group trial (n=70) will evaluate the efficacy, safety and tolerability of bitemporal electroconvulsive therapy (ECT) versus intravenous ketamine in adults with treatment-resistant major depressive disorder (TRD). The study will recruit adults aged 18-75 years with major depressive disorder who have not responded to at least two adequate antidepressant trials in the current episode and have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 20. Participants will receive either bitemporal ECT twice weekly for 4 weeks or intravenous ketamine 0.5 mg/kg infused over 40 minutes twice weekly for 4 weeks. The primary outcome is change in MADRS score 3 weeks post-procedure. Exclusion criteria include psychotic or bipolar disorder, current substance use disorder, significant neurological disease or traumatic brain injury, uncontrolled hypertension, recent cardiovascular disease, and pregnancy or breastfeeding.

Started
July 1, 2025
Type
interventional
Blinding
none
Randomized
Yes
Registry ID
NCT07526454

Explore further

Search all Placebo papers Search all Treatment-Resistant Depression (TRD) trials Full Placebo profile Full Treatment-Resistant Depression (TRD) profile