Ketamine and Psilocybin Update in Treatment-Resistant Depression

psychedelic-assisted therapy, ketamine MDMA LSD psilocybin
Use of precision medicine for ketamine dosing is linked to higher rates of treatment response in the management of treatment-resistant depression. Credit: Getty Images
Studies from Psych Congress 2022 show the efficacy of ketamine and psilocybin in reducing symptoms of treatment-resistant depression.

Highlights from Psych Congress 2022 include studies on the efficacy of psychedelics in patients with treatment-resistant depression. Two studies found that treatment with COMP360 psilocybin therapy reduced depression symptoms in patients with treatment-resistant depression, and a third study found that using precision medicine for ketamine dosing may decrease the high efficacy-low effectiveness gap in the management of treatment-resistant depression. Psych Congress 2022 was held from September 17 to 20, 2022, in New Orleans, Louisiana.

COMP360 Psilocybin Reduces Depression Symptoms

A single 25-mg dose of oral COMP360 psilocybin, a synthetic form of psilocybin, combined with psychological support, reduced symptoms of depression and was well tolerated by patients with treatment-resistant depression, according to research from 2 studies presented by Goodwin et al in a poster session.1

The first study, COMP001 ( Identifier: NCT03775200), was a monotherapy double-blind phase 2b controlled trial (N=233) that included psilocybin therapy doses of 25 mg, 10 mg, and 1 mg. The second study, COMP003 ( Identifier: NCT04739865), was an open-label trial (N=19) examining COMP360 (25 mg) psilocybin therapy coupled with psychological support as adjunctive therapy in patients taking serotonergic antidepressants. The primary outcome in both trials was change from baseline to week 3 in patients’ total score in the Montgomery-Asberg Depression Rating Scale (MADRS). According to the manufacturer, rapid response to therapy was seen in patient’s taking the 25-mg dose, starting from day 2 to week 3.

In COMP001 from day 2 through the end of week 3, the researchers found dose-dependent reductions in MADRS scores with 25-mg COMP360 showing statistical superiority over 1 mg. Response and remission rates with the 25-mg dose in COMP001 were 36.7% and 29.1%, respectively. The week 3 response and remission rates were better for COMP360 25 mg than for 1 mg, and the rate of sustained response at week 12 was with higher with the 25-mg dose (24.1%) compared with the 1-mg dose (10.1%). In COMP003, similar effects of COMP360 25 mg on MADRS scores were observed, and response and remission rates at week 3 were 42.1% for both.

The novel RESTORE infusion protocol represents a clinically applicable methodological approach to ketamine infusion therapy that results in significantly improved effectiveness by 3-fold and response durability by 9-fold compared to the standard ketamine infusion.

The 25-mg dose was well-tolerated and more than 90% of treatment-emergent adverse events (TEAEs) were mild/moderate severity in both trials. The most common TEAEs across treatment groups (>10% overall incidence) were headache, nausea, fatigue, and insomnia. The study authors called for further safety and efficacy evaluation of COMP360 psilocybin in large, controlled studies.

Disclosure: This research was supported by COMPASS Pathways, Inc. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Precision Medicine Decreases the Efficacy-Effectiveness Gap

A ketamine infusion protocol that uses precision medicine, including analyzing individual’s medical history, genetic, metabolic profile, and blood type, to achieve a targeted blood concentration was associated with improved effectiveness and response durability among patients with treatment-resistant depression, according to findings presented by Grass et al.2

Previous studies on ketamine show an efficacy-effectiveness gap in the treatment of depression with efficacy reported as high (70%-85%) and effectiveness as low (18.3%-45.5%) in community-based studies. Researchers in the Rigorous Evaluation and Systemic Therapeutic Optimization for increased Response/Remission Effectiveness (RESTORE) trial sought to address this gap by using a novel ketamine infusion protocol.

Patients (N=87) with treatment-resistant depression received a ketamine infusion dose using pharmacokinetic modeling to achieve optimal blood concentrations. Infusions were given on 3 days and lasted over 30 minutes. Two additional infusions were administered within 3 to 6 months after which time patients entered the maintenance phase of treatment. The study lasted a total of 60 months. Findings from this novel protocol study were compared with studies from Wilkinson et al at Yale (N=54) and Sakurai et al from Harvard (N=85), which used standard infusions and lasted 30 and 12 months, respectively.

In the RESTORE trial, the acute outcomes at 3 days indicated that 88.4% of patients responded to treatment. The dropout rate was 1.2% and 5.7% experienced an adverse event. By comparison, at 2 weeks in the Yale study, 45.5% of patients responded to treatment, 11.4% dropped out, and 33.3% had an adverse event. At 3 weeks in the Harvard study, 18.3% of patients responded, 30.6% dropped out, and 8.2% had an adverse event.

Table. Outcomes From 3 Ketamine Trials

Sakurai et al (Harvard)
Wilkinson et al (Yale)
Treatment response88.4% at day 318.3% at week 345.5% at week 2
Dropout rate1.2%30.6%11.4%
Adverse events5.7%8.2%33.3%
Data extracted from Grass et al.2

In the RESTORE trial, 90.7% of patients entered maintenance therapy and 9.3% dropped out. The cumulative response rate increased from 88.3% to 100%, with an average durability of efficacy of 245.1 days (range, 48-1103). No adverse events were reported during the maintenance phase.

In the Yale and Harvard studies, 31.8% and 49.4% entered the maintenance phase; 68.2% and 28.8% dropped out; and the average durability of response was 22.3 (range, 2-189) and 28 (range, 4.9-51.1) days, respectively. In the Yale cohort, 9 of the original 14 responders maintained their response in the maintenance phase. Treatment response was not reported in the Harvard study.

This analysis may be limited by comparing data from multiple studies with differing patient populations.

“The novel RESTORE infusion protocol represents a clinically applicable methodological approach to ketamine infusion therapy that results in significantly improved effectiveness by 3-fold and response durability by 9-fold compared to the standard ketamine infusion,” the authors concluded.

Disclosure: The Restore trials were conducted at the Ketamine Institute. Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

This article originally appeared on Clinical Advisor


1. Goodwin G, Marwood L, Mistry S, et al. COMP360 psilocybin therapy in treatment-resistant depression: results of a large randomized controlled phase IIb monotherapy study and an exploratory uncontrolled adjunctive therapy study. Abstract presented at: Psych Congress 2022; September 17-20, 2022; New Orleans, LA. Poster 107.

2. Grass GW. A new methodological approach to improve the “real world” effectiveness of ketamine infusion therapy for treatment-resistant depression. Abstract presented at Psych Congress 2022; September 17-20, 2022; New Orleans, LA. Abstract 51.