Mora is a 39-year-old African-American man with a history of severe and recurrent major depressive disorder (MDD) without psychosis. The onset of his depression occurred in his early adolescence. Mora previously failed trials of sertraline, bupropion, venlafaxine, nortriptyline, lithium, aripiprazole and perphenazine. He also sees a psychotherapist for monthly cognitive behavioral therapy. His current regimen includes 80 mg of fluoxetine per day and 20 mg of extended-release amphetamine-dextroamphetamine per day, to which he has had a partial response.
At his most recent outpatient appointment, Mr. Mora asks if he is a candidate for treatment with adjuvant psychedelics and asks specifically about psilocybin. As his psychiatrist, how would you respond?
Treatment-resistant depression (TRD) was defined as failure of 2 different courses of treatment. Patients with ESRD have greater illness duration, illness severity, disability, physical illness, suicide risk, and economic costs than patients with treatment-responsive depression. Psilocybin has demonstrated antidepressant properties in patients with MDD and TRD.1-3
The Current Study
Goodwin and colleagues4 conducted a phase 2, double-blind, dose-finding, parallel-group, randomized clinical trial. The study sponsor, COMPASS Pathfinder, designed and funded the trial and provided a pharmaceutical-grade synthetic form of psilocybin (COMP360).
An independent contract research organization (MedAvante-ProPhase) was responsible for evaluating participants using the Montgomery-sberg Rating Scale (MADRS), performed by trained, blinded, remote raters, as well as statistical analyses. The sponsor performed data interpretation and post-hoc statistical analysis and paid for professional assistance in writing the first draft of the manuscript.
The authors recruited adults aged 18 years or older with ESRD, defined as a depressive episode without psychotic features, with failure to respond to an adequate dose and duration (8 weeks) of 2 to 4 pharmacological treatments for the current episode. The trial was conducted at 22 sites in Europe and North America between March 2019 and September 2021. Eligible participants completed a 3- to 6-week adaptation period, during which they took antidepressants and medications that affect the central nervous system. (CNS) were tapered gradually and stopped at least 2 weeks before baseline. During this period, participants met at least 3 times with a study therapist.
Patients were randomized 1:1:1 to a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control). The administration session lasted 6 to 8 hours and was supervised by a lead therapist. Blood pressure was monitored continuously. Participants wore face shields and headphones with a specifically designed music playlist. The trial followed participants for 12 weeks post-treatment, including 2 post-treatment integration sessions.
The primary efficacy endpoint was the change in MADRS from baseline (day -1) to week 3 in the 25 mg and 10 mg dose groups compared to the 1 mg dose. Secondary endpoints were the proportion of responders (50% improvement in MADRS total score) and remitters (MADRS total score 10) at week 3 and sustained response (week 3 response maintained through week 12). Safety assessments included assessment of adverse events, Columbia Suicide Severity Rating Scale, vital signs, clinical laboratory tests, and electrocardiogram (ECG).
The authors calculated that a sample of 216 participants (72/group) would have 90% power to detect a 6-point difference in the mean change in MADRS total score from baseline to week 3. Efficacy analyzes were performed on the intention modified. analysis set to deal with. The primary efficacy endpoint (change in MADRS total score) was assessed using mixed model repeated measures analysis. Response and remission were analyzed using generalized linear mixed models, and sustained response was analyzed using binary logistic regression.
A total of 428 participants were selected and 233 were randomized and received psilocybin treatment (79 25 mg, 75 10 mg, 79 1 mg). The average age of participants was 40 years old, 52% of participants were women, and 92% were white. Two-thirds of participants were receiving antidepressant treatment and mean MADRS scores were 32 to 33 at baseline.
The least squares mean change from baseline to week 3 in MADRS total score was -12.0 in the 25 mg group, -7.9 in the 10 mg group, and -5.4 in the 1 mg group. This change was statistically significant for the 25 versus 1 mg groups, but not for the 10 versus 1 mg groups. The incidence of response was 37% in the 25 mg group, 19% in the 10 mg group, and 18% in the 1 mg group, corresponding to a 2.9-fold increase in the probability of response in the 25 mg group versus 1 mg. mg. mg groups.
The incidence of remission was 29% in the 25 mg group, 9% in the 10 mg group, and 8% in the 1 mg group, corresponding to a 4.8-fold increase in the probability of response in the 25 mg group versus 1 mg. mg. mg groups. The incidence of sustained remission was 20% in the 25 mg group, 5% in the 10 mg group, and 10% in the 1 mg group, which was not statistically significant between groups.
Adverse events occurred in 84% in the 25 mg group, 75% in the 10 mg group, and 72% in the 1 mg group, which was not statistically significant between groups. The most frequent adverse events on the day of administration were headache, nausea, dizziness and fatigue. Serious adverse events from day 2 to week 3 in the 25 and 10 mg groups included suicidal ideation (n=4), non-suicidal self-injurious behaviors (n=3), and hospitalization for depression (n=1). There were no serious adverse events in the 1 mg group during this period. There were no clinically significant changes in vital signs, clinical laboratory tests, or ECG.
The authors concluded that the study showed the feasibility of psilocybin monotherapy for up to 12 weeks in patients with ESRD. The change from baseline to week 3 in MADRS total score was significantly better with 25 mg, but not with 10 mg, versus the 1 mg dose. Reported adverse effects included headache, nausea, dizziness, and fatigue, as well as numerically higher suicidal ideation and self-injurious behavior in the 25 and 10 mg groups.
Limitations of the study include the lack of an active comparator, the lack of an ethnically diverse sample of participants, and the exclusion of participants at clinically significant risk for suicide. The intensity of the acute subjective effects of 25 and 10 mg psilocybin may have reduced the effectiveness of trial blinding, although participants’ ability to guess dose assignment was not assessed.
The end result
A single dose of 25 mg versus 1 mg of psilocybin significantly reduced depression scores over 3 weeks in patients with ESRD. Larger and longer trials, including comparisons with existing treatments, are needed to determine the efficacy and safety of psilocybin in this patient population.
Dr. Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as head of the schizophrenia section of the Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Davis AK, Barrett FS, May DG, et al. Effects of Psilocybin-Assisted Therapy in Major Depressive Disorder: A Randomized Controlled Trial [published correction appears in JAMA Psychiatry. 2021 Feb 10;:].JAMA Psychiatry. 2021;78(5):481-489.
2. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression.N Engl J Med. 2021;384(15):1402-1411.
3. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.Psychopharmacology (Berl). 2018;235(2):399-408.
4. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant episode of major depression.N Engl J Med. 2022;387(18):1637-1648.
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