Clinical Pearls & Morning Reports
Published November 2, 2022
Goodwin et al. conducted a phase 2 trial that evaluated a synthetic, proprietary formulation of psilocybin (at doses of 25 mg, 10 mg, and 1 mg, with the 1-mg dose serving as a control group), administered together with psychological support, in patients with a treatment-resistant major depressive episode. Read the NEJM Original Article here.
Q: How is treatment-resistant depression generally defined?
A: Treatment-resistant depression is a challenging disorder to treat, as shown in the Sequenced Treatment Alternatives to Relieve Depression trial. Incidences of remission became progressively lower from the first course of antidepressant treatment (36.8%) to the second course (30.6%), third course (13.7%), and fourth course (13.0%). Failure of two courses of treatment has generally been considered to define a group of patients who have treatment-resistant depression.
Q: What is psilocybin?
A: Psilocybin is a tryptamine alkaloid found in several species of psilocybe mushrooms. Its potential antidepressant efficacy was suggested by preliminary studies involving patients with life-threatening cancer. Amelioration of symptomatic depression in pilot studies of major depressive disorder, including those that compared psilocybin with escitalopram and that investigated its use in treatment-resistant depression, has suggested therapeutic potential for this agent.
A: The primary end point of the trial was the change from baseline to week 3 in the total score on the Montgomery–Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating greater severity of depression). The least-squares mean change from baseline to week 3 in the MADRS total score was −12.0 points in the 25-mg group, −7.9 in the 10-mg group, and −5.4 in the 1-mg group. The difference in the least-squares mean change between the 25-mg group and the 1-mg group was −6.6 (95% confidence interval [CI], −10.2 to −2.9; P<0.001), and the difference between the 10-mg group and the 1-mg group was −2.5 (95% CI, −6.2 to 1.2; P = 0.18). In addition to headache, nausea, and dizziness, some participants had suicidal ideation or self-injurious behavior, and the proportions of these participants were numerically higher in the 25-mg and 10-mg groups than in the 1-mg group.
A: Limitations of the current trial included the lack of an active comparator, the lack of an ethnically diverse participant sample, and the exclusion of persons judged to be at a clinically significant risk for suicide. The intensity of the acute subjective effect of the 25-mg and 10-mg doses, as compared with the 1-mg dose, reduced the effectiveness of the double-blind structure of the trial. The authors did not assess participants’ ability to guess their dose assignment, and ensuring blinding is an inherent limitation of studies of drugs that produce psychedelic subjective effects. Whether other preparations of psilocybin than the proprietary one used in this trial would show the same effects cannot be determined.