Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression Notes

Background

• Psilocybin being studied for treatment-resistant depression.

Methods

• Phase 2 double-blind trial.
• Randomly assigned adults with treatment-resistant depression.
• Received a single dose of synthetic psilocybin:
  • 25 mg
  • 10 mg
  • 1 mg (control)
• Along with psychological support.
• Primary end point: Change from baseline to week 3 in the total score on the Montgomery–Åsberg Depression Rating Scale (MADRS).
  • Range: 0 to 60, higher scores indicate more severe depression.
• Secondary end points:
  • Response at week 3: ≥50% decrease from baseline in MADRS total score.
  • Remission at week 3: MADRS total score ≤10.
  • Sustained response at 12 weeks: Meeting response criteria at week 3 and all subsequent visits.

Results

• 79 participants in the 25-mg group.
• 75 in the 10-mg group.
• 79 in the 1-mg group.
• Mean MADRS total score at baseline was 32 or 33 in each group.
• Least-squares mean changes from baseline to week 3 in the score:
  • −12.0 for 25 mg.
  • −7.9 for 10 mg.
  • −5.4 for 1 mg.
• Difference between the 25-mg group and 1-mg group: −6.6 (95% confidence interval [CI], −10.2 to −2.9, P<0.001).
• Difference between the 10-mg group and 1-mg group: −2.5 (95% CI, −6.2 to 1.2, P=0.18).
• In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results.
• Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness.
• Suicidal ideation or behavior or self-injury occurred in all dose groups.

Conclusions

• In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects.
• Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder.
• Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.

Treatment-Resistant Depression

• Treatment-resistant depression is challenging to treat, as shown in the STAR*D trial.
• Incidences of remission became progressively lower:
  • First course of antidepressant treatment: 36.8%
  • Second course: 30.6%
  • Third course: 13.7%
  • Fourth course: 13.0%
• Failure of two courses of treatment generally defines treatment-resistant depression.
• Patients with treatment-resistant depression have:
  • Greater severity and duration of illness
  • Disability
  • Physical illness
  • Higher incidences of hospitalization
  • Risk of suicide
  • Higher economic costs

Psilocybin

• Psilocybin is a tryptamine alkaloid found in several species of psilocybe mushrooms.
• Potential antidepressant efficacy suggested by preliminary studies involving patients with life-threatening cancer.
• Pilot studies of major depressive disorder suggest therapeutic potential:
  • Compared psilocybin with escitalopram.
  • Investigated its use in treatment-resistant depression.
• Objective: To identify an acceptable efficacious dose and assess the safety of a synthetic, proprietary formulation of psilocybin, administered with psychological support, in patients with a treatment-resistant major depressive episode.

Trial Oversight

• Phase 2 double-blind, dose-finding, parallel-group, randomized clinical trial.
• Sponsor: COMPASS Pathfinder.
  • Designed and funded the trial.
  • Provided COMP360 (proprietary pharmaceutical-grade synthetic psilocybin formulation).
  • Analyzed for stability and purity.
• Contract research organization (Worldwide Clinical Trials) supervised the trial.
• Independent contract research organization (MedAvante-ProPhase) responsible for MADRS assessment.
  • Trained remote raters unaware of trial details and group assignments.
• Statistical analysis by the contract research organization and reviewed by the sponsor.
• Interpretation and post hoc statistical analyses by the sponsor.
• Sponsor paid for professional writing assistance for the first draft.
• Authors reviewed and approved the manuscript and vouch for:
  • Adherence of the trial to the protocol.
  • Completeness and accuracy of the data.
  • Reporting of adverse events.
• Confidentiality agreements between investigators and COMPASS Pathfinder.
• Trial conducted according to ICH Good Clinical Practice guidelines and the Declaration of Helsinki.
• Protocol approved by independent ethics committees or institutional review boards.
• All participants provided written informed consent.

Participants

• Men and women 18 years or older.
• Met DSM-5 criteria for a single or recurrent episode of major depressive disorder, without psychotic features.
  • Based on clinical assessment and medical records.
  • Documented by the Mini-International Neuropsychiatric Interview (version 7.0.2).
• Recruitment through:
  • Referrals from primary care and specialized psychiatry services
  • Online advertisements
  • Word of mouth
• Outpatients who met criteria for treatment-resistant depression.
  • Current episode of depression not responding to two to four adequate trials (≥8 weeks) of treatment.
  • According to the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ).
• Augmentation agents or other antidepressants not in MGH ATRQ qualified as treatment failure if they failed to ameliorate depression and had local regulatory approval.

Trial Design and Procedures

• Conducted at 22 sites in 10 countries in Europe and North America from March 1, 2019, through September 27, 2021.
• All but one principal investigator was a psychiatrist.
• Assisting and lead therapists:
  • Psychologists with at least master’s-level qualifications, psychiatrists, master’s-level practitioners, nurses, diploma-level cognitive behavioral therapists, or doctorate-level mental health specialists.
  • Experience in adult mental health, addiction, dementia, physical health, child or developmental health, family therapy, or eating disorders.
  • Experience with patients having severe psychological distress.
• Therapist-training program:
  • Online learning platform
  • In-person training
  • Clinical training
  • Ongoing individual mentoring and webinars
• Therapists completed the first three components before leading sessions independently and engaged in the fourth for professional development.
• Therapists in training could act as assisting therapists.
• All therapists unaware of trial-group assignments, did not collect efficacy assessments, and were discouraged from speculating about doses.
• Eligible participants completed a run-in period of 3 to 6 weeks.
  • Antidepressants and other prohibited medications affecting the central nervous system were tapered and discontinued at least 2 weeks before the baseline visit.
• During this period, the participant met with a therapist at least three times to build trust, receive psychoeducation, and prepare for the psychedelic experience.
• Participants randomly assigned in a 1:1:1 ratio to receive a single dose of psilocybin of 25 mg, 10 mg, or 1 mg (control).
• Randomization performed centrally and stratified according to country and previous psilocybin experience.
• Administration session (day 1) lasted 6 to 8 hours, with the lead therapist and an assisting therapist in attendance.
• A trial psychiatrist was available on site for consultation.
• Administration rooms designed to provide a nonclinical, calming atmosphere.
• Participants listened to a specially designed music playlist while wearing eyeshades to help direct attention internally.
• After at least 6 hours and when the psychedelic effects of the drug had fully dissipated, participants returned home.
• Followed participants for 12 weeks after treatment.
• Participants received two integration sessions, with the same lead and assisting therapists at the day 2 visit and with the lead therapist at the week 1 visit.
• Goal of the integration sessions: to support participants in deriving their own insights and solutions from the experience with psilocybin.
• Therapists advised to remain open and supportive, without active guiding.
• Participants requested to remain off antidepressant treatment during the first 3 weeks after trial-drug administration; however, these medications could be started at any time during the trial if deemed clinically necessary by a physician investigator.

Efficacy End Points

• Primary end point: Change from baseline (day −1, the day before trial-drug administration) to 3 weeks in the MADRS total score (range, 0 to 60, with higher scores indicating greater severity of depression).
• Primary analysis: of the 25-mg dose and 10-mg dose each compared with the 1-mg dose.
• MADRS administered by experienced mental health clinician raters by telephone at baseline, on day 2, and at weeks 1, 3 (primary end-point assessment), 6, 9, and 12.
• Structured Interview Guide for the MADRS provided structured probes to ensure standardization of administration and comprehensive coverage of the 10 questions.
• Three key secondary efficacy end points:
  • Response (≥50% decrease from baseline to week 3 in the MADRS total score)
  • Remission (MADRS total score ≤10 at week 3)
  • Sustained response (week 3 response maintained through week 12).

Safety End Points

• Adverse events evaluated at every visit and recorded and coded with the use of the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0.
• All visits conducted in person except for the week 6 and 9 visits, which were conducted remotely.
• Adverse events that emerged or worsened after trial-drug administration were categorized as serious adverse events on the basis of the ICH Good Clinical Practice criteria and with the use of additional information from the Columbia Suicide Severity Rating Scale.
• Suicidal ideation with intent or endorsement of any items in the suicidal-behavior section, including nonsuicidal self-injurious behavior, was reported as a serious adverse event.
• Safety assessments also included evaluation of vital signs, clinical laboratory tests (including urine drug screening), and 12-lead electrocardiography (ECG).

Statistical Analysis

• Using a two-sample t-test, a sample of 216 participants (72 per group) would provide 90% power at a two-sided alpha level of 0.05 to detect a 6-point difference in the mean change from baseline to week 3 in the MADRS total score between the 25-mg group or the 10-mg group and the 1-mg group, assuming a common standard deviation of 11.0
• Efficacy analyses were performed in the modified intention-to-treat analysis set, which included all randomly assigned participants who received treatment and had at least one postbaseline efficacy assessment.
• A “hypothetical strategy” estimand was applied in which MADRS total scores for participants who initiated a new antidepressant treatment were imputed at visits after initiation with the use of a missing-not-at-random mechanism that progressively worsened the MADRS total score.
• The aim was to hypothesize what would have happened to the MADRS total score had a new treatment for depression not been available to use.
• This same method was also applied to missing MADRS total scores after trial withdrawal for reasons of lack of efficacy or adverse events.
• All other missing data on MADRS total scores, both intermittent and after trial withdrawal for other reasons, were imputed with the use of a missing-at-random mechanism.
• The primary efficacy end point (change from baseline to week 3 in the MADRS total score) was evaluated with the use of a mixed model for repeated measures (MMRM) analysis comparing the 25-mg dose with the 1-mg dose and comparing the 10-mg dose with the 1-mg dose.
• The MMRM analysis included treatment, visit, pooled trial site, treatment-by-visit interaction, baseline MADRS total score, and an unstructured correlation matrix.
• The estimates of the least-squares means and mean differences and 95% confidence intervals were then pooled with the use of Rubin’s combination rules.
• This analysis method combined the between-imputation variability with the within-imputation variability to obtain one single point and confidence interval estimate to address imputation uncertainty.
• Response and remission were analyzed with the use of a generalized linear mixed model, and sustained response was analyzed with the use of a logistic-regression model.
• A “composite strategy” estimand was applied, whereby participants who initiated a new antidepressant treatment or withdrew from the trial for reasons of lack of efficacy or adverse events were classified as not having a response, remission, or a sustained response at all visits after these events.
• To control the overall type I error rate, a hierarchical test procedure was applied across the primary and three key secondary efficacy end points.
• The 25-mg group and then the 10-mg group were sequentially examined for each end point before proceeding to the next end point.
• All testing was done at the two-sided 0.05 alpha level.
• Descriptive statistics were used to analyze safety data from all randomly assigned participants who received single-dose treatment (safety analysis set), including adverse events, concomitant medications, evaluation of vital signs, clinical laboratory tests, findings from 12-lead ECG, and suicidality assessments.

Results: Participants

• A total of 428 participants were screened, and 233 were enrolled, underwent randomization, and received psilocybin treatment (safety analysis set) and had at least one postbaseline efficacy evaluation (modified intention-to-treat analysis set).
• A total of 79 participants were assigned to the 25-mg group, 75 to the 10-mg group, and 79 to the 1-mg group.
• By week 12, a total of 5 participants (6%) in the 25-mg group, 9 (12%) in the 10-mg group, and 10 (13%) in the 1-mg group had withdrawn from the trial.
• The demographic and clinical characteristics of the participants at baseline were similar across the three groups:
  • Mean age: 39.8 years.
  • 52% were female.
  • 92% were White.
• A total of 95% of the participants reported previous depressive episodes, with a mean of 6.9 lifetime depressive episodes, and 86% of the participants reported a duration of the current depressive episode of longer than 1 year.
• Two thirds of the participants were receiving antidepressant treatment at screening.
• At baseline, depression was:
  • Moderate (MADRS total score, 20 to 30) in 30% of the participants.
  • Severe (MADRS total score, ≥31) in 68% of the participants.
• Mean MADRS total scores at baseline were:
  • 31.9 in the 25-mg group.
  • 33.0 in the 10-mg group.
  • 32.7 in the 1-mg group.
• A total of 6% of the participants had previous exposure to psilocybin.
• Before the week 3 primary end-point assessment, initiation of treatment for depression was reported by:
  • 4 participants (5%) in the 25-mg group.
  • 9 (12%) in the 10-mg group.
  • 14 (18%) in the 1-mg group.
• After week 3 and up to week 12, the number of participants initiating a treatment for depression was:
  • 26 (33%) in the 25-mg group.
  • 18 (24%) in the 10-mg group.
  • 16 (20%) in the 1-mg group.

Results: Efficacy

• 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.
  • −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).
• The nonsignificant finding for the comparison between the 10-mg group and the 1-mg group terminated significance testing on the basis of the prespecified hierarchical test procedure, and all the subsequent key secondary efficacy end points are considered to be not significantly different between the 25-mg group or the 10-mg group and the 1-mg group.
• The incidence of response at week 3 was:
  • 37% in the 25-mg group
  • 19% in the 10-mg group
  • 18% in the 1-mg group
  • Odds ratio in the 25-mg group vs. the 1-mg group, 2.9 (95% CI, 1.2 to 6.6); odds ratio in the 10-mg group vs. the 1-mg group, 1.2 (95% CI, 0.5 to 3.0)
• The incidence of remission at week 3 was:
  • 29% in the 25-mg group
  • 9% in the 10-mg group
  • 8% in the 1-mg group
  • Odds ratio in the 25-mg group vs. the 1-mg group, 4.8 (95% CI, 1.8 to 12.8); odds ratio in the 10-mg group vs. the 1-mg group, 1.2 (95% CI, 0.4 to 3.9)
• The incidence of sustained response at week 12 was:
  • 20% in the 25-mg group
  • 5% in the 10-mg group
  • 10% in the 1-mg group
  • Odds ratio in the 25-mg group vs. the 1-mg group, 2.2 (95% CI, 0.9 to 5.4); odds ratio in the 10-mg group vs. the 1-mg group, 0.7 (95% CI, 0.2 to 2.0)
• Because of the failure of hierarchical testing, no definite conclusions can be drawn from secondary end-point results.
• The confidence interval for the odds ratio for sustained response at week 12 for both the 25-mg dose and the 10-mg dose as compared with the 1-mg dose included 1.
• A post hoc analysis of the primary end point that included sex or the number of lifetime episodes of depression showed results similar to those for the primary analysis.
• The results from per-protocol analysis of the primary end point were also consistent with the modified intention-to-treat population.

Results: Safety

• Adverse events occurred in:
  • 66 participants (84%) in the 25-mg group
  • 56 (75%) in the 10-mg group
  • 57 (72%) in the 1-mg group
• The most frequent adverse events reported in the 25-mg group with onset on the day of psilocybin administration (day 1) were headache (in 24% of the participants), nausea (in 22%), and dizziness and fatigue (in 6% each).
• Adverse events that were rated as severe on day 1 were reported by:
  • 4% of the participants in the 25-mg group
  • 8% of those in the 10-mg group
  • 1% of those in the 1-mg group
• Just one participant (in the 25-mg group) was treated with adjunctive medication (lorazepam for acute anxiety) on day 1.
• There were no serious adverse events reported on day 1.
• From day 2 up to week 3 (primary end-point assessment), severe adverse events were reported by:
  • 9% of the participants in the 25-mg group
  • 7% of those in the 10-mg group
  • 1% of those in the 1-mg group
• The serious adverse events:
  • 25-mg group: suicidal ideation (in two participants) and intentional self-injury (nonsuicidal self-injurious behavior) (in two participants)
  • 10-mg group: suicidal ideation (in two participants), intentional self-injury (in one participant), and hospitalization (for severe depression, in one participant)
  • No serious adverse events were reported from day 2 up to week 3 in the 1-mg group.
• After week 3 and up to week 12 (end of trial), severe adverse events were reported by:
  • 3% of the participants in the 25-mg group
  • 4% of those in the 10-mg group
  • no participants in the 1-mg group
• Serious adverse events:
  • 25-mg group: suicidal behavior (in three participants), codeine withdrawal syndrome (in one participant), and adjustment disorder with anxiety and depressed mood (in one participant)
  • 10-mg group: intentional self-injury (in one participant), depression (in one participant), and suicidal ideation (in one participant)
  • 1-mg group: intentional self-injury (in one participant).
• At the baseline visit, suicidal ideation (passive or active but with no intent or plan) was reported by:
  • 21 participants (27%) in the 25-mg group
  • 27 (36%) in the 10-mg group
  • 19 (24%) in the 1-mg group
• The number of participants who showed worsening of suicidal state from baseline to week 3 were:
  • 11 (14%) in the 25-mg group
  • 13 (17%) in the 10-mg group
  • 7 (9%) in the 1-mg group
• Three participants in the 25-mg group reported suicidal behavior after week 3.
• All three had a history of suicidal behavior or nonsuicidal self-injury before the trial and did not have a treatment response at week 3.
• No clinically significant changes in vital signs, clinical laboratory tests, or 12-lead ECGs were observed during the trial.

Discussion

• This phase 2 clinical trial showed the feasibility of psilocybin monotherapy for up to 12 weeks in patients with a treatment-resistant episode of major depression.
• The change from baseline to week 3 in the MADRS total score (primary end point) was significantly better with a 25-mg dose than with a 1-mg dose; there was not significant difference between the 10-mg dose and the 1-mg dose.
• In addition to headache, nausea, dizziness, and fatigue, 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.
• In view of the participants who showed worsening of suicidal state, suicidality demands clinical vigilance in future trials of psilocybin for depression.
• The incidences of response and remission at 3 weeks were generally in the same direction as the primary end-point results; however, the analyses of these end points were ordered in the prespecified hierarchical test procedure after the significance testing had terminated, and no definite conclusions can be drawn from these results.
• The confidence interval for the odds ratio for sustained response at week 12 for the 25-mg- group as compared with the 1-mg group included 1.
• The current trial was designed to address some limitations of previous pilot studies and trials, including limited power, short-duration crossover design, reliance on single-site recruitment of participants, and interpretation of treatment effects that may be confounded by intensive concurrent psychological therapy.
• The current trial:
  • had a primary end point at 3 weeks but observed participants over 12 weeks of follow-up in a parallel-group design
  • included a trial population in which more than 90% of the participants did not have previous exposure to psilocybin
  • used remote raters who were unaware of the details of the trial and the trial-group assignments to determine the primary end-point measure (MADRS total score)
• The manualized, time-limited approach to preparation, support, and integration of the psychedelic experience ensured safety and is not a stand-alone psychotherapy.
• For participants in this trial, psilocybin therapy represented a third-, fourth-, or fifth-line treatment.
• The incidence of response at week 3 of 37% in the 25-mg group in our trial was numerically lower than that described for first-line treatment of major depressive disorder in several large trials of citalopram, nefazodone, and escitalopram, sertraline, or venlafaxine but was higher than the incidences of response reported in the STAR*D trial for second-line treatments and beyond.
• Pharmacokinetic research has shown dose-dependent increases in receptor occupancy and subjective effects of psilocybin across the dose range of 3 to 30 mg. These findings may explain the differences in efficacy between the groups in the current trial.

Limitations

• Lack of an active comparator
• Lack of an ethnically diverse participant sample
• 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, reduces the effectiveness of the double-blind structure of the trial.
• We 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.

Conclusion

• In this trial of psilocybin administered in a single session with psychological support, a 25-mg dose but not a 10-mg dose resulted in a significantly greater reduction (improvement) in MADRS total scores than a 1-mg dose at 3 weeks in participants with treatment-resistant depression but was associated with adverse events.
• Secondary end-point results generally supported the primary analysis with the exception of 12-week sustained response, at which time point the observed numerical difference was not considered to be statistically significant.
• Longer and larger trials, including comparison with existing treatments for depression, are required to determine the efficacy and safety of psilocybin for treatment-resistant depression.