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

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Patients with treatment-resistant depression have greater severity and duration of illness, disability, physical illness, incidences of hospitalization, risk of suicide, and economic costs than patients with treatment-responsive depression.

“Patients with treatment-resistant depression have greater severity and duration of illness, disability, physical illness, incidences of hospitalization, risk of suicide, and economic costs than patients with treatment-responsive depression.[1][2][3]”

• cites [1] 1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-17. sourceNot checked — no full text of the source
• cites [2] 2. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D project results: a comprehensive review of find- ings. Curr Psychiatry Rep 2007; 9: 449-59. sourceNot checked — no full text of the source
• cites [3] 3. Pigott HE. The STAR*D trial: it is time to reexamine the clinical beliefs that guide the treatment of major depression. Can J Psychiatry 2015; 60: 9-13. sourceCould not verify

  The Methods passages discuss STAR*D remission, relapse, and treatment dropout, but do not compare treatment-resistant with treatment-responsive patients on illness burden. Searches for severity, disability, physical illness, hospitalization, suicide, and economic costs found no passage making the claimed comparison in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The Structured Interview Guide for the MADRS provided structured probes to ensure standardization of administration and comprehensive coverage of the 10 questions.

“The Structured Interview Guide for the MADRS provided structured probes to ensure standardization of administration and comprehensive coverage of the 10 questions.15”

• cites [15] 15. Williams JB, Kobak KA. Development and reliability of a structured interview guide for the Montgomery Asberg De- pression Rating Scale (SIGMA). Br J Psy- chiatry 2008; 192: 52-8. sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

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.

“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 (Fig. 1).”

May combine two claims.

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 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.”

May combine two claims.

The incidence of response at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group; the odds ratio was 2.9 (95% CI, 1.2 to 6.6) for 25 mg vs. 1 mg and 1.2 (95% CI, 0.5 to 3.0) for 10 mg vs. 1 mg.

“The incidence of response at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 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])”

• AssumptionRests on an assumption: The 1-mg dose of psilocybin is an inactive control that does not itself produce antidepressant effects.

May combine two claims.

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, and 16 (20%) 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, and 16 (20%) in the 1-mg group.”

May combine two claims.

The incidence of remission at week 3 was 29% in the 25-mg group, 9% in the 10-mg group, and 8% in the 1-mg group; the odds ratio was 4.8 (95% CI, 1.8 to 12.8) for 25 mg vs. 1 mg and 1.2 (95% CI, 0.4 to 3.9) for 10 mg vs. 1 mg.

“The incidence of remission at week 3 was 29% in the 25-mg group, 9% in the 10-mg group, and 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]).”

• AssumptionRests on an assumption: The 1-mg dose of psilocybin is an inactive control that does not itself produce antidepressant effects.

May combine two claims.

All three participants in the 25-mg group who reported suicidal behavior after week 3 had a history of suicidal behavior or nonsuicidal self-injury before the trial and did not have a treatment response at 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.”

May combine two claims.

The incidence of sustained response at week 12 was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group; the odds ratio was 2.2 (95% CI, 0.9 to 5.4) for 25 mg vs. 1 mg.

“The incidence of sustained response at week 12 was 20% in the 25-mg group, 5% in the 10-mg group, and 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];”

• AssumptionRests on an assumption: The 1-mg dose of psilocybin is an inactive control that does not itself produce antidepressant effects.

May combine two claims.

The serious adverse events in the 25-mg group from day 2 up to week 3 were suicidal ideation (in two participants) and intentional self-injury (nonsuicidal self-injurious behavior) (in two participants).

“The serious adverse events in the 25-mg group were suicidal ideation (in two participants) and intentional self-injury (nonsuicidal self-injurious behavior) (in two participants) and in the 10-mg group were suicidal ideation (in two participants), intentional selfinjury (in one participant), and hospitalization (for severe depression, in one participant).”

May combine two claims.

No clinically significant changes in vital signs, clinical laboratory tests, or 12-lead ECGs were observed during the trial.

“No clinically significant changes in vital signs, clinical laboratory tests, or 12-lead ECGs were observed during the trial (see the Supplementary Appendix).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The incidences of response and remission at 3 weeks were generally in the same direction as the primary end-point results.

“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.”

May combine two claims.

The serious adverse events in the 10-mg group from day 2 up to week 3 were suicidal ideation (in two participants), intentional self-injury (in one participant), and hospitalization (for severe depression, in one participant).

“The serious adverse events in the 25-mg group were suicidal ideation (in two participants) and intentional self-injury (nonsuicidal self-injurious behavior) (in two participants) and in the 10-mg group were suicidal ideation (in two participants), intentional selfinjury (in one participant), and hospitalization (for severe depression, in one participant).”

May combine two claims.

Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness.

“Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness.”

May combine two claims.

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, and 19 (24%) in the 1-mg group.

“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, and 19 (24%) in the 1-mg group.”

May combine two claims.

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, and no participants 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, and no participants in the 1-mg group.”

May combine two claims.

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, and 7 (9%) 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, and 7 (9%) in the 1-mg group (Table S8).”

May combine two claims.

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, and 1% of those in the 1-mg group.

“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, and 1% of those in the 1-mg group.”

May combine two claims.

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.

“Secondary end-point results generally supported the primary analysis with the exception of 12week sustained response, at which time point the observed numerical difference was not considered to be statistically significant.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Just one participant (in the 25-mg group) was treated with adjunctive medication (lorazepam for acute anxiety) on day 1.

“Just one participant (in the 25-mg group) was treated with adjunctive medication (lorazepam for acute anxiety) on day 1.”

May combine two claims.

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 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.”

May combine two claims.

Adverse events occurred in 66 participants (84%) in the 25-mg group, 56 (75%) in the 10-mg group, and 57 (72%) in the 1-mg group.

“Adverse events occurred in 66 participants (84%) in the 25-mg group, 56 (75%) in the 10-mg group, and 57 (72%) in the 1-mg group.”

Classified as probably not a substantial claim.

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.

“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.”

Classified as probably not a substantial claim.

The trial was a phase 2 double-blind, dose-finding, parallel-group, randomized clinical trial.

“This was a phase 2 double-blind, dose-finding, parallel-group, randomized clinical trial.”

May combine two claims.

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 subsequent key secondary efficacy end points are considered not significantly different between the 25-mg group or the 10-mg group and the 1-mg group.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Therapists were unaware of trial-group assignments, did not collect efficacy assessments, and were discouraged from speculating about doses.

“All the therapists were unaware of the trial-group assignments, did not collect efficacy assessments, and were discouraged from speculating about doses.”

Classified as probably not a substantial claim.

A hierarchical test procedure was applied across the primary and three key secondary efficacy end points to control the overall type I error rate.

“To control the overall type I error rate, a hierarchical test procedure was applied across the primary and three key secondary efficacy end points.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Randomization was performed at a central location and stratified according to country and the participant's previous experience with psilocybin.

“Ran-domization was performed at a central location and stratified according to country and the participant's previous experience with psilocybin.”

May combine two claims.

By week 12, 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.

“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.”

Classified as probably not a substantial claim.

MADRS assessments were performed by trained remote raters who were unaware of the details of the trial and the trial-group assignments.

“An independent contract research organization (MedAvante-ProPhase) was responsible for assessment of participants using the Montgomery-Åsberg Depression Rating Scale (MADRS), 12 performed by trained remote raters who were unaware of the details of the trial and the trial-group assign-ments.”

May combine two claims.

The trial population's characteristics were similar to those observed in population studies involving persons with treatment-resistant depression, and the representativeness of the trial population is shown in Table S11.

“These characteristics were similar to what has been observed in population studies involving persons with treatment-resistant depression, and the representativeness of the trial population is shown in Table S11.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All participants provided written informed consent.

“All the participants provided written informed consent.”

May combine two claims.

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.

“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, 1 nefazodone, and escitalopram, sertraline, or venlafaxine 17 but was higher than the incidences of response reported in the STAR*D trial for second-line treatments and beyond.”

• cites [1] 1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905-17. sourceNot checked — no full text of the source
• cites [17] 17. Saveanu R, Etkin A, Duchemin A-M, et al. The international Study to Predict Optimized Treatment in Depression (iSPOT-D): outcomes from the acute phase of antidepressant treatment. J Psy- chiatr Res 2015; 61: 1-12. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The manualized, time-limited approach to preparation, support, and integration of the psychedelic experience ensured safety and is not a stand-alone psychotherapy.

“The manualized, time-limited approach to preparation, support, and integration of the psychedelic experience ensured safety and is not a stand-alone psychotherapy.”

May combine two claims.

Limitations of the current trial include 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.

“Limitations of the current trial include 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.”

Probably not a substantial claim: may not pass S3 (load-bearing).

We did not assess participants' ability to guess their dose assignment.

“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.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The trial was conducted in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.

“The trial was conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki.”

May combine two claims.

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.

“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.”

• AssumptionRests on an assumption: The 1-mg dose of psilocybin is an inactive control that does not itself produce antidepressant effects.

Probably not a substantial claim: may not pass S3 (load-bearing).

The trial protocol was approved by independent ethics committees or institutional review boards at each participating site.

“The trial protocol was approved by independent ethics committees or institutional review boards at each participating site.”

May combine two claims.

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.

“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.”

• AssumptionRests on an assumption: The 1-mg dose of psilocybin is an inactive control that does not itself produce antidepressant effects.
• AssumptionRests on an assumption: Participants remained unaware of their trial-group assignment (dose) during the trial.

Classified as probably not a substantial claim.

These findings may explain the differences in efficacy between the groups in the current trial.

“These findings may explain the differences in efficacy between the groups in the current trial.”

Classified as probably not a substantial claim.

The trial 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).

“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).”