We shared a lot of our thoughts about the recent published study on psilocybin for treatment-resistant depression in Episode 9. Here we summarize the results and include some figures and information from the supplemental materials.
Primary End Point Results:
25 mg PSI treated participants had positive changes in their MADRS scores from BL to week 3 compared to 1 mg.
10 mg had a trend, but was not significant compared to BL or 1 mg PSI
The effects of 25 mg were sustained into the follow up period
After week 3 and up to week 12 (end of trial), initiation of treatment for depression was implemented by 26 (32.9%) in the 25-mg, 18 (24.0%) in the 10-mg, and 16 (20.3%) in the 1-mg dose groups.
Supplemental Figure 1. Change from Baseline in MADRS Total Score Over Time, Treatment Policy Estimand (Modified Intention-to-Treat Analysis Set)
Supplemental Figure 2. Forest Plot of Change from Baseline in MADRS Total Score at Week 3 Additional Supportive Analyses
Secondary End Point Results:
Less than 1/4 had decrease in response
30% remission in 25 mg group
20% sustained response in 25 mg group
They highlight that no definite conclusions can be drawn from any secondary end points
One major concern of ours for this study was whether prior antidepressant use or the weaning of antidepressants would alter outcomes in that subset of participants. They did the analysis and included in supplemental (see below). No difference was reported between those who were withdrawn from medications. They did not however, to our knowledge, assess those who returned to treatment for depression following week 3.
Adverse Events and Severe Adverse Events:
Adverse events like headache, nausea, dizziness, fatigue occurred in some participants, as to be expected with psychedelics
The number of participants showing any worsening from baseline were: 11 (13.9%) in the 25-mg, 13 (17.3%) in the 10-mg, and 7 (8.9%) in the 1-mg dose groups
The number of participants showing any worsening from baseline were: 12 (15.2%) in the 25-mg, 12 (16.0%) in the 10-mg and 12 (15.2%) in the 1-mg dose groups.
Definitions of AE:
Definition of SAE:
One of our main concerns was with the reported SAEs including suicidal ideation/self-injury, we wanted to share some supplemental tables associated with the data. These data are transformed into FDA-CASA 2012 ratings which is as follows:
Passive
Active: Non-specific (no method, intent, plan)
Active: Method, but no intent or plan
Active: Method and intent, but no plan
Active: Method, intent and plan.
Approximately 30% of participants overall reported passive or active (2-3) suicidal ideation at BL, with the highest reports in the assigned 10 mg and 25 mg groups, respectively.
C-SSRS and S-STS Conversion to FDA-CASA 2012 – Shift from Baseline to Worst Post-Baseline W1-3
C-SSRS and S-STS Conversion to FDA-CASA 2012 – Shift from Baseline to Worst Post-Baseline W3-12
They also include the MADRS suicidal scores. "The mean (SD) change from baseline in MADRS item 10 score showed a small reduction at day 2 for the 25-mg, 10-mg, and 1-mg dose groups of -0.7 (1.28), -0.5 (1.28), and -0.4 (1.11) respectively, which were maintained at week 3: -0.3 (1.57), -0.4 (1.33), and -0.3 (0.99), respectively." Similar patterns of worsening post-baseline scores were shown.
Overall, this study provided a super important contribution to the field. Some limitations of the study included no active comparator, which has shown to be increasingly difficult in the field of psychedelics, and no clear assessment of unblinding of the participants.
The role of expectancy bias in both participants and therapists in the reported outcomes of psychedelic treatments is not known. Study designs should be mindful to include analyses that can assess these things to better inform research strategies and potential effect of psychedelics.
It is also important to be aware of these serious adverse events and the potential of participants having worsening symptoms. Similarly with other medications like SSRIs and antipsychotics, it takes time for the person to adjust to medications and can cause increases in suicidal ideation, self-injury and other symptoms. Paying attention to serious adverse events is extremely important in clinical research.
This study, in our opinion, highlights a greater need for overall individualized medicine and approaches when it comes to treatment-resistant psychiatric illness.
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