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SAN FRANCISCO -- Withdrawing from antidepressants likely won't affect how well psilocybin works for treatment-resistant depression, according to a phase IIb randomized controlled trial.

In an analysis of 233 participants treated with a single dose of the investigational psilocybin treatment COMP360, there was a similar improvement in depression symptoms regardless of whether or not the patients withdrew from their antidepressants or antipsychotics, reported Guy Goodwin, MD, chief medical officer of COMPASS Pathway in London, which is developing the product.

"We have not seen any evidence to suggest patients benefit from continuing on their antidepressants compared to those who withdraw before taking COMP360 psilocybin therapy," Goodwin told 番茄社区app. "While interesting, this finding will need replication and further evaluation in controlled trials."

The findings also suggest that withdrawal from antidepressants is safe when initiating psilocybin treatment, the group noted on their poster presented at the American Psychiatric Association (APA) annual meeting.

Tested in three different dosage strengths, all participants reaped a significant benefit in total Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to 3 weeks after treatment:

• 25-mg dose: -12.2 (95% CI -16.1 to -8.2) for withdrawers vs -11.8 (95% CI -16.8 to -6.7) for continuers
• 10-mg dose: -8.5 (95% CI -12.2 to -4.7) for withdrawers vs -9.6 (95% CI -13.6 to -5.5) for continuers
• 1-mg dose: -6.4 (95% CI -9.9 to -3.0) for withdrawers vs -7.4 (95% CI -12.8 to -2.1) for continuers

This synthetic formation of psilocybin -- found in Psilocybe mushrooms and more commonly known as "magic mushrooms" -- acts as a 5HT2A receptor agonist. The investigational treatment first earned a in 2018 for treatment-resistant depression.

Main findings from the trial were presented at last year's APA meeting, which found a superior reduction in MADRS total score with the 25-mg dose compared with the 1-mg dose over 3 weeks (least square mean treatment difference -6.6, 95% CI -10.2 to -2.9, P<0.001).

The phase III clinical program testing this therapy is now underway, Goodwin noted.

On their poster, the researchers explained that chronic treatment with selective serotonin reuptake inhibitors (SSRIs) could dampen the therapeutic effects of psilocybin. A few prior studies testing psilocybin in psychiatric conditions have also suggested that prior antidepressant treatment could inhibit the 5HT2A receptor function, which ultimately served as the impetus for the current analysis.

The 1:1:1 trial included participants who were currently experiencing a treatment-resistant episode of major depression, defined as a non-response to two to four antidepressants. All participants had a Hamilton Depression Rating Scale 17-item score of 18 or higher. No participants had prior electroconvulsive therapy or ketamine treatment for their current episode.

About half of participants were women, average age was 40, nearly all were white, and baseline MADRS score was 32.5. Around 46% said their current depressive episode spanned 2 years or longer. Only a handful of participants reported prior psilocybin use.

During a 3- to 6-week screening period prior to randomization, 67% of participants withdrew from their antidepressant. Of withdrawers, 41% were withdrawing from one drug, 21% withdrew from two drugs, and 5% withdrew from more than two drugs.

Of note, depression didn't worsen during this withdrawal period.

Participant-reported psychedelic effects from psilocybin treatment also didn't significantly differ between antidepressant withdrawers and non-withdrawers as measured by the Five-Dimensional Altered States of Consciousness. This scale looked at symptoms of auditory alterations, visual restructuralization, anxious ego dissolution, oceanic boundlessness, and reduction of vigilance. These were most commonly reported with the 25-mg dose.

Goodwin added that his group is also currently conducting phase II clinical studies of COMP360 psilocybin therapy for post-traumatic stress disorder and anorexia nervosa.

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