Psilocybin might be effective for treatment-resistant depression even with ongoing SSRI use, study suggests

In a new exploratory phase II clinical trial, a single dose of psilocybin, when used as an adjunct to ongoing SSRI treatment and combined with supportive therapy, demonstrated a generally favorable safety profile and significant therapeutic efficacy in individuals with treatment-resistant depression. The results of the study have been published in the journal Neuropharmacology.

Psilocybin a naturally occurring psychoactive compound found in certain species of mushrooms, often referred to as “magic mushrooms.” It has been used for centuries in various cultures for its hallucinogenic and mind-altering effects. These effects can include visual and auditory hallucinations, changes in thought patterns, and a profound sense of interconnectedness.

Psilocybin-assisted psychotherapy is a therapeutic approach that involves the controlled administration of psilocybin in conjunction with psychological support and therapy. The process typically consists of several sessions in which a trained therapist guides the individual through their psychedelic experience. Psilocybin-assisted therapy is being explored as a potential treatment for various mental health conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD).

The new study aimed to understand whether the concurrent use of SSRIs, a common treatment for depression, could interfere with the therapeutic effects of a synthetic form of psilocybin (COMP360). Some reports and preclinical studies have suggested that SSRIs might reduce the subjective effects of psychedelics, potentially limiting their effectiveness.

“Many people living with treatment-resistant depression (TRD) take daily SSRI antidepressant drugs and it has long been thought that they could interfere with the potential therapeutic effect of psilocybin,” explained Guy Goodwin, the Chief Medical Officer at COMPASS Pathways and lead author of the study. “This is important because some patients are unwilling to withdraw from their SSRI to take another potential treatment, such as investigational COMP360 psilocybin treatment. It’s important for us to better understand this as it limits patient choice, if COMP360 psilocybin treatment receives regulatory approval for TRD in the future.”

The study recruited adults aged 18 and older who had been diagnosed with TRD. TRD was defined as individuals who met the criteria for major depressive disorder (MDD) and had failed to respond adequately to at least two to four previous pharmacological treatments, including their current SSRI antidepressant.

This phase II clinical trial was conducted as an open-label study, meaning that both participants and researchers were aware of the treatment being administered. Participants in the study were required to have been on a stable dose of a single SSRI antidepressant for a minimum of six weeks before participating in the study.

The final sample included 19 participants. The majority of participants were female (68.4%), white (78.9%), and had been experiencing their current depressive episode for over a year (84.2%).

Specially trained therapists conducted a series of three sessions with each participant, building trust, explaining the study procedures, providing psychoeducation, and helping participants mentally prepare for the psilocybin session. The actual psilocybin administration session involved a single 25 mg dose of psilocybin. Participants wore eyeshades and headphones playing a designated playlist of music to enhance their introspective experience. They were closely monitored by therapists, including a lead therapist and an assisting therapist.

At the outset of the study, the participants enrolled in the research had severe depressive symptoms, as indicated by their average Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 31.7. The MADRS is a standardized assessment tool used to measure the severity of depression, with higher scores indicating more severe depressive symptoms. A total score of 31.7 is well above the threshold for severe depression.

Additionally, the participants’ Clinical Global Impression–Severity (CGI-S) scores, which are another clinical rating scale used to assess the overall severity of a participant’s mental illness, suggested that they were in the “moderately ill” range. The CGI-S rates participants on a scale from 1 (normal, not ill at all) to 7 (among the most extremely ill), with higher scores indicating greater illness severity.

However, as the study progressed and participants received a single administration of psilocybin in conjunction with their ongoing selective serotonin reuptake inhibitor (SSRI) treatment, significant improvements in their depressive symptoms were observed.

By Week 3, the average MADRS total score had dropped to 16.8. This reduction is considered clinically meaningful, as it signifies a substantial improvement in depressive symptoms. At this point, the participants’ CGI-S scores also indicated that they were in the “borderline mentally ill” range, suggesting a significant improvement in their overall mental health status.

“The study suggests that SSRI antidepressants do not interfere with the potential therapeutic potential of investigational COMP360 psilocybin treatment,” Goodwin told PsyPost. “This would give people living with TRD the possibility to remain on their antidepressant without concern that it could limit the therapeutic benefit of psilocybin treatment.”

The safety profile was generally favorable. There were 17 adverse events reported by 12 participants, none of which were considered serious or led to study withdrawal. Most adverse events were mild, short-lived, and resolved on the day of onset. The most common adverse event was a headache, reported by 31.6% of participants. Three participants experienced increased blood pressure, which was considered related to the study treatment.

The acute subjective effects of psilocybin, as assessed by the Five-Dimensional Altered States of Consciousness questionnaire (5D-ASC), indicated alterations in consciousness in various dimensions, including visual restructuralization, oceanic boundlessness, and reduction of vigilance.

“It had long been thought that SSRI antidepressants could interfere with the potential therapeutic effect of psilocybin, but the study suggested that this is not the case: both the psychedelic experience and the reduction in depressive symptoms were maintained,” Goodwin explained.

While the results are promising, it’s important to note some caveats. The study lacked a control group and was conducted in an open-label format. This means that both the participants and the researchers were aware of the treatment being administered, which introduces the potential for bias and placebo effects. Since there was no comparator group (e.g., a group receiving a placebo or another active treatment), it is challenging to determine whether the observed improvements were solely due to the administration of psilocybin or if they might have occurred naturally over time or due to the continued use of SSRIs.

“The study was modest in size with 19 participants, so further studies in larger populations are required to validate these initial findings,” Goodwin said.

Nevertheless, the results of this study support the continued investigation of psilocybin as a treatment option for TRD, particularly in cases where discontinuation of SSRIs is not desirable or feasible.

“The efficacy findings were similar to those from our phase 2b study of 25mg of investigational COMP360 psilocybin in TRD, where patients were withdrawn from their antidepressants prior to receiving COMP360 (42% response and remission rates at week three in this study versus 37% and 29%, respectively in our study where patients had withdrawn from antidepressants),” Goodwin noted. “We are now conducting a phase 3 clinical program of COMP360 psilocybin treatment in TRD, the largest of its kind ever conducted.”

The study, “Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication“, was authored by Guy M. Goodwin, Megan Croal, David Feifel, John R. Kelly, Lindsey Marwood, Sunil Mistry, Veronica O’Keane, Stephanie Knatz Peck, Hollie Simmons, Claudia Sisa, Susan C. Stansfield, Joyce Tsai, Sam Williams, and Ekaterina Malievskaia.


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