PARIS — A single 25-mg dose of a synthetic formulation of psilocybin appears to improve the core symptoms of treatment-resistant depression (TRD), a new analysis of phase 2 trial data suggests.
Known as COMP360, the synthetic agent, a proprietary, purified form of psilocybin, improved symptoms related to mood and anhedonia while leaving aspects such as appetite and weight changes unaffected, report investigators led by Guy Goodwin, PhD, emeritus professor of psychiatry, University of Oxford, UK, and chief medical officer, COMPASS Pathways.
The study was presented here at the European Psychiatric Association (EPA) 2023 Congress.
100 Million Affected
Affecting up to 100 million people globally, TRD is “not an official diagnosis,” although it is often defined as the failure to elicit a response with at least two antidepressant treatments, said Goodwin.
Compared to their counterparts with non-TRD, those with TRD experience higher relapse rates, higher rates of suicidal behavior, and more residual symptoms even when they do respond to treatment.
Previous results from the study known as P-TRD indicated that a single 25-mg dose of COMP360 significantly reduced depression scores for up to 12 weeks when given along with psychological support, although a later analysis suggested the effect subsequently dropped off.
The vast majority of the patients in the trial were naive to psychedelics, and so, Goodwin explained, they undergo a preparation phase during which they receive psychoeducation and have at least two visits with a therapist, who then stays with them during administration of the drug to offer support if they experience psychological distress.
Following the psilocybin session, participants go through a process known as integration, which involves two sessions with a therapist within 2 weeks.
“That, in our view, is essentially about safety, and about identifying problems that have arisen as a result of taking the drug,” said Goodwin.
The phase 2b trial examined changes in specific depression symptoms after psilocybin treatment in 233 patients with TRD. Participants were a mean age of 39.8 years and 59% were women. They were randomized to receive one of three doses of the drug: a 1-mg dose (n = 79), a 10-mg dose (n = 75), or a 25-mg dose (n = 79).
The primary outcome was changes in individual items on the Montgomery-Åsberg Depression Rating Scale (MADRS) and 16-item Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR-16) scale.
While the effect on overall depression scores is important, said Goodwin, many of the items included in the depression assessment scales are “uninformative.”
Reduction in “Core” Symptoms
Participants were assessed by a blinded rater at baseline, day 1, day 2, and at 1, 2, 3, 6, 9, and 12 weeks after administration of COMP360. The primary endpoint was a reduction in individual items on MADRS and scored from baseline to 3 weeks. Individual items on the QIDS-SR-16 were rated by participants at the same time points.
Investigators found the largest mean changes from baseline were on reported and apparent sadness, lassitude, inability to feel, and concentration difficulties, with “very nice and clear dose-related differences,” Goodwin said.
The results indicate that the significant benefit with the largest dose at 3 weeks versus baseline was confined to items such as inability to feel and reported and apparent sadness on the MADRS and feeling sad and general interest on the QIDS-SR-16 (Table 1).
The results suggest the effect of COMP360 is “on the core symptoms of depression,” said Goodwin.
Table 1. Changes in MADRS and QIDS-SR-16 With COMP360 at Week 3
| Mean change from baseline at Week 3 (SD) | |||
|---|---|---|---|
Item | Psilocybin 25 mg | Psilocybin 10 mg | Psilocybin 1 mg |
| MADRS Inability to feel Apparent sadness Reported sadness Lassitude | –1.8 (1.81) –1.7 (1.94) –1.6 (1.95) –1.6 (1.81) | –0.9 (1.54) –1.1 (1.60) –1.0 (1.52) –1.2 (1.52) | –0.8 (1.61) –0.9 (1.62) –0.6 (1.53) –0.6 (1.53) |
| QIDS-SR | –1.1 (1.08) | –0.8 (1.07) | –0.4 (0.91) |
SD, standard deviation
Results were similar for individual items on the QIDS-SR-16, with the greatest changes in items including feeling sad, general interest, energy level, falling asleep, view of myself, concentration/decision-making, and feeling down.
Other scale items, such as decreased appetite, feel restless, and weight changes, showed negligible changes in response to COMP360 therapy and were described by Goodwin as “inconsequential.”
“Essentially, these items are contributing nothing but noise to the signal,” he said.
He added the results of the study need to be replicated and that plans for phase 3 trials are underway. These studies, he said, are designed to convince the US Food and Drug Administration that “this is not just a recreational drug, it’s a medicine.”
Enthusiasm Running Ahead of the Data
Commenting on the findings, Bertha K. Madras, PhD, professor of psychobiology, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, who was not involved in the study, said “hallucinogens are an intriguing class of drugs and I support ongoing high-quality research in this area.”
However, she told Medscape Medical News that the “breathtaking endorsement of this drug is far ahead of scientific data.”
She cited concerns such as the “narrow demographics” of participants, their previous experience with and expectations of hallucinogens, the “potential for symptom fluidity of enrollees,” such as depression evolving into psychosis, and the “undefined role” of the therapist during a hallucinogenic session.
“Finally, I am concerned that enthusiasm for therapeutic potential has been, and will continue to be, preempted and directed towards legalization and widespread access for vulnerable populations,” Madras said.
This, she said, “is occurring at breakneck speed in the US, with scant resistance or skepticism from the investigators engaged in therapeutic assessment.”
The study was funded by COMPASS Pathways. Goodwin has reported relationships with COMPASS Pathways, Buckley Psytech, Boehringer Ingelheim, Clerkenwell Health, EVA Pharma, Lundbeck, Janssen Global Services, Novartis, Ocean Neurosciences, P1vital, Sage Therapeutics, Servier, Takeda, and WebMD.
European Psychiatric Association (EPA) 2023 Congress. Abstract O0068. Presented March 27, 2023.
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