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NEW ORLEANS -- When combined with psychological support, just one dose of psilocybin therapy improved treatment-resistant depression, according to a phase IIb study reported here.

Compared with patients who had a 1-mg dose, those who received a 25-mg dose of investigational COMP360 psilocybin saw a significant reduction in Montgomery-Åsberg depression rating scale (MADRS) total score from baseline at week 3 (least square mean treatment difference of -6.6, 95% CI -10.2 to -2.9, P<0.001) -- meeting the study's primary endpoint -- said Guy Goodwin, MD, chief medical officer of COMPASS Pathway in London, which is developing the product.

The results, which he presented at the American Psychiatric Association (APA) annual meeting, showed that the 25-mg dose demonstrated a statistically significant improvement as early as the second day.

The therapeutic benefits were also sustained through week 12 of follow-up. Goodwin told 番茄社区app that 20.3% of patients who received the 25-mg dose were considered "sustained responders" at week 12. He added that his group is also conducting a long-term follow-up analysis of these patients to "understand durability beyond this."

The third arm of the trial, which measured a 10-mg dose of COMP360, wasn't significantly different compared with the 1-mg dose (MADRS score treatment difference -2.5 points, 95% CI -6.2 to 1.2, P=0.184), Goodwin said. Only 5.3% in the 10-mg group were considered sustained responders. By comparison, the sustained response rates at week 12 was 10.1% in the 1-mg group.

"Psilocybin therapy has long held promise for treating mental health conditions, but we didn't know what to expect in a larger, randomized, and controlled clinical trial," said Goodwin. "We were very pleased by the findings."

Acting as a tryptamine alkaloid, psilocybin is found in Psilocybe mushrooms and is commonly known as "magic mushrooms." The developer first received a from the FDA in 2018 for treatment-resistant depression.

"We generated highly statistically significant, robust data, showing a rapid and sustained response for patients in the 25-mg group, as well as improvement in measures of anxiety, positive and negative affect, quality of life, daily functioning, and self-reported depression," Goodwin said.

The next step, he said, is to understand what the results will look like in an even larger number of patients, and to test the investigational agent in a pivotal phase III program, expected to begin later this year.

"We are currently finalizing its design in discussion with regulators," he said.

A total of 233 eligible participants were randomized to one of the three study arms following a 2-week or longer washout period of other antidepressant treatments. All participants were age 18 or older and met the DSM-5 criteria for major depressive disorder (MDD). About half were female, and the average age was 40. A total of 92% of the participants were white, and 6% had reported prior psilocybin use.

On average, patients experienced 6.9 depressive episodes and 85.8% had recurrent MDD. The majority had a severe (≥31) MADRS total score at baseline.

All participants had a 17-item Hamilton Depression Rating Scale score of at least 18 at baseline. They also had to meet criteria for treatment-resistant depression, defined as having a current depressive episode that didn't respond to an adequate dose and duration of two to four antidepressant treatments based on the Massachusetts General Hospital Antidepressant Treatment History Response Questionnaire. Within that, augmentation therapy was considered an independent treatment if the add-on drug was approved for adjunctive treatment of MDD in the study site country.

Exclusion criteria included a history of a serious psychiatric comorbidity like schizophrenia or bipolar disorder, or treatment for the current depressive episode with electroconvulsive therapy, ketamine/esketamine, or cognitive behavioral therapy. Participants also couldn't meet the DSM-5 criteria for significant suicide risk or alcohol or substance use disorder.

COMP360 was administered once during a 6- to 8-hour long session supported by a trained therapist. On the day of administration, the most common adverse events were headache, nausea, and dizziness. One participant on the 25-mg dose was treated with lorazepam (Ativan) for acute anxiety.

While no serious treatment-emergent adverse events were reported in the 1-mg group during follow-up, a few participants on the higher doses experienced suicidal ideation, intentional self-injury, and hospitalization for severe depression.

Of note, among the three participants in the 25-mg group that experienced suicidal behavior as an adverse event, all three were MADRS non-responders at week 3.

There also weren't any significant differences between the treatment groups in regards to vital signs or clinical lab tests. On day 2, two 25-mg participants experienced a change from baseline QTcF over 60 msec with a 12-lead ECG (403 msec and 515 msec), but both normalized by day 9 (to 363 and 367 msec).

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