Psilocybin Single-Dose for Treatment-Resistant Major Depressive Disorder
FIELD VIGNETTE
A 39-year-old African American man named "Mr. Mora" has a history of severe major depressive disorder (MDD) that has come and gone without psychosis. Early youth was when his depression first appeared. Sertraline, bupropion, venlafaxine, nortriptyline, lithium, aripiprazole, and perphenazine studies that Mr. Mora had previously undergone were unsuccessful. Additionally, he receives monthly cognitive-behavioral therapy from a psychologist. His current medication includes amphetamine-dextroamphetamine extended-release 20 mg day and fluoxetine 80 mg daily, to which he has responded partially.
Mr. Mora inquires about psilocybin at his most recent outpatient clinic visit and specifically inquires about whether he qualifies for therapy with supplementary psychedelics. How would you react if you were his psychiatrist?
Failure of two distinct treatment modalities is the definition of treatment-resistant depression (TRD). Compared to patients with treatment-responsive depression, people with TRD experience longer illness duration, more severe illness, disability, physical sickness, a higher risk of suicide, and higher economic expenditures. In patients with MDD and TRD, psilocybin has proven to have antidepressant effects.1-3
The Present Research
A phase 2 double-blind, dose-finding, parallel group, randomized controlled trial was carried out by Goodwin and colleagues4. The trial was developed, funded, and supplied with a proprietary, pharmaceutical-grade synthetic version of psilocybin (COMP360) by the study's sponsor, COMPASS Pathfinder.
The statistical analyses, as well as the trained, blinded, remote raters' assessments of the participants using the Montgomery-Sberg Rating Scale (MADRS), were carried out by an independent contract research firm (MedAvante-ProPhase). In addition to doing post-hoc statistical analyses and data interpretation, the sponsor also paid for expert writing support for the first draft of the publication.
A TRD is a depressive episode without psychotic symptoms that has not responded to a sufficient dose and duration ( 8 weeks) of 2 to 4 pharmacological therapies for the current episode. The authors sought out persons 18 years of age and older with TRD. Between March 2019 and September 2021, the experiment was conducted at 22 locations across Europe and North America. Antidepressants and drugs that impact the central nervous system (CNS) were reduced and stopped at least two weeks prior to the baseline visit during the 3- to 6-week run-in phase for eligible participants. The individuals saw a study therapist at least three times throughout this time.
Patients were randomly assigned 1:1:1 to receive a single dose of 25 mg, 10 mg, or 1 mg of psilocybin (the control). A lead therapist was present for the 6- to 8-hour administration session. The measurement of blood pressure was continuous. Participants donned headphones with a specially created music playlist and sunglasses. After therapy, individuals were monitored for 12 weeks, during which time there were 2 post-treatment integration meetings.
The MADRS change from baseline (day -1) to week 3 in the 25 mg- and 10 mg-dosage groups relative to the 1-mg dose was the main effectiveness goal. The percentage of responders (MADRS total score improvement of at least 50%) and remitters (MADRS total score less than 10) at week 3 and sustained response (response from week 3 maintained through week 12) were considered secondary objectives. The Columbia Suicide Severity Rating Scale, vital signs, clinical laboratory tests, and electrocardiogram (ECG) were all evaluated as part of safety assessments.
According to the authors' calculations, a sample of 216 participants (72/group) would have 90% power to identify a 6-point difference in the mean MADRS total score between baseline and week 3. The modified intention-to-treat analysis set was used for efficacy analyses. Through the use of a mixed model for repeated measures analysis, the primary effectiveness endpoint (change in MADRS total score) was assessed. Binary logistic regression was used to examine sustained response, whereas generalized linear mixed models were used to analyze response and remission.
428 subjects in all underwent screening; 233 were randomly assigned to undergo psilocybin treatment (79 25 mg, 75 10 mg, 79 1 mg). Participants' average age was 40, 52% of them were women, and 92% were white. Mean MADRS scores were 32 to 33 at baseline, and two-thirds of the subjects were taking antidepressants.
The MADRS total score changed by a least-squares mean of -12.0 in the 25 mg group, -7.9 in the 10 mg group, and -5.4 in the 1 mg group from baseline to week three. For the 25- versus 1-mg groups, this change was statistically significant, but not for the 10- versus 1-mg groups. There was a 37% response rate in the 25 mg group, a 19% response rate in the 10 mg group, and an 18% reaction rate in the 1 mg group. This means that the 25 mg group had a 2.9-fold higher response rate than the 1 mg group.
There was a 29% incidence of remission in the 25 mg group, a 9% incidence in the 10 mg group, and an 8% incidence in the 1 mg group. This means that the 25 mg group had a 4.8-fold higher chance of responding than the 1-mg group. There was no statistically significant difference between the groups in the incidence of prolonged remission, which was 20% in the 25-mg group, 5% in the 10-mg group, and 10% in the 1-mg group.
There were adverse events in 84% of the 25 mg, 75% of the 10 mg, and 72% of the 1 mg groups, but there was no statistically significant difference between the groups. On the day of administration, headache, nausea, dizziness, and exhaustion were the most common side reactions. Between day two and week three, the 25- and 10-mg groups experienced serious adverse events, such as suicide ideation in four cases, non-suicidal self-injurious conduct in three cases, and one hospitalization for depression. During this time, there were no severe adverse events in the 1-mg group. Vital signs, clinical laboratory testing, and ECG showed no clinically significant alterations.
Study Findings
The trial, according to the authors, demonstrated the viability of psilocybin monotherapy for up to 12 weeks in TRD patients. With 25 mg, but not 10 mg, compared to the 1-mg dose, the MADRS total score shift from baseline to week three was noticeably superior. Headache, nausea, lightheadedness, and exhaustion were among the side effects that were reported. The 25- and 10-mg groups also showed statistically greater levels of suicidal ideation and self-harming behavior.
absence of an active comparator, absence of an ethnically varied participant sample, and exclusion of persons at clinically high risk for suicide are some of the study's weaknesses. Despite the fact that it was not tested, the strength of the immediate subjective effects of 25- and 10-mg psilocybin may have decreased the effectiveness of trial blinding.
The conclusion
In patients with TRD, a single dose of 25 mg psilocybin significantly decreased depression scores over the course of three weeks compared to 1 mg. To ascertain the effectiveness and safety of psilocybin in this patient population, larger and longer trials are necessary, along with comparisons with already available therapies.