Study Provides New Data About Treating Bipolar II Depression

As reviewed in recent posts, bipolar I and bipolar II disorders are associated with substantial functional impairments and increased mortality. Depressive episodes associated with bipolar disorder do not respond well to current treatments, and such treatments can have significant side effects. For example, treatment with antidepressants may trigger manic or hypomanic episodes.

Psilocybin coupled with a treatment-specific form of therapy may help treat major depressive episodes in individuals who do not have bipolar disorder. But can this treatment be safely administered to those with treatment-resistant, bipolar depression? In a small study published in JAMA Psychiatry, Scott Aaronson and colleagues report on the use of psilocybin together with therapy in 15 patients with treatment-resistant, bipolar II depression.

STUDY DESIGN

Because of the complexities in conducting clinical trials with psychedelic agents, we will describe this study in some detail to help readers understand how this type of research is conducted. These details also will likely impact how psychedelics are used if they are eventually approved for clinical use.

This was an open-label study, meaning that participants and investigators knew that people enrolled in the study would receive psilocybin. There was no control group. Therefore, results regarding efficacy must be interpreted cautiously and as preliminary.

Fifteen patients with treatment-resistant bipolar II depression were enrolled in the study. Their mean age was 37.8 years. Nine were female. They had suffered from bipolar II disorder for a mean duration of 9.4 years. Their current depressive episode must have lasted more than three months to be included in the study, and the mean duration was 2.5 years. All had failed at least two adequate pharmacologic treatments for their current episode. Individuals with a history of bipolar I disorder, schizophrenia, psychosis, borderline personality disorder, or substance use disorder were excluded from the study.

Participants were asked to discontinue current psychotropic medications at least two weeks before the administration of psilocybin. Before drug administration, they met for at least three hours with a specially trained therapist to “build rapport, receive psychoeducation, and prepare for the psychedelic experience.” Two therapists were present during 8 to 9 hours of treatment monitoring, and participants saw the study physician at the end of the day to ensure they were safe to go home. They also met with the physician the day after treatment. Participants subsequently met with study therapists for three 1-hour sessions during the two weeks following treatment. These sessions were “meant to support the participant in consolidating insights from their psychedelic experience.” Participants were asked to refrain, if possible, from taking psychotropic medications for three weeks after psilocybin treatment.

The primary measure of depression severity was the clinician-rated Montgomery-Ǻsberg Depression Rating Scale (MADRS). Other depression and quality of life scales were also utilized. The emergence of suicidal ideation—and or manic or hypomanic episodes—after treatment was assessed with the Columbia Suicide Severity Rating Scale and the Young Mania Rating Scale. The strength of the psychedelic experience was determined with the Five Dimension Altered State of Consciousness Questionnaire.

The Question of Safety

As emphasized in an accompanying editorial by David Yaden, Natalie Gukasyan, and Sandeep Nayak, the results of this study regarding safety are of central importance. However, it is important not to be overly confident in a safety profile that is based on only 15 participants. There were no significant adverse events following psilocybin administration; the most common side effect was headache. Participants exhibited no indications of increased symptoms of hypomania-mania or suicidality. Yaden and colleagues suggest that a careful safety study including individuals with bipolar I disorder could now be considered given these results.

What Is the Efficacy?

A standard definition of treatment response is a 50 percent or more decrease in MADRS scores. A standard definition of depression remission is a MADRS score of 10 or less. The participants in this study had a mean MADRS score of 31.3 at baseline, indicating moderately severe depression. They demonstrated rapid improvement after treatment, which was already evident at the one-week assessment. At three weeks, 12 of 15 participants met the criteria for response and 11 fulfilled the criteria for remission. At 12 weeks, 12 participants met the criteria for remission. The investigators found that there was a correlation between the strength of the psychedelic experience and MADRS scores: the stronger the psychedelic effect, the greater the antidepressant response.

A self-report scale for depression severity also showed improvement by one week, which was maintained throughout the 12 weeks of the study. Similarly, substantial improvements in quality of life measures were recorded at three and 12 weeks.

Words of Caution

The results of this small, unblinded (open-label) study suggest that psilocybin accompanied by intensive therapy might be a reasonably safe and effective treatment for people with treatment-resistant bipolar II depression. Similar to the authors of the editorial, however, we are concerned that these findings may be overly interpreted as indicating the definite utility of psilocybin for this condition, which is presently premature. Many potential confounds in open-label studies could lead to such positive findings. In addition, this particular study (and others of its type) had a large therapy component that might have contributed to a placebo effect.

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This preliminary study supports conducting large, randomized, double-blind, placebo-controlled trials of psilocybin with therapy for bipolar depression. If such well-controlled studies demonstrate similarly positive results, that would be a step forward in developing therapeutic options for this devastating illness. Until such studies occur, individuals with bipolar II depression should refrain from attempting psilocybin treatment unless it is offered in a credible, well-designed research study.

This column was written by Eugene Rubin M.D., Ph.D., and Charles Zorumski M.D.