Journal Club: Trial of Psilocybin versus Escitalopram for Depression

An interesting trial was published in the New England Journal of Medicine that compared Psilocybin versus the SSRI antidepressant, Escitalopram, for the treatment of depression. Psilocybin is a hallucinogenic mushroom that is commonly known as “shrooms” or “magic mushrooms”. This trial took place at the Centre for Psychedelic Research at the Imperial College in London. With funding from the Alexander Mosley Charitable Trust.¹

Background

Major depressive disorder is a mood disorder characterized by depressed mood and loss of interest or pleasure in activities that used to be pleasurable. Additional symptoms include changes in sleep, feelings of guilt, energy changes, concentration difficulties, appetite changes, psychomotor changes such as repetitive movements or decreased movements and suicidal ideations. To receive the official diagnoses, the symptoms must occur for at least two weeks and cause significant impairment.

Depression is typically treated with psychotherapy and medications. One of the biggest difficulties with current treatments is how long the treatments take to work. Medications can take over two months to take full effect. New treatments, like psilocybin, are being studied to see if they can work faster. Additionally, efficacy is a concern. Therapy is extremely helpful in forming new pathways in the brain and treating depression. One recent study found that 42-61% of patients had their depression scores cut in half at three months, and at 12 months, these numbers were between 61-76%.² Medications have similar efficacy with 40-60% of patients noting a benefit after 8 weeks.³

Psilocybin is currently a Schedule I substance in the United States, which means that it is illegal to have and use. The ritualistic use of mushrooms is ancient and statues from 100 – 1400 AD are found throughout Mexico and Central America. Low doses cause perceptual changes, relaxation, and physical heaviness or lightness. High doses can cause dizziness, lightheadedness, numbness, sweating, nausea, and anxiety. Experiences with hallucinogenic mushrooms vary from pleasant to scary.

One of the mysteries with hallucinogenic mushrooms is exactly how they work in the brain. It is believed that psilocybin stimulates subtypes of serotonin receptors such as 5HT-2A and 5HT-2C. Every experimental drug tested that stimulates 5HT-2A caused hallucinations. What is confusing is that standard antidepressants increase the effects of serotonin at all serotonin subtypes, including 5HT-2A, but they do not cause hallucinations.

Previous trials

1. An open label trial of 20 patients was conducted. The patients received two doses of psilocybin 10 and 25 mg in a supportive setting 7 days apart to treat their treatment resistant depression. At week five, nine (45%) of the patients had a response in their depression and four (20%) patients reached remission.⁴
2. A study assessed the difference between low dose and high dose psilocybin on cancer related anxiety and depression. They started the low dose group on 3 mg/ 70 kg but decreased the dose to 1 mg/ 70 kg after another study found significant effects from psilocybin at 5 mg/ 70 kg. The high dose group was also decreased from 30 mg/ 70 kg to 22 mg/ 70 kg after a few patients withdrew from the study after receiving the 30 mg/ 70 kg. The study found that after the second session, 75% and 58% of patients in the low dose group reached response and remission respectively. In the high dose group, 84% and 68% reached response and remission respectively. Additionally, the authors stated that although it is assumed 1 mg/ 70 kg would be inert, the possible effects cannot be ruled out entirely. ⁵

Trial Rationale

Psilocybin may have antidepressant properties but has not been extensively studied compared to existing treatments for depression.

Methods

This is a phase 2, double-blind randomized controlled trial in patients with moderate to severe major depressive disorder. A phase 2 trial is a trial conducted with an investigational medication in those with the disease state in question. This differs from a phase 1 trial, where the investigation medication is given to healthy subjects to test its safety. Phase 1 trials are conducted before phase 2 trials which are conducted before phase 3 trials.

Patients were assigned in a 1:1 ratio to two groups.

• Group one: 25 mg of psilocybin three weeks apart plus six weeks of daily placebo
• Group two: 1 mg of psilocybin three weeks apart plus six weeks of daily escitalopram

Patients were able to participate in the trial if they met the following inclusion criteria.

1. Diagnosis of major depressive disorder (DSM-IV), moderate to severe degree (17+ on the 21-item HAM-D).
2. No MRI or SSRI contraindications
3. Has a GP (general practitioner) or other mental healthcare professional who can confirm diagnosis
4. 18-80 years of age
5. Sufficiently competent with English language
6. Had to discontinue any psychiatric medications two weeks before starting a trial medication
7. Had to discontinue psychotherapy three weeks before starting a trial medication

Patients were excluded from the trial if they met the following exclusion criteria.

1. Current or previously diagnosed psychotic disorder or an immediate family member with a diagnosed psychotic disorder
2. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, abnormal QTc, hepatic or renal failure)
3. History of serious suicide attempts requiring hospitalization.
4. Significant history of mania (determined by study psychiatrist and medical records)
5. Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. borderline personality disorder
6. Blood or needle phobia
7. Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding or participants who do not agree to use an acceptable contraceptive method throughout their participation in study.
8. Current drug or alcohol dependence (previous use of psilocybin was allowed)
9. No email access
10. Use of contraindicated medication
11. Previous use of escitalopram

Trial Design

The patients were required to attend six visits over a six-week time period.

1. Visit one: visit one consisted of an MRI, a battery of cognitive exams and a preparatory therapeutic session.
2. Visit two: one day after visit one, the patients in the psilocybin group received 25 mg of psilocybin, and those in the escitalopram group received 1 mg of psilocybin, which was presumed to have negligible activity. During dosing days, two mental healthcare providers were assigned to each patient and they cared for the physical and psychological needs of the patients during and after the administration of the medication. Before patients left, they were given a bottle of capsules. The patients who received psilocybin 25 mg, received a placebo, and the patients who received 1 mg of psilocybin received 10 mg of escitalopram daily.
3. Visit three: Visit three occurred one day after visit two and included a psychological debriefing. An additional debriefing by telephone or video call occurred one week later.
4. Visit four: visit four occurred three weeks after visit two. During this visit, the patients received their second dose of psilocybin 25 mg or placebo (psilocybin 1 mg). After this session, the patients were asked to take two capsules daily (either two placebo capsules or two escitalopram 10 mg capsules)
5. Visit five: visit five took place one day after visit four. During this visit, a psychological integration session involving open, attentive listening was held.
6. Visit six: three weeks after visit five, the final visit took place. During this visit, patients received a final MRI, battery of cognitive exams and a psychological debriefing.

Outcomes

The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR-16) at 6 weeks.

Secondary outcomes included response at 6 weeks according to the QIDS-SR-16 (defined as a decrease in score of ≥50% from baseline); remission at 6 weeks according to the QIDS-SR-16 (defined as a score of 0 to 5) and more.

Statistical Analysis

The study was conducted with the ability to detect a difference between the groups at a two-sided level of P<0.05 with 80% power. This required 20 patients per treatment arm and more than that were included in the study.

The primary outcome was compared between the trial groups with the use of repeated-measures analysis of covariance (ANCOVA), with adjustment for baseline scores.

Results

1000 patients were screened and 59 were randomized. 30 patients received high dose psilocybin and 29 patients received low dose psilocybin and escitalopram. Of the enrolled patients, 23 (39%) discontinued a psychiatric medication before entering the trial, and 4 (7%) discontinued psychotherapy. The mean age of trial participates was 41 years and 34% of participants were female. 88% of participants were white. The average duration of depression was 22 years in the high-dose psilocybin group and 15 years in the low-dose psilocybin plus escitalopram group. QIDSSR-16 scores at baseline were 14.5 and 16.4, respectively.

The mean difference from baseline in the QIDS-SR-16 score at week six was −8.0±1.0 in the high dose psilocybin group and −6.0±1.0 in the low dose psilocybin group plus escitalopram group. This indicated no significant difference between the groups. Though not statistically significant, 70% of patients in the high dose psilocybin group were responders at six weeks compared to 48% of patients in the low dose psilocybin plus escitalopram group. Remission was met by 57% of high dose psilocybin patients as compared to 28% of low dose psilocybin plus escitalopram patients.

Safety

Neither group reported any serious side effects. 87% in the high dose psilocybin group and 83% in the low dose psilocybin group plus escitalopram reported some side effects. The most common side effects in both groups were headaches followed by nausea. Of note, the psychedelic experience or altered consciousness were not included as a side effect.

Discussion

The trial had several strengths. The first strength is that the experimental treatment of psilocybin was compared to a well-established treatment in escitalopram. The trial exceeded the number of patients necessary to reach statistical power. Additionally, the trial utilized a validated scale in the QIDS-SR-16.

A limitation of the trial is the duration, as traditional antidepressants require two months to reach maximum efficacy. Scores may continue to improve in the escitalopram group if the duration was longer. Additionally, blinding the participants to their group would be difficult because the high dose psilocybin group had more cognitive effects than the low dose psilocybin group plus escitalopram. The study participants were not from diverse backgrounds. The average age was 41 and 66% were men and 88% were white. This may limit the applicability to other population groups. Average depression scores were moderate and may limit extrapolation to severely depressed patients. Additionally, both groups received psilocybin. Low vs high dose psilocybin has not been extensively studied in the treatment of depression. Low dose psilocybin was assumed to be inert but may show efficacy in the future.

References

1. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994. PMID: 33852780.
2. Saloheimo HP, Markowitz J, Saloheimo TH, et al. Psychotherapy effectiveness for major depression: a randomized trial in a Finnish community. BMC Psychiatry. 2016;16:131. Published 2016 May 6. doi:10.1186/s12888-016-0838-1.
3. InformedHealth.org [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? [Updated 2020 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK361016/.
4. Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, Kaelen M, Giribaldi B, Bloomfield M, Pilling S, Rickard JA, Forbes B, Feilding A, Taylor D, Curran HV, Nutt DJ. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018 Feb;235(2):399-408. doi: 10.1007/s00213-017-4771-x. Epub 2017 Nov 8. PMID: 29119217; PMCID: PMC5813086.
5. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513. PMID: 27909165; PMCID: PMC5367557.