Psilocybin combined with pimavanserin for treating major depression

Investigating the Role of Serotonin in the Mechanism of Action of Psilocybin in Patients With Major Depressive Disorder

This study is testing whether combining psilocybin with a medication called pimavanserin can help people with major depression feel better compared to using psilocybin alone.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 21 Years to 80 Years
• Sex: All
• Sponsor: Icahn School of Medicine at Mount Sinai (Academic / other)
• Locations: 1 site (New York, New York)
• Trial ID: NCT06592833 on ClinicalTrials.gov

What this trial studies

This interventional study examines the effects of psilocybin in combination with pimavanserin compared to psilocybin alone in individuals diagnosed with Major Depressive Disorder (MDD). Participants will receive a single dose of either pimavanserin or a placebo alongside psilocybin, with evaluations conducted before and after dosing over a period of five weeks. The study aims to explore the role of the 5-HT2A receptor in the antidepressant effects of psilocybin, distinguishing between the psychedelic experience and the therapeutic response. By understanding these mechanisms, the research seeks to improve treatment strategies for MDD.

Who should consider this trial

Good fit: Ideal candidates are adults aged 21-80 with a primary diagnosis of Unipolar Major Depressive Disorder without psychotic features.

Not a fit: Patients with a recent history of substance use disorder or current psychiatric hospitalization may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to more effective treatment options for patients suffering from Major Depressive Disorder.

How similar studies have performed: Previous studies have indicated potential benefits of psilocybin for depression, but this specific combination approach is novel and has not been extensively tested.

Eligibility criteria

Inclusion Criteria:

* Age 21-80 years, any gender
* Current primary diagnosis of Unipolar Major Depressive Disorder (MDD) without psychotic features using DSM-5 criteria
* 24-item Hamilton Rating Scale for Depression (HRSD) ≥16
* Current diagnosis of Major Depressive Episode (MDE)
* Capable of providing informed consent and complying with study procedures
* Currently using or agreeing to use a highly effective contraception, if person of childbearing potential (such as condoms, IUD, or oral contraceptive), for duration of the study. Male participants agree to use highly effective contraception with partners of childbearing potential
* Discontinuation of any serotonergic drug for at least 2 weeks or 5 half-lives (whichever of the two is longer) prior to psilocybin exposure

Exclusion Criteria:

* Any severity of substance use disorder in the last 6 months (excluding tobacco use disorder) as determined by DSM-V criteria via the SCID
* Current psychiatric hospitalization or psychiatric hospitalization within the last 6 months
* Use of psychedelics in the last 12 months
* Non-medical or illicit use of ketamine in the past 12 months
* Negative reaction after prior use of psychedelics
* Past or current psychotic disorder (including psychotic MDD), mania, or bipolar disorder
* Severe depression as indicated by Clinical Global Impressions (CGI)-Severity score ≥ 5 at baseline
* Significant suicidal ideation as indicated by C-SSRS \> 2 in the past 6 months at time of screening
* Suicide attempt in the past 2 years, or clinician concern that the patient poses a risk to self or others
* Acute, severe, or unstable medical illness
* Weight \> 300 lbs., or girth size incompatible with scanner bore
* Any conditions/qualities that make participation in MRI imaging unsafe\*
* Any physical or intellectual disability adversely affecting ability to complete assessments.
* Current pregnancy or currently breast feeding.
* Any clinically significant abnormal lab test result, including clinically significant abnormal baseline liver and/or renal function tests
* Currently being treated with a contraindicated medication. Contraindicated medications include antipsychotic medications, serotonergic antidepressant medications, and mood stabilizers that may attenuate the effects of psilocybin. Strong CYP3A4 inhibitors and inducers are also contraindicated. UGT1A9 and UGT1A10 inhibitors, monoamine oxidase, and aldehyde or alcohol dehydrogenase inhibitors are prohibited concomitant medications.
* History of abnormal QT prolongation or QTc interval \>450 ms on screening
* Use of medications known to prolong the QT interval
* Any congenital prolongation of the QT interval or a family history of long QT syndrome
* A family history of sudden cardiac or unexplained death
* A family history in a first-degree relative of psychosis/schizophrenia or related disorders
* A first-degree family history of bipolar disorder
* A history of cardiac arrhythmias or who require treatment with an antiarrhythmic medication
* A history of any cardiovascular disorder/condition known to increase the possibility of QT prolongation, or any other risk factors for prolonged QT interval/tosades de pointes (including symptomatic bradycardia, hypokalemia, hypomagnesemia, hypocalcemia, heart failure, or Brugada Syndrome)
* Preexisting cardiovascular conditions, including cardiac valvulopathy, pulmonary hypertension, hypertension, tachycardia, and any cardiovascular conditions that may be worsened/exacerbated by elevated blood pressure or heart rate.
* Baseline vital sign parameters at screening and on day of dosing prior to dose that exceed to the following values for systolic blood pressure (SBP), diastolic (DBP), and heart rate (HR): SBP \> 139 mmHg, DBP 89 mmHg, and HR \> 90 bpm
* Hypersensitivity to either psilocybin or pimavanserin
* Psychiatric or other condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin
* Positive urine toxicology at screening
* Any clinically significant abnormalities on 12-lead electrocardiogram (ECG)
* Mini-Mental State Examination (MMSE) score \< 25
* Brief Psychiatric Rating Scale (BPRS-6) \> 5
* Potential fall risk

Where this trial is running

New York, New York

• Icahn School of Medicine at Mount Sinai, Center for Psychedelic Therapy Research — New York, New York, United States (Recruiting)

Study contacts

• Principal investigator: James Murrough — Icahn School of Medicine at Mount Sinai
• Study coordinator: Depression and Anxiety Center Icahn School of Medicine at Mount Sinai

Conditions Major Depressive Disorder