Psilocybin With Pimavanserin Compared to Psilocybin Alone for the Treatment of Major Depressive Disorder

Prior treatment

• Negative reaction after prior use of psychedelics
• 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.
• A history of cardiac arrhythmias or who require treatment with an antiarrhythmic medication
• 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

Other illness

• 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
• Past or current psychotic disorder (including psychotic MDD), mania, or bipolar disorder
• Acute, severe, or unstable medical illness
• Any conditions/qualities that make participation in MRI imaging unsafe\*
• 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
• 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.
• 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
• Brief Psychiatric Rating Scale (BPRS-6) \> 5

Lab values

• 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 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)

Other

• Use of psychedelics in the last 12 months
• Non-medical or illicit use of ketamine in the past 12 months
• 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
• Weight \> 300 lbs., or girth size incompatible with scanner bore
• 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
• Positive urine toxicology at screening
• Any clinically significant abnormalities on 12-lead electrocardiogram (ECG)
• Mini-Mental State Examination (MMSE) score \< 25
• Potential fall risk

• 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