Table 1.

Inclusion and exclusion criteria

Inclusion criteria

Adult out-patients aged 18–65 years

Willingness to comply with all study procedures and agreement to lifestyle considerations throughout the study duration

Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent

Ability to take oral medication

All blood work within normal limits, including an eGFR > 40 mL/min/1.73 m2

Primary DSM-5 diagnosis of non-psychotic MDD, single or recurrent, based on the SCID-5 administered during the screening visit

Treatment-resistant depression defined as having a major depressive episode with a baseline HRSD score of >14 and no response to two or more trials of antidepressants at an adequate dosage and duration, based on the ATHF; there is no upper limit on the number of antidepressant treatment trials

Being off any antidepressant or antipsychotic medications for at least 2 weeks (or more depending on the medication) before baseline (visit 2) and for the duration of the study, with the participant's physician confirming that it is safe for the participant to do so

Being off any inhibitors of 5′-diphospho-glucuronosyltransferase (UGT)1A9 and 1A10, aldehyde dehydrogenase inhibitors and alcohol dehydrogenase inhibitors for at least 2 weeks (it can be longer depending on the medication) before baseline and for the duration of the study, with the participant's physician confirming that it is safe for the participant to do so

If the participant is capable of becoming pregnant, use of highly effective contraception for at least 1 month before screening and agreement to use such a method during study participation

Exclusion criteria

Pregnant as assessed by a urine pregnancy test at screening (visit 1) or baseline (visit 2), or intending to become pregnant during the study, or breastfeeding

Treatment with another investigational drugs or interventions within 30 days of screening or initiation of psychotherapy in the 12 weeks before screening

DSM-5 diagnosis of substance use disorder within the preceding 6 months (recreational use of tobacco, alcohol or cannabis, and prescribed opioids are permitted)

Active suicidal ideation with intent and plan as determined by item 3 of the HRSD

Any DSM-5 lifetime diagnosis (as determined by the SCID-5 clinical) of a schizophrenia spectrum disorder, other psychotic disorder (unless substance-induced or because of a medical condition), bipolar disorder type 1 or 2, obsessive–compulsive disorder or neurocognitive disorder Any DSM-5 lifetime diagnosis of paranoid or borderline personality disorder as determined by history

Any first-degree relative with a diagnosis of schizophrenia spectrum disorder, other psychotic disorder (unless substance-induced or because of a medical condition) or bipolar disorder type 1 or 2, as determined by interview of the participant and the family medical history form

Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke, uncontrolled hypertension, labile blood pressure, recent myocardial infarction, cardiac arrhythmia, severe coronary artery disease or moderate-to-severe renal or hepatic impairment

Presence of baseline prolonged QTc or torsade de pointes on the electrocardiogram, or history of long QTc syndrome or related risk factors

Lifetime use of serotonergic psychedelic drugs

Allergy or contraindication to risperidone, including insulin-dependent diabetes and history of hypoglycaemia on oral hypoglycaemic agent(s)

Any other clinically significant physical illness, including chronic infectious diseases, or any other concurrent illness that, in the opinion of the investigator, constitutes a health risk for the participant if they take part in the study or may interfere with the interpretation of the study results

eGFR, estimated glomerular filtration rate; MDD, major depressive disorder; SCID-5, Structured Clinical Interview for DSM-5; HRSD, Hamilton Rating Scale for Depression; ATHF, Antidepressant Treatment History Form; QTc, corrected QT interval.