Swinburne Three-dose Psilocybin Assisted Psychotherapy (3PAP): a clinical trial of 2 vs 3 doses of psilocybin-assisted psychotherapy vs psychotherapy with placebo for Treatment-Resistant Depression

INTERVENTION: There will be two intervention arms and one control arm. Arm 1: 3 dose‐sessions of 25 mg oral psilocybin + psychotherapy Arm 2: 2 dose‐sessions of 25 mg oral psilocybin + psychotherapy Arm 3 (control): 3 dose‐sessions of oral inactive placebo + psychotherapy Each dose session will be 6‐8 hours in length, and will occur at the following time points: 1: 1 week post baseline; 2: 5 weeks post baseline; 3: 18 weeks post baseline. Administration of psilocybin and inactive placebo will be by oral tablet with neutral excipient, and will occur under direct supervision of a medical practitioner at the study site. All psychotherapy associated with the intervention will be administered face‐to‐face by a trained co‐therapist dyad consisting of one medically‐trained health professional (psychiatrist, psychiatry registrar, GP, or physician) and one psychologist. Psychotherapy will involve 2 Preparatory Sessions prior to Dose Session 1, at which time participants will be provided with information relating to psilocybin and its psychotropic effects. Supportive psychotherapy provided on‐site during Dose Sessions will consist of non‐directive psychological support within the context of a largely non‐interventional approach. Each Dose Session will be followed by 3 Integration Sessions, during which participants will be invited to discuss their experience during the Dose Session, and engage in analysis and meaning‐making to consolidate any therapeutic outcomes accrued during the experience. CONDITION: Mental Health ‐ Depression Treatment‐Resistant Depression; ; Treatment‐Resistant Depression PRIMARY OUTCOME: To determine if two dosing sessions of psilocybin‐assisted psychotherapy (PAP) significantly reduces depressive symptoms compared to psychotherapy with placebo: i) immediately after the second dosing session (week 5), and ii) at short‐term follow‐up 3‐months after the second dosing session (week 17) using the clinician‐rated Montgomery‐Åsberg Depression Rating Scale (MADRS) in comparison to baseline (week 0).[Weeks 5 and 17 after baseline measure] SECONDARY OUTCOME: Changes in participant anxiety (Generalized Anxiety Disorder 7‐item: GAD‐7) compared to psychotherapy with placebo. [17 weeks after baseline measures.] Changes in participant cognitive function (using a brief battery) compared to psychotherapy with placebo.[17 weeks after baseline measures.] Changes in participant employment status (World Health Organization Health and Performance Questionnaire: HPQ) compared to psychotherapy with placebo.[17 weeks after baseline measures.] Changes in participant quality of life (Assessment of Quality of Life – 8 Dimensions: AQOL‐8D) compared to psychotherapy with placebo.[17 weeks after baseline measures.] Comparison of three‐dose PAP versus two‐dose PAP versus psychotherapy with placebo on depression as determined using the MADRS.[6 and 12 months after 2nd dosing session.] Long‐term sustainability of change on the MADRS in response to two‐dose PAP.[6 and 12 months after 2nd dosing session.] Perceptions of individuals with TR‐MDD in terms of their recovery in relation to PAP (Recovery Assessment Scale – Domains and Stages: RAS‐DS).[17 weeks after baseline measures.] Self‐reported changes on the Beck Depression Inventory II (BDI‐II).[Every 4 weeks after baseline measures until the final face‐to‐face assessment at 12 months after baseline.] INCLUSION CRITERIA: ‐ Adults aged 18 to 65 years. ‐ Those currently experiencing major depressive disorder (DSM‐5) as determined by the SCID‐5. ‐ Those with current moderate to severe depression according to the MADRS. ‐ Treatment‐resistance using the criteria of Sforzini et al. (2022). ‐ Under the care of a psychiatrist, psychologist, physician, or GP. ‐ Proficiency in English. ‐ Safe tapering and wash‐out of current antidepressant pharmacotherapy prior to baseline assessment, as confirmed by treating GP, psychiatrist, or physician. ‐ Abstinence from illicit or extra‐medical drug and alcohol use for at least 2 days prior to each dose session. ‐ Participants who agree to have their drug dosing sessions recorded to video for treatment fidelity and clinical supervision within the study team. ‐ Participants who are able to swallow tablets.