Evaluating the management of treatment resistant depression with psychedelic (psilocybin) assisted psychotherapy (EMPACT)

The study is a randomised, double blinded, 4 arm parallel adaptive trial comparing the efficacy and safety of psychedelic (psilocybin) assisted psychotherapy (PAP) in people with treatment resistant depression, with an active comparator medication, dexamfetamine. The multi-arm adaptive design will compare three different psilocybin regimens to a control. All participants will engage in identical study procedures and therapy sessions, only the drug used within the groups will be varied. Within the 4 arms: Arm A is the control arm with Dexamfetamine administered in all three treatment sessions. Arm B and C include combined therapies of either Dexamfetamine or Psilocybin across the three treatment sessions. Arm D is the active arm with Psilocybin administered in all three treatment sessions. only. Each medication session will involve either a single dose of 25mg of psilocybin or 7.5mg of dexamfetamine (depending on treatment arm) via an oral tablet, up to 3 times, 2-4 weeks apart. At the start of the study, participants will be randomly assigned by chance through a computer-generated sequence to one of four groups (arms) and neither the participant nor any member of the treating team will know what group the participant has been allocated to, or what medication will be given during the sessions. The first 50 participants will be equally randomised to the initial 4 treatment arms in a 1:1:1:1 ratio. From then on, response adaptive randomisation (RAR) with control protection favouring the best performing arms will be used, with the probability of allocation to the remaining arms reassessed every 20 additional participants. Arms can be stopped for efficacy or futility at each interim analysis until the trial itself is stopped, or the maximum sample size of 130 (evaluable) participants is reached. Psychedelic assisted psychotherapy refers to the integration of the administration of a psychedelic drug with a specific form of trauma-informed psychological support/therapy. The aim of psychological support is to provide the participant with psychoeducation, develop therapeutic alliance and support strategies, establish trust and psychological safety, minimise anxiety, and support participants in staying with their emerging experience while maintaining safety, for both the participant and therapist. The therapists conducting these sessions are health/healing professionals (doctor, psychiatrist, psychologist, psychotherapist, counsellor, nurse) trained in the administration of psychedelic assisted psychotherapy. Therapy sessions common across all groups will involve several components: Preparation sessions: Within three weeks prior to the first medication session there will be two separate preparation sessions, at a minimum of four days apart. These sessions will be conducted either remotely via video conference or in person, with an experienced therapist who will be supporting the participant throughout the program. These two sessions will each take approximately 1-2 hours and will be scheduled as per the therapist’s assessment of the participants needs. Preparation 1: - Alliance development and formulation: the primary aims of the initial session will be the development of a therapeutic alliance, build trust and safety between the study therapists and the participant. - Listening to participant’s narrative of depression and treatment history to understand patterns of psychological inflexibility that are most prominent and ability to observe experience e.g., using mindfulness skills. - Clarify participant intentions for the medication session, anxieties and hopes for the experience. - Discuss ethical considerations and participant choices around use of touch, grounding techniques, and preferences such as music playlist, utilising eye mask, what can arise during a medication session, expectations and concerns and previous experience, media awareness or knowledge of psychedelic therapy. - Psychoeducation around psychological and physiological effects of psilocybin, who will be present, and the integration process. Preparing social support and integration for after the dosing session. Support person should be informed of the nature of the study. - Introduce Acceptance and Commitment Therapy (ACT), concept of psychological flexibility and observing experience with curiosity and openness, rather than avoidance. - Grounding exercises and scripts for difficult experience, information on non-ordinary states of consciousness, based on the study manual. Preparation 2: - Therapist continues to build trust and rapport with participant. - More explicitly focussed on ACT principles as they apply to the therapy process. - Collaboratively set intentions for the medicine session. - Discuss common experiences in psilocybin session including transpersonal, spiritual aspects and approaching difficult and intense experiences with openness and curiosity. - Collaborate on the use of various grounding exercises i.e., breathing techniques, sense of touch. - Practical guidance and safety instructions, including departure requirements with a nominated companion. Medication sessions: There will be three medication sessions conducted in person between two and four weeks apart. Each session will last up to 8 hours and will be conducted with each individual participant separately. Prior to the participant’s arrival, the room will be prepared such that it provides a safe, warm, private atmosphere with the provision for music, eye shades, gentle lighting, and the ability for the participant to lie down with an appropriate blanket and pillow. The participant will be allowed sufficient time to meet any additional medical / nursing staff who are going to be involved in the session and to understand everyone’s roles. Prior to commencement of the session the participant’s blood pressure, pulse and temperature will be checked to make sure these are within the acceptable/normal range. If the participant is of childbearing potential, they will be asked to perform a urine pregnancy test. A negative sample is required before medication administration. There will be a brief review of the expectations for the day along with an orientation to the space. Therapists will review participant consent and intentions for the medication session, and the techniques that the participant can use to deal with distress during a session (including asking for support and focusing on the breath). Participants will have the opportunity to trial and make comfortable the headphones/music and eyeshades used for the session prior to taking the medication. Therapists check in again with the participant around consent for supportive physical contact, as well as assuring participant they can say no to these interventions without offending therapists. Participants are required to stay at the clinic for the full duration of the treatment session after ingesting the medication. Clear commitment from participants is required during the trial consenting processes to stay in the study facility, even if they feel well and want to leave, until cleared to leave by study staff. For each dose administration, the participant will be given a single capsule of either psilocybin 25 mg or dexamfetamine 7.5mg, depending on the randomised treatment arm. After the participant has been cleared to proceed with the dosing session, the administration of the blinded substance will be carried out by a study doctor and registered nurse (or two registered nurses) and recorded into a study specific register. Both the participant and the treating study team will not know what medication is administered during the session. The capsule will be offered to the participant with a full cup of water and the ingestion of the capsule will be supervised by study personnel to ensure compliance. Administration of medication and completion of session will be documented within the treatment cycle timepoint data form. The participant’s blood pressure and heart rate will be monitored every 30 minutes during the first two hours and hourly afterwards until up to 3 hours (or longer if there is any indication or elevation on initial readings) by a medical practitioner or nurse who will be onsite for all sessions. In the unlikely event that more serious medical complications occur which require intensive medical attention, an ambulance will be called via 000. Interaction within the session: The therapist/s in attendance will adopt an approach of attentiveness but non-intrusiveness. Interaction should be predominantly supportive and not be specifically psychotherapeutic. The therapist/s can check on how the participant is going at the time of vital sign monitoring but otherwise typically respond only to the participant rather than initiating contact, unless the participant is showing signs of significant emotional distress. If the participant demonstrates an interest in talking, the therapist should respond in a supportive manner and after a short time gently redirect the participant towards an inward-directed focus. More dialogue is expected towards the end of the session. End of session: The effects of the medication will be expected to have markedly diminished by between six and seven hours. The therapists will assess whether the participant is ready to leave based on assessment of their mental state, vital signs, observation of coordination and steadiness of gait and whether the participant reports any lingering effects of the medication. The participant must leave with a nominated companion and is required to have either this same companion or another nominated companion with them for the rest of the day. Integration sessions: The participant will engage in an in-person integration session within 5 – 10 days of each dosing session. An additional 4th integration session will follow within two weeks of the third final dosing session. Each integration session will take approximately 1-2 hours. The purpose of the integration sessions is to support the participant in their ability to reflect on the medication sessions and to help them to reach insights that may have been developed. The primary activity of the therapists in these sessions is to ask open-ended questions to elicit insights that the participant may have come to. The therapist may identify elements of the participant’s narrative consistent with ACT principles and help them to understand their experience in this context. The integration sessions may also involve an exploration of values and how these may have evolved through the process of the treatment sessions. There may be some discussion of how the insights the participant has come to, and changes in their values, may be reflected in alterations they may make in specific day-to-day behaviours. An ACT framework will be used to guide this process. The overall duration of the intervention, involving the preparation, medication and integration sessions, is approximately 12 weeks.