Toward Patient-Tailored Care for Treatment-Resistant Depression: A Pilot Patient-Preference Clinical Trial of Music and Mindfulness in Psilocybin-Assisted Psychotherapy
Toward Patient-Tailored Care for Treatment-Resistant Depression: A Pilot Patient-Preference Clinical Trial of Music and Mindfulness in Psilocybin-Assisted Psychotherapy
The goal of this pilot clinical trial is to learn whether it is feasible to individually tailor psilocybin-assisted psychotherapy (PAP) for people with treatment-resistant depression (TRD) based on their personal preferences. The study also aims to explore whether two different psychotherapy styles, music-centered and mindfulness-centered, influence how people respond to psilocybin treatment.
The main questions it aims to answer are:
Researchers will compare music-centered PAP to mindfulness-centered PAP to see if aligning psychotherapy with individual preferences is a practical and potentially beneficial approach for improving treatment efficacy and tolerability.
Participants will:
This feasibility trial will also collect information on participants' cultural and personal factors influencing psychotherapy preferences using a modified Cultural Formulation Interview, and explore physiological measures of therapeutic alliance, an important factor in psychotherapy outcomes.
Depression is one of the top causes of disability worldwide. Psilocybin-assisted psychotherapy (PAP) is an emerging treatment for Treatment-Resistant Depression (TRD) that pairs one or two doses of psilocybin, a serotonergic psychedelic, with a brief course of psychotherapy. While multiple studies of PAP have found safe, rapid, and lasting antidepressant effects, much remains unknown about how to optimize this promising intervention's psychotherapy component.
This pilot study aims to explore a novel strategy for improving the efficacy and tolerability of PAP: individually-tailoring its psychotherapy based on patient preferences for two important nonpharmacological treatment elements: music and mindfulness. These core treatment components were selected based on their ubiquitousness in psilocybin studies and their potential for significant patient preference effects.
The investigators will conduct a patient-preference randomized clinical trial where 16 patients with TRD will receive two doses of psilocybin (PEX010, Filament Health, 25mg). For each patient, one psilocybin dose will be administered with music-centered psychological support and the other with mindfulness-centered psychological support. In the first 4-week phase, patients will be asked to rate their preferences for these different psychotherapeutic approaches. Patients will then be 50:50 randomized to first receive either their preferred or their non-preferred treatment approach. In a second 4-week crossover phase, patients will receive the other treatment approach. All patients will thus undergo both music-centered and mindfulness-centered PAP interventions, but in an order dictated by their preferences and randomization. Each treatment phase entails pre-treatment and post-treatment psychotherapy following standard protocols.
Similar patient-preference clinical trial designs have shown that preferences can significantly influence the efficacy and tolerability of existing psychiatric treatments. The primary aim of this pilot trial is to examine this design's feasibility for exploring such preference effects in PAP, which the investigators hypothesize will be substantial. As secondary aims, the trial will generate preliminary estimates about the magnitude of preference effects, compare the music- and mindfulness-centered approaches, and yield qualitative data about the diverse sociocultural factors that influence patient preferences, including with a modified Cultural Formulation Interview administered at baseline. An additional exploratory aim is to examine novel physiological measures of therapeutic alliance, a crucial factor in psychiatric care.
Depression affects millions of Canadians and new treatments are sorely needed. This line of research seeks to produce systematic approaches to tailoring the psychotherapy of PAP for TRD. Its ultimate goal is to improve this promising intervention's efficacy, safety, and applicability to diverse populations.
Inclusion Criteria:
Exclusion Criteria:
Deemed to be greater than low risk of suicide on psychiatric interview.
Currently or previously diagnosed with any of the following, according to available information and psychiatric interview: major depression with psychotic features, schizophrenia spectrum or other psychotic disorders, and/or bipolar affective disorder I or related disorders.
Current or past diagnosis of personality disorder deemed to pose a significant risk for safety and/or trial compliance.
Family history (first-degree relative) of psychosis.
Current or recent (< six months) substance use disorder, except for tobacco use disorder.
Deemed to be greater than low risk of future substance use disorder.
Currently receiving and deemed to be unsuitable, on psychiatric interview, to discontinue medications with significant serotonin 2A antagonism (e.g., trazodone) or known potential for serious interactions with psilocybin including serotonin syndrome (e.g., monoamine oxidase inhibitors), seizures (e.g., lithium), or which may affect psilocybin pharmacokinetics (e.g. UDG modulators, aldehyde dehydrogenase inhibitors).
Unwilling or unable to maintain current psychotropic medications throughout the treatment phase of the trial.
Currently undergoing psychotherapy that will not remain stable for the duration of the study or was initiated within 21 days of baseline.
Prior use of serotonergic psychedelics in the past year and/or more than five life-time uses.
Use of any serotonergic psychedelic or ketamine, or any other illicit substance during the active treatment period of the trial.
Medical contraindications:
Current or past history of seizure disorder with the exception of infantile febrile seizures.
Significant cardiovascular disease including uncontrolled blood pressure (> 140/90mmHg), clinically significant arrhythmia, heart failure, coronary artery disease, history of ischemic or hemorrhagic stroke, or history of myocardial infarction.
Abnormal and clinically significant results on the physical examination, laboratory investigations, or ECG at screening.
Any other clinically significant illness deemed to pose significant health risks for participation in the study.
Pregnant or lactating.
For women of child-bearing potential, defined as all women physiologically capable of becoming pregnant: unwilling to utilize highly effective contraceptive during the 10-week active intervention (e.g., oral contraceptive). Acceptable forms of highly effective contraception methods include: a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b. Male/female sterilization defined as: 1) Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed and documented by follow up hormone level assessment; 2) Male sterilization of the sole partner (at least 6 months prior to screening) of a female patient on the study. c. A combination of any two of the following (i+ii or i+iii or ii+iii):
i) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository ii) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception iii) Placement of an intrauterine device (IUD) or intrauterine system (IUS).
Men unwilling to not attempt to father a child or not donate sperm, while participating the active treatment period of this study.