Trazodone’s Effects on Moderation of Psilocybin Outcomes (TEMPO)

Prior treatment

• Current comorbidity with, or a previous diagnosis of, any of the following DSM-5 disorders: Major depressive disorder with psychotic features (ICD- 10: F32.3). Schizophrenia spectrum and other psychotic disorders, including schizotypal (personality) disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, substance/medication-induced psychotic disorder, or psychotic disorder due to another medical condition (ICD-10: F20–F29). Bipolar and related disorders (ICD-10: F30/F31). Cluster A personality disorders (paranoid, schizoid, schizotypal) and/or borderline personality disorder; screening for these disorders will be performed using the SCID-5-PD. Post-traumatic stress disorder (PTSD; ICD-10: F43.1)
• Use of prohibited medications or substances, unless an appropriate washout period (minimum 7–14 days) is completed prior to dosing.
• Current or recent history (within the past 6 months) of clinically significant suicidal ideation, corresponding to a score of 4 (active suicidal ideation with some intent to act, without a specific plan) or 5 (active suicidal ideation with specific plan and intent) on the Columbia–Suicide Severity Rating Scale (C-SSRS), or a history of suicidal behavior within the past year, as assessed during screening using the C-SSRS. Subjects with a prior suicide attempt or serious suicidal ideation/plan occurring more than 6 months ago should undergo careful screening and may only be included at the investigator’s discretion

Other illness

• Allergy to any of the components of study drugs
• Uncontrolled endocrine or metabolic disorders, including: Untreated or decompensated hyperthyroidism Severe respiratory failure or acute respiratory depression Neurological conditions, including: Established diagnosis of epilepsy or a known family history of epileptic seizures
• Severe somatic illness or any condition that, in the investigator's opinion, would increase risk or interfere with the study protocol
• Known allergy or hypersensitivity to psilocybin, trazodone, or any excipients in the study drugs
• A family history of psychosis and/or bipolar disorder in a first-degree relative
• Presence of a current comorbid substance use disorder within the past 12 months (excluding tobacco- or caffeine-related disorders)
• High cardiovascular risk according to the SCORE2 risk prediction algorithms. Intracranial hypertension, pulmonary hypertension, uncorrected arterial hypertension (BP> 150/100 mmHg). History of stroke or myocardial infarction within the last 6 months Heart failure
• Pulmonary or intracranial hypertension
• Other serious somatic diseases or any other circumstance in which a significant increase in blood pressure would pose a serious threat to health (to be assessed by the study clinician)
• Established diagnosis of epilepsy or a positive familial history of epileptic disorders

Other

• Inability to establish sufficient therapeutic rapport with both study therapists, as determined after the first two preparatory sessions
• Pregnancy or breast-feeding or plan to become pregnant within the next 3 months
• Use of classical psychedelics (LSD, psilocybin, mescaline, dimethyltryptamine) within the past year, or more than five lifetime uses of classical psychedelics

• Age: Individuals aged between 18 and 65 years
• Fluency in language: Participants must be fluent in the language in which study assessments are administered (Italian)
• Compliance: Participants must be willing and able to comply with all study procedures, including five study visits, blood and urine sampling, pregnancy and toxicological screening, and completion of psychometric assessments
• Diagnosis of TRD: Participants must have a diagnosis of Major Depressive Disorder (MDD) according to DSM-5 criteria. Additionally, subjects should be non-responders to at least two antidepressant medications at adequate doses (i.e., SSRIs, SNRIs, or equivalent) administered for a duration of 4-6 weeks.
• Hospitalization Status: Hospitalized patients or those receiving outpatient care, as assessed by the investigator’s clinical judgment, may be included if they meet other inclusion criteria
• Informed Consent: Patients must be able and willing to provide written informed consent to participate in the study
• Agreement to Use Highly Effective Contraception Methods: For patients of childbearing potential, agreement to use adequate contraception methods during the course of the study and for a defined period after study completion (see section “CONTRACEPTION REQUIREMENTS”)
• No Major Substance Abuse: Participants should not have a history of severe substance use disorder within the past year (e.g., alcohol, illicit drugs) that might interfere with the study protocol or outcomes
• Antidepressants discontinuation: Patients have discontinued any monoaminergic psychiatric medication (i.e. SSRIs, SNRIs) for at least 2 weeks (fluoxetine: 5 weeks) before the first dosing session. Patients who are still on any monoaminergic psychiatric medication at screening must agree to down-titrate over an individualized down-titration schedule in close supervision by their out-patient psychiatrist and the study team. The treating psychiatrist must agree to supervise and monitor the down-titration and to collaborate with the study team
• Current use of monoamine oxidase inhibitors (MAOIs). Patients can be enrolled if the MAOI treatment will be completely discontinued following tapering at least 2 weeks prior to baseline visiit
• BMI and body weight: Participants must have a body mass index (BMI) between 18.0 and 30.0 kg/m² and weigh at least 45 kg at screening