Major Depressive Disorder
Conditions
Keywords
Psilocybin, Cognitive Behavioral Therapy (CBT), Randomized Controlled Trial, Psychedelic Therapy, Inflammatory Markers
Brief summary
This randomized controlled clinical trial evaluates the effectiveness of psilocybin and psilocybin-assisted cognitive behavioral therapy (CBT) in the management of Major Depressive Disorder (MDD). The study aims to compare the effects of psilocybin-only therapy, CBT, and psilocybin-assisted CBT on depression symptoms, neurochemical markers, inflammatory markers, and neuroplasticity in individuals with MDD. Participants will continue their routine depression medications and will be assessed for changes in depression scores, biochemical markers, and brain activity patterns using validated tools and tests.
Detailed description
This single-masked randomized controlled trial investigates novel therapeutic interventions for Major Depressive Disorder (MDD). MDD is a leading cause of disability worldwide, with a significant proportion of patients being treatment-resistant or showing only partial response to conventional antidepressants. Emerging evidence suggests that psilocybin, a serotonergic psychedelic, has potential as a rapid-acting antidepressant. The study will recruit 60 participants meeting DSM-V criteria for MDD, randomized into four groups: Control group (Conventional therapy only), Psilocybin therapy group, Cognitive Behavioral Therapy (CBT) group, and Psilocybin-assisted CBT group. Participants will receive interventions over 10 weeks, with psilocybin administered in two heroic doses six weeks apart, and CBT delivered in 8-10 structured sessions. Biochemical and neurochemical markers such as CD4/CD8 ratio, TNF-α, IL-6, BDNF, and oxytocin will be measured, along with inflammatory markers (resistin and visfatin). Depression scores will be assessed using scales like HAM-D, MADRS, and BDI. EEG recordings will evaluate changes in brain activity pre- and post-intervention. The primary objective is to assess improvements in depression symptoms, while secondary objectives include evaluating changes in immune, inflammatory, and neurochemical markers and EEG activity. Data will be analyzed using ANOVA with Tukey's post-hoc tests to determine statistical significance.
Interventions
DRUGPsilocybin
Psilocybin is a naturally occurring serotonergic psychedelic compound found in Psilocybe mushrooms. It is metabolized in the body into its active form, psilocin, which has a high affinity for serotonin 5-HT2A receptors. This enables psilocin to bypass the default serotonin pathway, producing antidepressant effects. For this study: Psilocybin will be administered orally in a dose of 5-6 grams per session. Each participant in the Psilocybin and Psilocybin-assisted CBT arms will receive two sessions spaced six weeks apart. The therapy will be conducted in a controlled hospital setting with medical monitoring during the session to ensure safety until the hallucination phase subsides. Psilocybin will be added to routine antidepressant medication.
BEHAVIORALCognitive Behavioral Therapy (CBT)
Cognitive Behavioral Therapy (CBT) is a structured, time-limited psychotherapy aimed at alleviating symptoms of depression. It involves addressing negative thoughts and behavioral patterns through the following steps: Identifying troubling life situations. Recognizing thoughts, emotions, and beliefs about those situations. Identifying negative or inaccurate thinking patterns. Restructuring those thoughts into positive and realistic perspectives. In this study: CBT will consist of 8-10 structured sessions, each lasting approximately 90 minutes. Participants will attend therapy sessions twice weekly over a six-week period. The intervention will be delivered by trained psychotherapists in a controlled hospital setting. Routine antidepressant medications will be continued alongside CBT.
Sponsors
Khyber Medical University Peshawar
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Randomized (Random allocation will be performed using a simple lottery method.)
Intervention model description
Parallel Assignment (The study has four distinct intervention groups: Control, Psilocybin Therapy, CBT, and Psilocybin-assisted CBT.)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Individuals aged 18-70 years. * Diagnosed with Major Depressive Disorder (MDD) according to DSM-V criteria. * Active depressive symptoms as indicated by a score \> 16 on the Hamilton Depression * Rating Scale (HAM-D) over the preceding two weeks. * Female participants of childbearing potential must be using a highly effective form of contraception and willing to maintain contraceptive use throughout the study period. * Participants must have been taking one SSRI antidepressant (e.g., citalopram, escitalopram, fluoxetine) for at least 6 weeks with at least 75% adherence.
Exclusion criteria
* Resting blood pressure \>140/90 (average of four separate measurements). * Risk of suicidal tendencies as indicated by a score of 3 or higher on item 3 of the HAM-D scale. * Use of multiple SSRIs or any antidepressant not specified in the inclusion criteria. * Presence of concurrent psychiatric disorders (e.g., bipolar disorder, schizophrenia). * Use of psychedelics or ketamine within the last 12 months. * Pregnancy, breastfeeding, or attempting to conceive. * History of substance abuse or alcohol use in the last 6 months. * Cardiovascular conditions (e.g., hypertension, stroke history). * History of seizures or epilepsy. * Diabetes (especially insulin-dependent).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression Scores (Hamilton Depression Rating) | Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention). | Assessment of changes in depression scores using the Hamilton Depression Rating Scale (HAM-D), a clinician-administered tool for evaluating the severity of depression. Unit of Measure: Points on the HAM-D scale. The HAM-D consists of 17 items, each assessing a specific depressive symptom. Each item is rated on a 0-4 or 0-2 scale, depending on the item. The total score ranges from 0 to 52. Higher scores indicate greater severity of depressive symptoms. 0-7: Normal 8-13: Mild depression 14-18: Moderate depression 19-22: Severe depression * 23: Very severe depression |
| Change in Depression Scores (Montgomery-Åsberg Depression Rating Scale) | Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention). | Assessment of changes in depression scores using the Montgomery-Åsberg Depression Rating Scale (MADRS), a clinician-administered scale for evaluating depressive symptom severity. Unit of Measure: Points on the MADRS scale. The MADRS consists of 10 items, each assessing a specific depressive symptom. Each item is rated on a 0-6 scale. The total score ranges from 0 to 60. Higher scores indicate greater severity of depressive symptoms. 0-12: Normal 13-19: Mild depression 20-34: Moderate depression * 35: Severe depression |
| Change in Depression Scores (Beck Depression Inventory) | Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention). | Assessment of changes in depression scores using the Beck Depression Inventory (BDI), a self-reported measure designed to evaluate the severity of depression symptoms. Unit of Measure: Points on the BDI scale. The BDI consists of 21 items, each assessing a specific depressive symptom. Each item is rated on a 4-point scale. The total score ranges from 0 to 63. Higher scores indicate greater severity of depressive symptoms. 0-13: Normal 14-19: Mild depression 20-28: Moderate depression 29-63: Severe depression |
| Change in Anxiety Scores (Beck Anxiety Inventory) | Baseline, Week 6 (end of the first psilocybin session), and Week 10 (end of intervention). | Assessment of changes in anxiety scores using the Beck Anxiety Inventory (BAI), a self-reported questionnaire for evaluating the severity of anxiety symptoms. Unit of Measure: Points on the BAI scale. The BAI consists of 21 items, each assessing a specific anxiety symptom. Each item is rated on a 0-3 scale. The total score ranges from 0 to 63. Higher scores indicate greater severity of anxiety symptoms. 0-7: Normal 8-15: Mild anxiety 16-25: Moderate anxiety 26-63: Severe anxiety |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxytocin Levels | Baseline, Week 6, and Week 10 | Assessment of changes in serum oxytocin levels from baseline to the end of the intervention. Unit of Measure: pg/mL. |
| EEG Pattern Changes | Baseline, Week 6, and Week 10. | Analysis of changes in EEG activity patterns before and after the intervention, focusing on frequency bands (e.g., Alpha, Beta, Theta, and Delta waves) and their relative power across these bandwidths. Unit of Measure: Relative power (percentage or dB). |
| Change in Brain-Derived Neurotrophic Factor (BDNF) Levels | Baseline, Week 6, and Week 10 | Assessment of changes in serum BDNF levels from baseline to the end of the intervention. Unit of Measure: ng/mL. |
| Change in Inflammatory Markers | Baseline, Week 6, and Week 10. | Evaluation of changes in serum levels of TNF-α, IL-6, resistin, and visfatin to monitor systemic inflammation. Unit of Measure: pg/mL or ng/mL, depending on the specific biomarker. |
| Deviation from Balanced Time Perspective (DBTP) | Baseline, Week 6, and Week 10. | Measurement of deviation from a balanced time perspective using the Zimbardo Time Perspective Inventory (ZTPI). Unit of Measure: ZTPI score. |
Countries
Pakistan
Outcome results
None listed