A Randomized Neuroimaging Trial of Psilocybin in Depression

Changes in cerebral blood flow within three a priori-defined brain regions relevant to mood regulation and depression as assessed by arterial spin labeling acutely at expected peak drug concentration during treatment visits.

Changes in the MADRS relative to baseline at study follow-up visits. Higher scores with respect to the MADRS minimum (0) and maximum (60) values represent a worse treatment outcome .

Changes in voxel-wise functional connectivity within four a priori-defined and established functional networks relevant to mood regulation and depression as assessed by resting state functional magnetic resonance imaging acutely at the time of expected peak drug concentration during treatment visits.

Baseline grid-version of the 17-item Hamilton Depression Rating Scale score. The GRID-HAMD is a 17-item clinician-administered rating scale designed to assess severity of depressive symptoms. The score range is 0 to 52, with higher score indicating more severe depression .

Incidence of response, calculated as the proportion of participants with a response (defined as a ≥ 50% improvement in MADRS total score from Baseline) at at follow-up after psilocybin administration.

Incidence of remission, calculated as the proportion of participants with remission (defined as MADRS total score <11) at week 3 and 6 following the initial psilocybin/niacin administration.

The PHQ-9 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The PHQ-9 is a self-rated measure of depressive symptom severity in the past two weeks. Each of the nine items is rated on a Likert scale, ranging from 0 (not at all) to 3 (nearly every day), and summed for a total score between 0 (no symptoms) to 27 (most severe).

The QIDS-SR-16 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The QIDS-SR-16 is a self-report scale with scores that range from 0 to 27. Higher scores indicate greater depression .

The C-SSRS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The C-SSRS evaluates suicidal ideation and behaviour. The suicidal ideation score ranges from 0 (no ideation) to 5 (active suicidal ideation with specific plan and intent). Suicidal ideation intensity score ranges from 0 (no ideation) to 25 (most severe). The presence of suicidal behaviour is rated as a binary response; the lethality of previous actual attempts is rated on a scale of 0 (no or very minor physical damage) to 5 (death) and the potential lethality of actual attempts are rated on a scale of 0 (behaviour not likely to result in injury) to 2 (behaviour likely to result in death despite available medical care) .

The BPRS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The BPRS rating scale has 18 items, each item rated on a severity scale of 1 (not present) to 7 (extremely severe). 0 is entered if the item is not assessed.

The SDS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The SDS total score ranges from 0 to 30, with 0 representing no impairment and 30 representing severe impairment. The last two items of the scale (Days Lost and Days Unproductive) range from 0 to 7 (higher number denotes greater impairment) .

The GAD-7 will be collected at baseline as well as week 3 and 6 post-psilocybin administration. Scores from 0 ("Not at all") to 3 ("Nearly every day"), and total score ranges from 0 to 21; a higher score denotes greater symptom severity.

The SHAPS will be collected at baseline as well as week 3 and 6 post-psilocybin administration. The SHAPS is rated on a 4-point Likert scale from 0 ("strongly disagree") to 3 ("strongly agree"). Total score ranges from 14 to 56, wherein a higher score indicates greater hedonic capacity (lower anhedonic severity) .

The CADSS-6 is a simplified 6-item scale that will be collected at both treatment visits as well as week 3 and 6 post-psilocybin administration. Responses range from 0 ("not at all") to 4 ("extremely"). Total scores range from 0-24, wherein a higher score indicates greater dissociation.

The MoCA total score will be collected at baseline as well as week 6 (3 weeks after second treatment visit). This is scale is a cognitive screening assessment tool that tests six domains of cognition, with scores ranging from 0-30, wherein a higher score indicates better cognitive performance: 18-25 points ("Mild cognitive impairment"), 10-17 points ("Moderate cognitive impairment"), less than 10 points ("Severe cognitive impairment").

The revised HVLT-R total Score will be collected at baseline as well as week 6 (3 weeks after second treatment visit). A list learning test that contains 12 nouns that are read to a participant for three consecutive trials. After each trial, a participant is asked to recall the words that were read to them. The number of words recalled on each trial is summed together to produce a total score. The higher total score equates to a better outcome.

We will use the CANTAB software program for evaluating cognitive domains baseline as well as week 6 (3 weeks after second treatment visit). Sustained attention will be measured by the Rapid Visual Information Processing task. Responses will be scored as the number of responses recorded as having occurred within 1800 milliseconds of the final digit presentation for each of the target sequences, with more responses reflecting better sustained attention.

We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Psychomotor speed will be measured by the Reaction Time (RTI) task. Simple reaction time will be the outcome of interest, with faster reaction time (lower latency) reflecting better psychomotor speed.

The CANTAB software program for evaluating cognitive domains is used at baseline as well as week 6 (3 weeks after second treatment visit). Executive function will be measured by the Spatial Working Memory (RTI) task. This is a search task that stresses executive function and spatial working memory, requiring subjects to use heuristic search strategies. A higher score indicates better performance in spatial working memory.

We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Executive function will be measured by the One Touch Stockings of Cambridge (OTS) task. This is a spatial planning task that stresses executive function, requiring subjects to use reordered stacked objects to match a presented pattern. Fewer 'moves' indicates better executive function.

We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Memory will be measured by the Delayed Matching to Sample (DMS) task. This is a memory task that stresses encoding, requiring subjects to remember and differentiate complex patterns when presented after a delay. More correct responses, or greater accuracy, reflects better memory.

We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Memory will be measured by the Paired-Associates Learning (PAL) task. This is a memory task =sensitive to changes in functioning of the medial temporal lobe, requiring subjects to remember and identify previous locations of complex patterns when presented after a delay. More correct responses, or greater accuracy, reflects better memory.

We will use the CANTAB software program for evaluating cognitive domains at baseline as well as week 6 (3 weeks after second treatment visit). Social/emotional cognition will be assessed by the Emotion Recognition Task (ERT). Subjects are briefly shown faces morphed to display various emotions of varying intensities, and then required to identify the emotion. Better accuracy defined as number of correct responses reflects better emotional cognition.

The MEQ30 is a validated self-report revised 30-item questionnaire recording elements that comprise the mystical experience. 0 ("none (not at all)") to 5 ("extreme (more than any other time in my life and stronger than 4)"), with a total scoring range from 0 to 150. Higher scores indicate a more profound mystical experience.

The PEQ is a non-validated self-report 145-item questionnaire that describe any changes in the participants' lives that may be attributed to the psilocybin treatment. Comprises of 6 categories with items rated on a 6-point scale from 0 ("none") to 5 ("extreme"). Higher scores indicate a greater magnitude of the persistent effects following their psilocybin experience.

Correlation of blood for circulating biomarkers will occur at baseline. Plasma-derived proteins (brain-derived neurotrophic factor, S100Beta, C-reactive protein) will be measured in blood samples collected at the baseline visit and second treatment visit using fluorometric immunoassays and evaluated as predictors of subsequent treatment response as defined above based on MADRS scores.