Table 7 Exploratory measures

Anxiety symptoms

HAM-A [37] assessed at baseline and at the 8-week time point.

14 items, clinician-rated on a 4-point Likert scale; these scores combined to give a final composite score.

Depression, stress, and anxiety symptoms

DASS-21 [38], assessed at baseline and at the 8-week time point.

21 items, 5-point Likert scale, from 0 (never) to 4 (almost always). Three subscales reported as summed scores.

Anhedonia symptoms

DARS [39], assessed at baseline and 8-week time point.

4 domains that call for participant examples, rated on a 5-point Likert scale (0–4). Total and each of its four subscales will be compared.

EEG doors paradigms [40] will be measured at baseline, dosing, and measure time points.

Trials where participants are presented with two doors to select from. In half the trials, they receive feedback indicating monetary gain or loss. Positive ERP ~ 250–300 ms after feedback.

Ruminative symptoms

RRS [41], assessed at baseline and at the 8-week time point

22 items, four scales measuring two aspects of rumination, rated from 1 (almost never) to 4 (almost always).

Quality of life

WHOQOL-BREF [42], assessed at baseline and 8-week time point

26 items, scored on a 5-point Likert scale. Each of its four subscales will be compared.

Connectedness

Watts Connectedness Scale [43], assessed at baseline and 8-week time point.

19 items marked on a visual analogue scale between 0 (“not at all”) and 100 (“entirely”). Each of the three subscales will be compared.

Te Whare Tapa Whā

Hua Oranga [31, 44], assessed at baseline and 8-week time point. Each of its four subscales will be compared.

16 items where each of the constructs is scored by participants on a 5-point scale with descriptors of each provided. Each of its four subscales will be compared.

Daily mood

HAMD-6 self-report [45] will be assessed from baseline daily through until follow-up 1.

6-item scale, clinician-rated. Captures core features of depression.

EEG

The EEG long-term potentiation (LTP) [46, 47], mismatch negativity (MMN) [48], loudness-dependent auditory evoked potential (LDAEP) [49], as well as resting state will be measured at baseline, dosing, and measure time points.

Recorded with 64 channel caps, 5 min eyes-open 5 min eyes-closed resting state, sensory LTP with vertical and horizontal sine gratings on grey background, MMN 5–11 sinusoidal tones, classic oddball response, LDAEP measures serotonergic function, 100-Hz stimulus tones at differing intensities.

Plasma/serum BDNF and mRNA biomarkers

Plasma/serum BDNF samples will be measured baseline. Dosing (pre and 6 h post) and measure time points. Buffy coats will be taken for mRNA samples.

BDNF plasma levels, expression of mRNA markers including proBDNF, BDNF, TrkB, p75NTR, sortilin, 5HT2A, and 5HT1A.

Genotype prediction of outcome measures

Whole blood samples will be taken from participants at baseline.

ValMet66 polymorphism of BDNF gene, SNP analysis related to CYPs and 5HT2A receptor.

Personality trait modification

BFI-2 [50], CFI [51], FFM-Q [52], and MODTAS [53] are measured at screening and measure points.

BFI 60 items on Likert 1–5, for the main personality traits, CFI 20 items from 1–7 giving total score and 2 subscales, FFM-Q 38 items on a 5-point Likert scale, and 34 items on a 5-point Likert scale.

Expectancy

CEQ [54] and short expectancy interview will be measured at baseline and dosing sessions.

6-item scores on a 9-point Likert scale.

Sexual dysfunction

CSFQ-14 [55] will be measured at baseline and measure sessions.

14 items, rated on a 5-point Likert scale.

Sleep, activity, and physiology

Fitness tracker data will be recorded continuously from baseline through to 1 month after completion of regimen.

Wearing of a Garmin activity tracker logging basic measurements including sleep duration, quality, physical activity, heart rate, and stress levels

Daily experience

Daily VAS scales completed every evening in the study app. Participants will be encouraged to record an audio journal in the study app.

HAMD-6 self-report with VAS scales for connected, creative, energy, happy, irritable, and jittery. Adverse event reporting. 

Withdrawal/discontinuation symptoms

DESS [56] will be measured at the follow-up 1 time point.

Checks for symptoms of discontinuation syndrome.

Acceptability of study app

Acceptability questionnaire completed every 2 weeks.

5 items considering usability of the app.

Engagement with therapeutic journaling

Journal entries.

Number of journal entries submitted accessed via the app.

Subjective experience

A semi-structured interview.

Conducted with the participant (and whānau member) to record their subjective experiences of being involved in the trial.

Plasma pharmacokinetics

Pharmacokinetic samples will be taken at baseline and 20, 40, 60, 90, 120, 180, 240, and 360 min (± 5 min) after the first dose (dosing).

Quantification by liquid chromatography mass spectrometry

Pharmacodynamics

Pharmacodynamic measurements will be recorded at baseline and at 20, 40, 60, 90, 120, 180, 240, and 360 min (± 5 min) after the first dose (dosing).

Vital signs, speech task, and VAS scales.

Extension period

An intervention extension period is offered to all patients for 8 weeks.

The number of doses administered in this period is the endpoint.

Durability of antidepressant response

MADRS [35] assessments will be conducted at three follow-up time points (1, 3, and 6 months after the final measure session).

10 items, each clinician-rated on a 7-point Likert scale, summed to give a total score between 0 and 60.