Clinical High Risk for Psychosis (CHR), Prodromal Symptoms, Psychotic Disorders
Conditions
Keywords
Neuromodulation Therapy, Non-invasive Brain Stimulation, Accelerated Treatment, Transcranial Magnetic Stimulation, Outpatient treatment, iTBS, TMS, psychosis, CHR
Brief summary
The goal of this study is to learn whether an accelerated form of neuromodulation therapy is safe, feasible, and well tolerated in young people at clinical high risk for psychosis (CHR-P), and whether it is associated with changes in candidate biomarkers of treatment response. Participants will be randomly assigned to receive either active accelerated intermittent theta burst stimulation (iTBS) or sham stimulation to the left dorsolateral prefrontal cortex, delivered over five consecutive days. The study will look at whether this accelerated treatment approach is safe and feasible for people at clinical high risk for psychosis, whether depressive symptoms improve after treatment, and whether computerized behavioural tasks and passive digital monitoring (wearables, smartphone apps, and speech analysis) can detect treatment-related changes that may serve as biomarkers for future, larger trials. Participants will complete clinical interviews and questionnaires, a cognitive battery, and computerized behavioral tasks; wear a Fitbit and use smartphone applications for at least two weeks before and throughout treatment; receive neuromodulation therapy or sham stimulation over five consecutive days; and attend follow-up visits at 1 week, 1 month, and 3 months after treatment.
Detailed description
There is currently no clinically validated treatment that reduces the risk of psychosis onset or mitigates the severity of a first psychotic episode in individuals at clinical high risk for psychosis (CHR-P). CHR-P is associated with attenuated psychotic symptoms, functional decline, and high rates of affective symptoms, including a comorbid mood disorder prevalence of 40% or higher. Repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral prefrontal cortex (LDLPFC) is an established treatment for depression and is increasingly supported for negative symptoms in psychotic disorders, making it a promising low-burden candidate for early intervention in CHR-P. This pilot study evaluates an accelerated intermittent theta burst stimulation (iTBS) protocol, delivered over five consecutive days, in individuals at CHR-P (SIPS-confirmed, aged 18-34). Forty participants will be randomized 1:1 to active accelerated iTBS or sham stimulation to the LDLPFC, using standard scalp-based (BEAM-F3) targeting rather than MRI-guided neuronavigation, reflecting the pilot nature and funding constraints of this early-phase study. Given the variable incidence of and long latency to psychosis onset in the CHR-P population, this study also incorporates a battery of neurocomputational tasks (analyzed using Hierarchical Gaussian Filter modeling) and a multimodal digital phenotyping framework (wearables, smartphone-based passive sensing, facial/vocal affect analysis, and structured speech analysis) to assess candidate biomarkers of treatment response. Primary outcomes are the safety, feasibility, and tolerability of the accelerated protocol in this population. Secondary outcomes include the sensitivity of neurocomputational biomarkers to treatment and change in depressive symptoms. Exploratory outcomes include treatment-related change across multiple domains of real-world functioning captured through digital phenotyping. This study is not designed to establish definitive treatment efficacy but to inform the design of future, adequately powered trials.
Interventions
DEVICEActive Intermittent Theta Burst Stimulation (BEAM-F3 Targeting)
Active iTBS is delivered using a MagVenture MagPro X100 stimulator with Cool-B65 A/P coil, targeting the LDLPFC at 110% of resting motor threshold (motor threshold determined via the PEST algorithm). Each session consists of 60 trains of 10 bursts of three pulses at 50 Hz, delivered every 200 ms, with an 8-second intertrain interval (1,800 pulses/session; up to 18,000 pulses/day; 90,000 pulses total over 5 days). The number of daily sessions is reviewed after every five participants and may be reduced from 10 to 8, or to 6, if needed; missed sessions are made up during the following week to preserve total pulse dose.
DEVICESham Comparator: Sham iTBS
Sham iTBS is delivered using the same MagVenture Cool B65 A/P coil (device-integrated sham mode), with identical coil placement, session structure, and treatment schedule as the active arm.
Sponsors
Douglas Mental Health University Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Masking description
Participants, treaters (care providers), and raters (outcomes assessors) are blinded to treatment allocation. Blinding is supported by device-integrated sham stimulation (MagVenture Cool B65 A/P coil) and topical application of 2% lidocaine jelly to the stimulation site in both arms. Blinding integrity is formally assessed at multiple time points across the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to 34 Years
Healthy volunteers
No
Inclusion criteria
* Meets clinical CHR-P criteria, confirmed by the Structured Interview for Psychosis-Risk Syndromes (SIPS) * Clinical team confirms sufficient stability to participate * Able to provide informed consent
Exclusion criteria
* Pregnancy, lactation, or intrauterine device * History of electroconvulsive therapy (ECT) in the past 6 months * Substance use during the treatment week (cigarettes and cannabis excluded from this consideration) * Contraindications for TMS (e.g., metal implants in head/neck, seizure history, brain tumor/neurosurgery, severe cardiac disease) * Previous rTMS treatment * Documented history of significant intellectual disability
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Initiation Rate | Through end of treatment week (Day 5) | Proportion of consenting participants who begin the treatment protocol (receive at least one stimulation session). |
| Treatment Acceptability Rate | Through study completion, an average of 18 months. | Proportion of approached, eligible individuals who consent to participate in the study. |
| Treatment Adherence | Through end of treatment week (Day 5) | Number of treatment sessions completed per participant, out of the planned schedule (up to 10 sessions/day over 5 days). |
| Treatment Completion Rate | Through end of treatment week (Day 5) | Proportion of participants who initiate treatment and complete the full course; expected completion rate of approximately 80%, based on prior work at the study site. |
| Incidence of Adverse and Serious Adverse Events | Baseline through 3-month follow-up | Rate of treatment-related adverse events (e.g., scalp pain, headache, fatigue, symptom worsening) and serious adverse events (e.g., seizure, hospitalization, emergent suicidality), assessed via daily clinical ratings and structured interviews. |
| Qualitative Treatment Experience | End of treatment (Day 5) | Themes related to participant experience of tolerability and treatment burden, derived from a structured end-of-treatment qualitative interview and analyzed using inductive thematic analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Affective Conditioned Hallucinations Task Parameters | Baseline to 1 week, 1 month, and 3 months post-treatment | Change in individual-level information-processing parameters (Hierarchical Gaussian Filter modeling) derived from an affective variant of the Conditioned Hallucinations task. |
| Change in Social Appraisal Task Parameters | Baseline to 1 week, 1 month, and 3 months post-treatment | Change in HGF-derived parameters of social inference and belief updating. |
| Change in Beads Task Parameters | Baseline to 1 week, 1 month, and 3 months post-treatment | Change in probabilistic reasoning bias related to delusion-proneness. |
| Change in Prisoner's Dilemma Task Parameters | Baseline to 1 week, 1 month, and 3 months post-treatment | Change in HGF-derived parameters of social inference. |
| Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Score | Baseline to 1 week, 1 month, and 3 months post-treatment | Change in clinician-rated depressive symptom severity. Total scores range from 0 to 60, with higher scores indicating greater severity. |
| Change in Quick Inventory of Depressive Symptomatology (QIDS) Score | Baseline, Daily from Day 1 to Day 5, and at 1 week, 1 month, and 3 months post-treatment | Change in self-reported depressive symptom severity on the Quick Inventory of Depressive Symptomatology, 16-item Self-Report (QIDS-SR16). Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity. |
Countries
Canada
Contacts
CONTACTAshley Choucroun
PRINCIPAL_INVESTIGATORDavid Benrimoh
McGill University, Department of Psychiatry
Outcome results
None listed