Accelerated Neuromodulation Therapy for Negative Symptoms of Schizophrenia

Accelerated, Neuronavigated Neuromodulation Therapy for Negative Symptoms of Schizophrenia

The goal of this clinical trial is to learn if an accelerated form of neuromodulation therapy can help improve negative symptoms of schizophrenia. Negative symptoms can include low motivation, reduced emotional expression, and difficulty with social interaction. The study will also look at how safe and tolerable this treatment is when given over a short period of time.

Participants will be randomly assigned to receive either active neuromodulation therapy or sham (placebo) stimulation. The study will also compare two different ways of choosing where to place the stimulation.

The investigators want to learn whether this accelerated treatment approach is safe and feasible for people with schizophrenia, whether negative symptoms improve after treatment, and whether the way the stimulation site is chosen affects outcomes

Participants will be asked to complete clinical interviews and questionnaires, undergo a brain scan, receive neuromodulation therapy or sham stimulation over five consecutive days, and attend follow-up visits after treatment

This study is being conducted at three hospitals in Canada and is designed to help plan larger studies in the future.

Negative symptoms of schizophrenia, including diminished motivation, reduced emotional expression, and impaired social functioning, are a major contributor to long-term disability and remain inadequately treated by existing interventions. Repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex has demonstrated potential benefit for negative symptoms, but conventional treatment schedules often require multiple weeks of daily sessions, which may limit feasibility in this population.

Accelerated neuromodulation therapy delivers multiple stimulation sessions per day over a condensed time period and may improve accessibility, adherence, and tolerability. This pilot study evaluates an accelerated iTBS protocol delivered over five consecutive days in individuals with schizophrenia spectrum disorders who exhibit clinically significant negative symptoms.

Participants are randomized to receive either active neuromodulation therapy or sham stimulation. In addition, the study evaluates two approaches to stimulation targeting. Targeting approach is assigned according to study procedures designed to preserve participant and rater blinding.

All participants undergo baseline clinical, behavioral, and functional assessments, followed by the accelerated treatment protocol and post-treatment follow-up assessments. Primary outcomes focus on changes in negative symptom severity, while secondary outcomes assess depressive symptoms, functional outcomes, and task-based behavioral measures.

Inclusion Criteria:

• Confirmed diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder
• Duration of illness ≥ 6 months
• Clinically significant negative symptoms
• Must have been on a stable pharmacological treatment for at least 4 weeks before entering the study
• Clinicians will confirm that patients' negative and positive symptoms have been stable per their clinical opinion for at least 3 months.
• Participants must be able to provide informed consent
• Ability to undergo MRI scanning

Exclusion Criteria:

• Pregnancy, lactation, or an intrauterine device
• History of electroconvulsive therapy (ECT) in the past 6 months
• Use of licit or illicit substances (excluding cannabis) during the week of treatment and in the 24 hours prior to fMRI scans
• Contraindications for TMS
• Previous treatment with rTMS
• Documented history of significant intellectual disability
• Primary diagnosis of psychotic disorder secondary to a medical condition or substance-induced psychosis.