Non-invasive Neuromodulation for Schizophrenia

Overseen By Ariel Graff, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must be taking: Antipsychotics

Disqualifiers: Hearing aids, Eye surgery, Cardiovascular, Seizures, others

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

4 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to determine the clinical and functional imaging effects of serial CVS on illness awareness in schizophrenia. Specifically, the investigators aim to: 1. Determine if twice-daily CVS for 4 weeks will improve illness awareness compared to the sham condition in participants with schizophrenia. Illness awareness will be assessed at pre- and post-CVS, and weekly thereafter for 4 weeks. 2. Examine changes in brain network activity (blood oxygen level dependent-BOLD in response to an illness awareness task) pre- and post-CVS. This will serve as a biomarker to rigorously test whether repeated CVS engages the PPA associated with illness awareness.

Will I have to stop taking my current medications?

The trial requires that participants stay on a stable dose of their current antipsychotic and other medications for at least 2 months before and during the study, so you will not need to stop taking them.

What data supports the effectiveness of this treatment for schizophrenia?

Research shows that non-invasive brain stimulation, a type of neuromodulation, has been promising in treating symptoms of schizophrenia, especially for patients who do not respond to traditional medications. This suggests that the investigational brainstem neuromodulation device might also be effective for similar cases. ^{1 2 3 4 5}

Is non-invasive neuromodulation safe for treating schizophrenia?

Research on transcutaneous noninvasive vagus nerve stimulation (tVNS) for schizophrenia shows it is generally safe and well-tolerated, with no significant adverse effects reported in a study involving 20 patients. ^{6 7 8 9 10}

How is non-invasive neuromodulation different from other treatments for schizophrenia?

Non-invasive neuromodulation is unique because it uses techniques like transcranial magnetic stimulation to alter brain activity without surgery or medication, potentially helping those who don't respond well to traditional drug therapies. It focuses on improving neural plasticity (the brain's ability to change and adapt), which is thought to be impaired in schizophrenia. ^{1 2 5 11 12}

Research Team

Philip Gerretsen, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

Adults diagnosed with schizophrenia or schizoaffective disorder, who have a moderate-to-severe lack of illness awareness and are stable on their current medications. Participants must be fluent in English, able to consent, and not planning medication changes during the study. Excluded are those with recent ear or eye surgery, active ear issues, severe medical conditions like heart disease or seizures, substance dependence (except caffeine/nicotine), pregnancy, vestibular dysfunction, metal implants/pacemakers affecting MRI scans.

Inclusion Criteria

Fluent in English

I am willing and able to agree to participate in this study.

I've been on a steady dose of my psychiatric medication for 2 months.

Exclusion Criteria

I have been diagnosed with a balance disorder.

I currently have an ear infection or a ruptured eardrum.

I have not had eye surgery in the last 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive twice-daily CVS or sham stimulation for 4 weeks

4 weeks

Daily visits (in-person or virtual)

Follow-up

Participants are monitored for changes in illness awareness and brain network activity

4 weeks

Weekly assessments (in-person or virtual)

Open-label extension

Participants may opt into receiving active stimulation for up to 12 weeks

Up to 12 weeks

Treatment Details

Interventions

• Investigational brainstem neuromodulation device

Trial Overview The trial is testing a non-invasive brainstem neuromodulation device to see if it can improve illness awareness in people with schizophrenia. It involves twice-daily sessions for four weeks and compares this treatment against a sham (fake) procedure. The effects will be measured through self-awareness assessments and brain imaging before and after the treatment period.

Participant Groups

Group I: Open Label Experimental Treatment 1 Intervention

After completion of sham or active stimulation over 4 weeks, participants can choose to receive \~18-minute active stimulation twice daily for up to 12 weeks.

Group II: Active Treatment Active Control 1 Intervention

Study participants will receive \~18-minute active stimulation twice daily over 4 weeks, using a non-invasive brainstem modulation device.

Group III: Sham Treatment Placebo Group 1 Intervention

Study participants will receive \~18-minute of sham stimulation twice daily over 4 weeks using a non-invasive brainstem modulation device.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Scion NeuroStim

Industry Sponsor

Trials

14

Recruited

550+

Findings from Research

Neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, are emerging as potential treatment options for patients with psychiatric disorders who do not respond well to traditional drug therapy or psychotherapy.

The rationale behind using neuromodulation is based on research that identifies specific brain areas linked to persistent psychiatric symptoms, suggesting a targeted approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation in psychiatric disorders. Temel, Y., Hescham, SA., Jahanshahi, A., et al.[2012]

Recent randomized-controlled trials indicate that noninvasive brain stimulation can provide long-lasting relief from symptoms in patients with treatment-resistant schizophrenia.

Innovative stimulation techniques, such as theta burst stimulation and new electrical methods, have shown promising results, suggesting that optimizing stimulation parameters could enhance treatment efficacy for schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in noninvasive brain stimulation for schizophrenia. Brunelin, J., Adam, O., Mondino, M.[2023]

A review of 119 studies on non-invasive brain stimulation (NIBS) for treatment-resistant schizophrenia revealed a low quality of assessment, with an average score of only 3.38 out of 11, indicating inadequate reporting of treatment resistance.

Most studies inadequately defined treatment resistance, often focusing on a single symptom without considering factors like treatment adherence and functional impairment, which limits the understanding of NIBS's true efficacy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of treatment resistance criteria in non-invasive brain stimulation studies of schizophrenia. Kronick, J., Sabesan, P., Burhan, AM., et al.[2022]

Approximately one-third of patients with schizophrenia do not respond adequately to non-clozapine antipsychotics, and about half show poor response to clozapine and other treatments, highlighting the challenge of treatment-resistant schizophrenia (TRS).

The review discusses the potential of neuromodulation techniques, such as electroconvulsive therapy and transcranial magnetic stimulation, as promising treatments for TRS, and suggests that a precision medicine approach could improve outcomes by targeting the specific neurobiological pathways involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. Wada, M., Noda, Y., Iwata, Y., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) shows promise in reducing cannabis and tobacco use in individuals with schizophrenia, based on a review of seven studies.

While rTMS appears to be a safe and effective approach for managing substance use disorders in patients with psychotic disorders, the evidence for transcranial direct current stimulation (tDCS) remains inconclusive, highlighting the need for further research with larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation to Treat Substance Use Disorders in People With Schizophrenia and Other Psychoses: A Systematic Review. Johnstone, S., Sorkhou, M., Al-Saghir, N., et al.[2022]

Deep brain stimulation is an effective treatment for movement disorders, involving an implanted electrode and pulse generator, but its mechanisms of action are not fully understood and were developed without extensive preclinical safety studies.

Complication rates for deep brain stimulation can exceed 25%, with 4-6% of patients experiencing permanent neurological issues, highlighting the need for better understanding of adverse events and safer stimulation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety considerations for deep brain stimulation: review and analysis. Grill, WM.[2007]

A study involving 20 stable schizophrenia patients tested the safety and efficacy of transcutaneous vagus nerve stimulation (tVNS) over 26 weeks, finding that the treatment was well tolerated with no significant adverse effects.

However, the study did not show a statistically significant improvement in schizophrenia symptoms compared to sham stimulation, suggesting that while tVNS is safe, it may not be effective for this condition in the current trial setup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Hasan, A., Wolff-Menzler, C., Pfeiffer, S., et al.[2018]

Current antipsychotics may not effectively address negative symptoms of schizophrenia, highlighting the need for targeted treatments specifically for these symptoms.

Recent studies have explored various novel treatment approaches, including glutamatergic and nicotinic-acetylcholinergic therapies, as well as behavioral interventions like physical exercise, but challenges in trial design and variability in symptom assessment complicate the evaluation of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Negative Symptoms of Schizophrenia: How Far Have We Come? Kantrowitz, JT.[2018]

Deep brain stimulation (DBS) is an effective treatment for various disorders, including movement and epilepsy disorders, but it is vulnerable to external electromagnetic interference (EMI) that can cause device malfunction or tissue injury.

The study highlights the need for more comprehensive guidelines on EMI sources, as real-world instances of interference from devices like MRI scans and airport body scanners have been documented, indicating potential risks for patients with DBS devices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation and electromagnetic interference. Rahimpour, S., Kiyani, M., Hodges, SE., et al.[2022]

A review of 221 unique adverse events related to deep brain stimulation (DBS) devices for Parkinson's disease revealed that the most common complications were infections (16.2%) and lead migrations (8.6%).

Over 40% of the reported adverse events required patients to return to the operating room for device explantation or revision, highlighting the need for further research to improve the safety and reliability of DBS systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterizing Complications of Deep Brain Stimulation Devices for the Treatment of Parkinsonian Symptoms Without Tremor: A Federal MAUDE Database Analysis. Bennett, J., MacGuire, J., Novakovic, E., et al.[2023]

Non-invasive brain stimulation techniques show promise in modulating neural plasticity and treating schizophrenia, supported by numerous clinical trials demonstrating efficacy.

Despite the encouraging results, there is still a limited understanding of the neurobiological mechanisms behind these treatments, indicating a need for further research to enhance their effectiveness and consistency among individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. Hasan, A., Wobrock, T., Rajji, T., et al.[2022]

Electroconvulsive therapy (ECT) is a well-established and recommended treatment for acute psychosis symptoms, particularly effective in patients with treatment-resistant first episode psychosis, such as schizophrenia.

Other neuromodulation techniques like transcranial magnetic stimulation and vagus nerve stimulation lack sufficient evidence to support their use in treating psychosis, making ECT a more reliable option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electroconvulsive Therapy and Other Neuromodulation Techniques for the Treatment of Psychosis. Maley, CT., Becker, JE., Shultz, EKB.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Neuromodulation in psychiatric disorders. [2012]

2. United States pubmed.ncbi.nlm.nih.gov

Recent advances in noninvasive brain stimulation for schizophrenia. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Assessment of treatment resistance criteria in non-invasive brain stimulation studies of schizophrenia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Dopaminergic dysfunction and excitatory/inhibitory imbalance in treatment-resistant schizophrenia and novel neuromodulatory treatment. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Neuromodulation to Treat Substance Use Disorders in People With Schizophrenia and Other Psychoses: A Systematic Review. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Safety considerations for deep brain stimulation: review and analysis. [2007]

7. Germany pubmed.ncbi.nlm.nih.gov

Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Managing Negative Symptoms of Schizophrenia: How Far Have We Come? [2018]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Deep brain stimulation and electromagnetic interference. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Characterizing Complications of Deep Brain Stimulation Devices for the Treatment of Parkinsonian Symptoms Without Tremor: A Federal MAUDE Database Analysis. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

Modulating neural plasticity with non-invasive brain stimulation in schizophrenia. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Electroconvulsive Therapy and Other Neuromodulation Techniques for the Treatment of Psychosis. [2019]