Brain Stimulation for Schizophrenia

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Centre for Addiction and Mental Health

Must be taking: Antipsychotics

Must not be taking: Psychotropics, others

Disqualifiers: Bipolar, Major depression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to assist individuals with schizophrenia through brain stimulation. The focus is on the dorsolateral prefrontal cortex, a brain region linked to thinking and decision-making. Participants might receive Paired Associative Stimulation (PAS), a type of brain stimulation designed to enhance brain activity and cognitive performance. Suitable candidates include those diagnosed with schizophrenia or schizoaffective disorder who have not recently changed their medication and have not been hospitalized in the past three months. As an unphased trial, this study offers participants the chance to contribute to groundbreaking research that could improve future treatments for schizophrenia.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on antipsychotic medication, you must have had no change in dosage for at least 4 weeks before joining the study.

What prior data suggests that this protocol is safe for use in schizophrenia patients?

Studies have shown that Paired Associative Stimulation (PAS) is safe for people. In one study, participants experienced no negative side effects and responded well to the treatment. PAS caused noticeable changes in brain activity without harm. These findings suggest that PAS is safe for everyone, including those with conditions like schizophrenia. While more research is needed, current evidence supports its safety in humans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the paired associative stimulation (PAS) technique for schizophrenia because it offers a novel approach to brain stimulation. Most current treatments for schizophrenia, such as antipsychotic medications, target neurotransmitter systems, while PAS aims to enhance brain plasticity and improve motor cortex functions. PAS-25 specifically induces long-term potentiation-like plasticity, which is believed to be linked to better motor learning and cognitive tasks, potentially opening up new avenues for treatment beyond traditional drug therapies. PAS-100, on the other hand, serves as a control to ensure that any observed effects are due to the PAS protocol itself and not other factors. This innovative focus on brain plasticity and non-invasive stimulation is what sets PAS apart from existing treatment options.

What evidence suggests that Paired Associative Stimulation is effective for schizophrenia?

Research shows that Paired Associative Stimulation (PAS) can increase brain activity in specific areas. In this trial, participants will receive either the PAS-25 or PAS-100 protocol. Earlier studies have shown that the PAS-25 method effectively boosts brain signals, particularly in areas controlling movement, by strengthening connections between brain cells. Another study found that PAS improved performance on thinking tasks, offering promise for enhancing mental skills in people with schizophrenia. Although results can differ, these findings suggest that PAS might help improve brain function in individuals with schizophrenia. ^{1 6 7 8 9}

Who Is on the Research Team?

Tarek K Rajji, MD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for adults diagnosed with schizophrenia or schizoaffective disorder, stable in their condition and medication. They must be able to understand English, provide consent, and have adequate vision and hearing. Excluded are those with bipolar disorder, major depression, recent drug dependence, certain psychiatric diagnoses, a family history of psychosis in close relatives, unstable psychotropic medication use, left-handedness or other neurological issues.

Inclusion Criteria

People of all races and ethnicities are eligible.

You currently have a diagnosis of schizophrenia or schizoaffective disorder according to the DSM-IV TR criteria.

I haven't been hospitalized recently and my medication dose hasn't changed in the last month.

Exclusion Criteria

I have been on a stable dose of my psychotropic medication for at least 4 weeks.

A close family member has had a severe mental health disorder.

I have not had electroconvulsive therapy in the last 6 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 2-week course of PAS-25 or PAS-100

2 weeks

Follow-up

Participants are monitored for changes in working memory using the N-back task

1 week

1 visit (1 day post-treatment), 1 visit (7 days post-treatment)

What Are the Treatments Tested in This Trial?

Interventions

• Paired Associative Stimulation

Trial Overview

The study tests the effects of brain stimulation (Transcranial Magnetic Stimulation) on the dorsolateral prefrontal cortex in schizophrenia patients. It aims to see if this can improve cognitive tasks related to that brain area by inducing long-term potentiation (LTP), which is like strengthening brain connections.

How Is the Trial Designed?

Group I: PAS 25 Active Control 1 Intervention

In humans, paired associative stimulation (PAS-25) is a transcranial magnetic stimulation (TMS) protocol that has been shown to result in LTP-like plasticity (PAS-LTP) in the motor cortex (M1). PAS-LTP has been shown to be dependent on the NMDAR and to correlate significantly with performance on a motor learning task.

Group II: PAS 100 Placebo Group 1 Intervention

To control for non-specific effects of PAS protocol, the investigators will use a modified PAS protocol (PAS-100) that does not result in any neurophysiologic effects. Patients with schizophrenia and healthy controls will be assessed first with the N-back task and then randomized

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

National Alliance for Research on Schizophrenia and Depression

Collaborator

Trials

97

Recruited

4,100+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

In a study involving nine patients with schizophrenia, the combination of transcranial direct current stimulation (tDCS) and cognitive training did not show significant improvements in psychotic symptoms as measured by the Positive and Negative Syndrome Scale (PANSS).

The lack of effectiveness suggests that this specific tDCS protocol may not enhance clinical outcomes in schizophrenia, highlighting the need for larger studies to explore the potential of electric and cognitive stimulation therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcranial direct current stimulation (tDCS) over the prefrontal cortex combined with cognitive training for treating schizophrenia: a sham-controlled randomized clinical trial. Shiozawa, P., Gomes, JS., Ducos, DV., et al.[2022]

Deep brain stimulation (DBS) is being explored as a potential treatment for schizophrenia (SZ), a condition that currently has significant unmet needs due to issues like relapse and ineffective treatments for negative and cognitive symptoms.

Research suggests that SZ may be a circuit disorder, and DBS could help by modulating striatal dysregulation, with ongoing clinical trials assessing its efficacy and ethical considerations for patients with severe symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approaches to neuromodulation for schizophrenia. Gault, JM., Davis, R., Cascella, NG., et al.[2022]

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]

In a preliminary study of ten patients with treatment-resistant schizophrenia, high-frequency transcranial random noise stimulation (hf-tRNS) significantly reduced auditory hallucinations by an average of 36.1%, indicating its potential efficacy as a noninvasive treatment.

The study involved 10 sessions of hf-tRNS targeting specific brain areas, suggesting that this method may offer a promising alternative to conventional treatments, although further sham-controlled studies are necessary to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Frequency Transcranial Random Noise Stimulation for Auditory Hallucinations of Schizophrenia: A Case Series. Mondino, M., Janin, D., Galvao, F., et al.[2023]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12110737/

A Methodological Evaluation of Four Different Paired ...

Results: PAS-25 with 225 pairings produced a robust enhancement of corticospinal excitability, while PAS-25 with 180 pairings was less effective ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S0149763424004020

Investigating the effects of cortico-cortical paired ...

The study found an increase in CSE and a decrease in short interval intracortical inhibition (SICI) measured at rest after the ccPAS intervention, suggesting ...

3.

journals.plos.org

journals.plos.org/plosone/article?id=10.1371/journal.pone.0154880

Effects of Different Analysis Strategies on Paired Associative ...

The non-significant PAS effects across studies and a wide range of responder rates between studies indicate a high variability of this method.

4.

frontiersin.org

frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2017.00095/full

Paired-Associative Stimulation-Induced Long-term ...

Results: All participants completed PAS procedures. No adverse events occurred. PAS was well tolerated. PAS-induced significant increases in the ratio of post- ...

5.

clinicaltrial.be

clinicaltrial.be/en/details/191342?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Paired Associative Stimulation in the Dorsolateral Prefro...

Hypothesis 3b: Patients with schizophrenia who are randomized to receive a 2-week course of PAS-25 will have improved performance on the N-back ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5447079/

Paired-Associative Stimulation-Induced Long-term ...

No adverse events occurred. PAS was well tolerated. PAS-induced significant increases in the ratio of post-PAS MEP to pre-PAS MEP amplitudes (p < 0.01) at ...

7.

mdpi.com

mdpi.com/2076-3425/15/5/461

A Methodological Evaluation of Four Different Paired ...

Results: PAS-25 with 225 pairings produced a robust enhancement of corticospinal excitability, while PAS-25 with 180 pairings was less effective. Surprisingly, ...

8.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10193754/

A Possible Role of BDNF Polymorphism

rTMS is favorably safe and has no severe adverse effects such as weight gain, tardive dyskinesia, diabetes, etc. It has been proposed that HF-rTMS could ...

9.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1388245725008211

Paired associative electroacupuncture and transcranial ...

This study confirmed that EA-PAS can modulate the excitability of the human M1 and identified new temporal windows, indicating potential ...