Deep Brain Stimulation for Schizophrenia

Overseen By Hila Abush Segev, Ph.D

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Bradley Lega

Must be taking: Antipsychotics

Must not be taking: Antidepressants, Amphetamines

Disqualifiers: Substance use disorder, Suicidal risk, Seizure disorder, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

Trial Summary

What is the purpose of this trial?

There are three hypotheses proposed for this study: 1) Participants will report no unanticipated serious adverse events during the eight months of treatment. 2) Investigators will successfully model psychotic versus non-psychotic brain states using support vector machine (SVM) classifiers. 3) Participants specific brain stimulation parameters can induce a change in the brain state consistent with non-psychotic states as measured by classifier output. Hypotheses 1, 2, and 3 address safety and tolerability, efficacy, and the putative mechanism of successful treatment. The overall objective is to use next generation Deep Brain Stimulation (DBS) combined with antecedent stereo electroencephalogram (SEEG) mapping to establish a new therapy for treatment-refractory schizophrenia given the limitations of current treatment modalities. The primary objective is to demonstrate safety of acute and chronic network guided stimulation for treatment-refractory schizophrenia. Exploratory Objectives: 1. Use intracranial mapping (SEEG) combined with pharmacological manipulation of psychotic states to create a protocol for participant specific deep brain stimulation to treat treatment-refractory schizophrenia. 2. Develop closed loop stimulation protocols to modify brain states during psychotic brain activity induced by low-dose ketamine administration. 3. Investigate the use of mnemonic similarity to characterize brain networks related to symptoms of treatment-refractory schizophrenia. 4. Treatment-related objectives: Record a reduction in psychotic symptoms, as well as an improvement in psychosocial function and cognition.

Will I have to stop taking my current medications?

The trial requires participants to have a stable antipsychotic medication regimen for the month before surgery, so you may need to maintain your current antipsychotic medications. However, if you are taking antidepressants or medications that interact with ketamine, you may need to stop those. The protocol does not specify a washout period for other medications, so it's best to discuss your specific situation with the trial team.

What data supports the effectiveness of the treatment Deep Brain Stimulation for schizophrenia?

Deep Brain Stimulation (DBS) has shown promise in early trials for schizophrenia, with some patients experiencing improvement in symptoms. It has been effective in other psychiatric and neurological disorders, suggesting potential benefits for schizophrenia as well. ^{1 2 3 4 5}

Is Deep Brain Stimulation generally safe for humans?

Deep Brain Stimulation (DBS) has been used safely for various conditions, but complications like infections and bleeding can occur, sometimes requiring device removal. In early trials for schizophrenia, one out of eight participants experienced such complications, indicating some risk, but more data is needed to fully understand the safety for this specific condition. ^{1 4 5 6 7}

How is deep brain stimulation different from other treatments for schizophrenia?

Deep brain stimulation (DBS) is unique because it involves surgically implanting electrodes in specific brain areas to modulate brain activity, unlike traditional treatments like antipsychotic medications or electroconvulsive therapy. This approach targets brain circuits directly and may help patients who do not respond to standard treatments. ^{1 2 3 5 6}

Research Team

Bradley Lega, MD

Principal Investigator

UT Southwestern Medical Center

David McDonagh, M.D.

Principal Investigator

UT Southwestern Medical Center

Carol A Tamminga, MD

Principal Investigator

UT Southwestern Medical Center

Nader Pouratian

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for individuals with treatment-refractory schizophrenia, meaning their condition hasn't improved after trying other treatments. Participants will undergo a procedure to implant the Infinity™ DBS system and must be comfortable with intracranial mapping and potential ketamine administration.

Inclusion Criteria

PANSS score greater than or equal to 90 on two separate assessments over a 1-month period

I am between 22 and 70 years old and not pregnant.

My antipsychotic medication has not changed in the last month.

Exclusion Criteria

Any condition that makes the participant a poor candidate

I cannot have surgery due to a medical condition like an infection.

I am a woman able to have children and am not using strong birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open-label Period

Participants receive open-label deep brain stimulation to optimize settings

8 weeks

Randomized Discontinuation Period

Participants undergo randomized discontinuation with alternating 'ON' and 'OFF' DBS periods

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Deep Brain Stimulation

Trial Overview The study tests the safety and effectiveness of Abbott Laboratories' Infinity™ deep brain stimulation system in managing schizophrenia symptoms. It involves brain mapping, machine learning techniques to identify non-psychotic states, and personalized stimulation protocols.

Participant Groups

Group I: Randomized Discontinuation Period: OFF then ON DBS Experimental Treatment 1 Intervention

Subjects randomized to this arm are initially "OFF" DBS after the open label period then gradually decreased in their optimized setting's amplitude for 8 weeks and then "ON" DBS for 8 weeks.

Group II: Experimental: Randomized Discontinuation Period: ON then OFF DBS Experimental Treatment 1 Intervention

Subjects randomized to this arm are initially "ON" DBS with optimized stimulation settings for 8 weeks after the open label period and then "OFF" DBS with gradually decreasing amplitude for 8 weeks.

Deep Brain Stimulation is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Deep Brain Stimulation for:

• Essential tremor
• Parkinson's disease
• Dystonia
• Obsessive-compulsive disorder
• Epilepsy
• Chronic pain
• Stroke-related motor deficits (under investigation)

Approved in European Union as Deep Brain Stimulation for:

• Essential tremor
• Parkinson's disease
• Dystonia
• Obsessive-compulsive disorder
• Epilepsy
• Chronic pain

Approved in Canada as Deep Brain Stimulation for:

• Essential tremor
• Parkinson's disease
• Dystonia
• Obsessive-compulsive disorder
• Epilepsy
• Chronic pain

Who Is Running the Clinical Trial?

Bradley Lega

Lead Sponsor

Trials

1

Recruited

10+

Findings from Research

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]

Deep brain stimulation (DBS) has shown promise in treating treatment-resistant schizophrenia, with four out of seven patients meeting symptomatic response criteria after stimulation in either the subgenual anterior cingulate cortex or the nucleus accumbens.

DBS was associated with significant changes in glucose metabolism in various brain regions, suggesting that it may improve symptoms by modulating activity in the cortico-basal-thalamic-cortical circuit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain metabolic changes in patients with treatment resistant schizophrenia treated with deep brain stimulation: A series of cases. Roldán, A., Portella, MJ., Sampedro, F., et al.[2021]

Deep brain stimulation (DBS) targeting the nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) shows potential therapeutic effects in treatment-resistant schizophrenia, with 58% improvement in PANSS scores for NAcc and 68% for subgenual ACC among patients who met improvement criteria.

While physical side effects were rare, two patients experienced persistent psychiatric adverse effects, highlighting the need for larger trials to assess the safety and efficacy of DBS in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial. Corripio, I., Roldán, A., Sarró, S., et al.[2021]

In a comparison of surgical outcomes, patients with schizophrenia/schizoaffective disorder (SZ/SAD) showed lower postsurgical mortality rates (1.01-4.11% lower) than those with Parkinson's disease (PD), suggesting that surgical risks may not be as high as previously thought for DBS in SZ/SAD.

While morbidity was slightly higher in SZ/SAD patients (1.91-2.73% higher), there was no increase in serious complications like hemorrhages or infections, indicating that DBS could be a viable option for these patients under careful selection criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postsurgical morbidity and mortality favorably informs deep brain stimulation for new indications including schizophrenia and schizoaffective disorder. Gault, JM., Hosokawa, P., Kramer, D., et al.[2023]

In a one-year study involving four treatment-resistant patients with schizophrenia and bipolar disorder, deep brain stimulation (DBS) led to significant clinical improvements, including reduced scores on the Clinical Global Impression and Hamilton Depression Rating Scale.

DBS was found to be safe, with no side effects or cognitive changes reported, and allowed three patients to discontinue maintenance electroconvulsive therapy, suggesting it may be a viable treatment option for complex psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deep brain stimulation and digital monitoring for patients with treatment-resistant schizophrenia and bipolar disorder: A case series. Bioque, M., Rumià, J., Roldán, P., et al.[2023]

Deep brain stimulation (DBS) of the habenula has shown promise as a safe and effective treatment for severe, chronic, and treatment-resistant schizophrenia in two young adult male patients, with initial improvements in symptoms observed within the first 6 months after surgery.

While one patient maintained clinical benefits at the 12-month follow-up, the other experienced a worsening of symptoms, highlighting that while DBS may be beneficial for some, it does not guarantee long-term success for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Habenula deep brain stimulation for intractable schizophrenia: a pilot study. Wang, Y., Zhang, C., Zhang, Y., et al.[2021]

A systematic review of 96 studies found that the most common complications from Deep Brain Stimulation (DBS) procedures include infections (5.12% of patients) and lead migration (1.60%), highlighting the importance of monitoring for these issues post-surgery.

Patients with conditions like dystonia and off-label indications such as Tourette's syndrome are at a higher risk for hardware-related complications, suggesting that these patients should receive thorough pre-surgical counseling and close follow-up care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of hardware-related complications of Deep Brain Stimulation: Do new indications pose an increased risk? Jitkritsadakul, O., Bhidayasiri, R., Kalia, SK., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Approaches to neuromodulation for schizophrenia. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Brain metabolic changes in patients with treatment resistant schizophrenia treated with deep brain stimulation: A series of cases. [2021]

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

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Postsurgical morbidity and mortality favorably informs deep brain stimulation for new indications including schizophrenia and schizoaffective disorder. [2023]

5. Spain pubmed.ncbi.nlm.nih.gov

Deep brain stimulation and digital monitoring for patients with treatment-resistant schizophrenia and bipolar disorder: A case series. [2023]

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

Habenula deep brain stimulation for intractable schizophrenia: a pilot study. [2021]

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

Systematic review of hardware-related complications of Deep Brain Stimulation: Do new indications pose an increased risk? [2022]