Auditory Stimulation for Schizophrenia

(RESPITE Trial)

Overseen by Fabio Ferrarelli, MD, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Fabio Ferrarelli

Must be taking: Antipsychotics

Disqualifiers: Intellectual disability, Head injury, Neurological disorder, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial investigates if playing sounds during deep sleep can improve sleep and memory in people with early-course schizophrenia. The study aims to see if enhancing specific brain activities during sleep helps with cognitive functions.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications. However, it mentions that participants with early-course schizophrenia can have a lifetime exposure to antipsychotic medications of up to 5 years, suggesting that continuing current antipsychotic medications might be allowed.

What data supports the effectiveness of the treatment Closed-loop auditory stimulation for schizophrenia?

The research shows that auditory stimulation in patients with schizophrenia can evoke a brain response similar to healthy individuals, increasing certain sleep activities. Although this did not improve memory in the study, it suggests potential for addressing sleep-related issues in schizophrenia. ^{1 2 3 4 5}

Is auditory stimulation safe for humans?

Research on auditory stimulation, including studies with healthy adults and patients with schizophrenia, shows it is generally safe. Participants experienced changes in brain activity during sleep, but no harmful effects were reported. ^{1 6 7 8 9}

How does auditory stimulation treatment differ from other treatments for schizophrenia?

Auditory stimulation for schizophrenia is unique because it uses sound to enhance sleep-related brain activity, aiming to improve memory and brain function without medication. Unlike traditional drug treatments, this non-invasive approach targets sleep patterns to potentially address cognitive issues in schizophrenia. ^{1 2 3 6 7}

Research Team

Fabio Ferrarelli, MD, PhD

Principal Investigator

University of Pittsbrugh

Eligibility Criteria

This trial is for individuals aged 18-40 with early-course schizophrenia, schizophreniform, or schizoaffective disorder without a family history of similar conditions. They must have experienced psychosis for ≤5 years and had limited exposure to antipsychotic meds (≤5 years). Healthy controls without psychiatric disorders can also join. Exclusions include pregnancy, inability to consent, intellectual disabilities, significant neurological issues, certain sleep disorders, substance abuse (except cannabis/alcohol), and medical illnesses affecting the brain.

Inclusion Criteria

I have been diagnosed with schizophrenia or a related disorder, without drug causes, and haven't had a psychotic episode before.

My immediate family has no history of schizophrenia or mood disorders with psychosis.

My condition is early-stage schizophrenia.

Exclusion Criteria

Current or past co-morbidity for alcohol or psychoactive substance dependence

Substance abuse other than cannabis and/or alcohol within the past one year

DSM-IV intellectual disability

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants complete clinical evaluation, IQ assessment, and initial sleep EEG recordings

1 week

1 visit (in-person)

Treatment

Participants undergo closed-loop auditory stimulation during sleep across multiple nights

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for changes in sleep spindle and slow wave activity and memory consolidation

2 weeks

Treatment Details

Interventions

• Closed-loop auditory stimulation (Behavioural Intervention)
• Sham auditory stimulation (Behavioural Intervention)

Trial Overview The study aims to compare brain activity during sleep between healthy individuals and those with schizophrenia-related diagnoses. It will test if playing tones during deep sleep can improve specific sleep features and cognitive performance in patients. Participants will receive either sham auditory stimulation or closed-loop auditory stimulation as part of the research.

Participant Groups

Group I: Experimental: Night three- sham, night four - active Experimental Treatment 2 Interventions

This arm will receive sham auditory stimulation for the first 3 nights and active auditory stimulation for the fourth night. Night one - sham auditory stimulation, night 2 - sham auditory stimulation, night 3 - sham auditory stimulation, night 4 - active auditory stimulation

Group II: Experimental: Night three - active, night four - sham Experimental Treatment 2 Interventions

This arm will receive sham auditory stimulation for the first two nights, active auditory stimulation for the third night, and sham auditory stimulation for the fourth night. Night one - sham auditory stimulation, night two - sham auditory stimulation, night three - active auditory stimulation, night four - sham auditory stimulation

Who Is Running the Clinical Trial?

Fabio Ferrarelli

Lead Sponsor

Trials

2

Recruited

280+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Dr. Joshua A. Gordon

National Institute of Mental Health (NIMH)

Chief Executive Officer since 2016

MD, PhD

Dr. Shelli Avenevoli

National Institute of Mental Health (NIMH)

Chief Medical Officer

PhD

Findings from Research

In a study involving 18 patients with schizophrenia, real-time auditory stimulation during sleep successfully increased slow wave and sleep spindle activity, similar to responses seen in healthy individuals.

Despite the positive electrophysiological changes, the auditory stimulation did not lead to any improvement in memory performance, indicating that while the approach shows promise, it currently does not enhance memory consolidation in patients with schizophrenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Auditory stimulation in-phase with slow oscillations to enhance overnight memory consolidation in patients with schizophrenia? Weinhold, SL., Lechinger, J., Timm, N., et al.[2022]

A randomized-controlled trial involving 144 patients with schizophrenia will test the efficacy of high-frequency transcranial random noise stimulation (hf-tRNS) to alleviate persistent symptoms, with the primary outcome being a 25% reduction in symptoms after 10 sessions.

The study aims to explore not only the clinical effects of hf-tRNS on symptoms like auditory hallucinations but also its impact on brain activity and cognitive functions, potentially establishing it as a new treatment option for patients resistant to traditional antipsychotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM'Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial. Brunelin, J., Mondino, M., Haesebaert, J., et al.[2022]

Transcranial direct current stimulation (tDCS) has shown potential in reducing the severity and frequency of auditory hallucinations in schizophrenia, with three out of six randomized controlled trials reporting therapeutic benefits.

Despite these promising results, the overall evidence is inconclusive and insufficient, as many studies lack large sample sizes, preventing tDCS from being established as a reliable treatment option for auditory hallucinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of transcranial direct current stimulation for the treatment of auditory hallucinations of schizophrenia - a systematic review. Pondé, PH., de Sena, EP., Camprodon, JA., et al.[2020]

In patients with schizophrenia and major depression, higher stimulation frequencies enhanced the amplitude of the N1 auditory evoked potential, indicating altered auditory processing in these conditions.

Schizophrenic patients showed a prolonged latency of the N1 component and P2 latency was also extended in those treated with high-potency neuroleptic drugs, suggesting that medication may affect auditory processing timing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of stimulation parameters on auditory stimulus processing in schizophrenia and major depression: an auditory evoked potential study. Adler, G., Adler, J., Schneck, M., et al.[2019]

A novel auditory closed-loop stimulation technique was successfully used to manipulate theta activity during REM sleep in a study involving 16 healthy young adults, demonstrating the ability to entrain EEG activity to 5 Hz.

The stimulation led to an initial increase in theta power followed by a prolonged suppression, along with an increase in beta power, suggesting potential for further research into the effects of REM sleep on behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase-locked auditory stimulation of theta oscillations during rapid eye movement sleep. Harrington, MO., Ashton, JE., Ngo, HV., et al.[2021]

Closed-loop auditory stimulation can enhance sleep rhythms, specifically increasing delta, theta, and sigma power during non-rapid eye movement (NREM) sleep, which is crucial for brain recovery and memory consolidation.

The study found that this stimulation specifically improved the coupling between delta and sigma activity in the right parietal area, suggesting a targeted approach to enhance sleep-dependent neuroplasticity in specific brain regions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in cross-frequency coupling following closed-loop auditory stimulation in non-rapid eye movement sleep. Krugliakova, E., Volk, C., Jaramillo, V., et al.[2021]

Auditory closed-loop stimulation effectively enhanced slow oscillatory activity and spindle activity during sleep, as confirmed by the study involving 12 healthy males.

Despite these enhancements, the stimulation did not improve the overnight retention of semantically-incongruent associations, indicating that this method may not be beneficial for all types of memory consolidation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No benefit of auditory closed-loop stimulation on memory for semantically-incongruent associations. Harrington, MO., Ngo, HV., Cairney, SA.[2022]

References

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

Auditory stimulation in-phase with slow oscillations to enhance overnight memory consolidation in patients with schizophrenia? [2022]

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

Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM'Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial. [2022]

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

Use of transcranial direct current stimulation for the treatment of auditory hallucinations of schizophrenia - a systematic review. [2020]

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

Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study. [2022]

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

Influence of stimulation parameters on auditory stimulus processing in schizophrenia and major depression: an auditory evoked potential study. [2019]

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

Phase-locked auditory stimulation of theta oscillations during rapid eye movement sleep. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Changes in cross-frequency coupling following closed-loop auditory stimulation in non-rapid eye movement sleep. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

A system based on machine learning for improving sleep. [2023]

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

No benefit of auditory closed-loop stimulation on memory for semantically-incongruent associations. [2022]