Schizophrenia / Schizoaffective DisorderCLARITY WP1NCT07820553
Building a Computational Model of Auditory Hallucinations
An observational study of Schizophrenia / Schizoaffective Disorder and Schizophrenia and Disorders With Psychotic Feature, run by King's College London.
Trial summary
Some people hear voices or sounds that other people cannot hear; these are called auditory hallucinations. The study aims to understand what is happening in the brain when this occurs and will use brain scans to learn more. Greater understanding should help develop better treatments in the future. Read more about this study
- Who is it for?
- Ages 16 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Schizophrenia / Schizoaffective Disorder, Schizophrenia and Disorders With Psychotic Feature, Psychosis
- How many people
- 146 participants
- Where
- No sites listed yet
- Study dates
- Sep 2026to Aug 2030
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 65 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: PWLEP: people with auditory perceptual alterations able to get to the study site in London. Controls: people without psychosis or auditory perceptual alterations able to get to the study site in London.
Who may be able to join
- PWLEP:
- Age 16-65 years.
- A score of at least 3 on the state section of the Auditory Perceptual Trait and State scale (APTS).
- If using an antipsychotic drug, participants must be on a stable dose of any medication during the baseline measures.
- Sufficient understanding of the nature of the study and any hazards of participating in it, or suitable consultee who can understand this and provide an opinion of what the participant's wishes would be if the participant does not have capacity, if appropriate to do so.
- Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire study.
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- Capacity to give written consent to participate after reading the information and consent form and after having the opportunity to discuss the study with the investigators or their delegates, or suitable consultee who can understand this and provide an opinion of what the participant's wishes would be if the participant does not have capacity, if appropriate to do so.
- Healthy controls:
- Age 16-65 years.
- Sufficient understanding of the nature of the study and any hazards of participating in it, or suitable consultee who can understand this and provide an opinion of what the participant's wishes would be if the participant does not have capacity, if appropriate to do so.
- Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire study.
- Capacity to give written consent to participate after reading the information and consent form and after having the opportunity to discuss the study with the investigators or their delegates, or suitable consultee who can understand this and provide an opinion of what the participant's wishes would be if the participant does not have capacity, if appropriate to do so.
Who cannot join
- PWLEP:
- Clinically relevant abnormal history, or laboratory values at the pre-study screening assessment or participation in other research studies that could interfere with the objectives of the study or the safety of the participant, as deemed significant for a study researcher.
- Impaired endocrine, cardiac, pulmonary, thyroid, haematological, hepatic, respiratory, neurological, immunological or renal function, or other major disease (e.g. cancer) deemed clinically significant at the time of the study.
- Recent history (i.e. in the last 12 months) of epilepsy or seizures.
- Homicidal ideation or intent, as judged by a researcher; suicidal ideation, with some intent to act, or suicidal behaviour, as judged by a researcher.
- History of drug or alcohol dependence (except for caffeine and nicotine and mild/moderate cannabis dependence) in the 3 months before study start.
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- Likelihood that the participant will not comply with the requirements of the protocol.
- Contraindication to MRI, EEG or other study procedures (for example history of metal implants or metal pieces entering the body that cannot be removed safely, severe claustrophobia, allergy or skin sensitivity to EEG electrode gel).
- Any other condition or disability that would make participation in the study procedures not possible (for example severe vision or hearing impairment).
- Healthy controls:
- As above, and also:
- 1. No relevant family history of schizophrenia and psychosis (as judged relevant by a study researcher).
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Building a Computational Model of the Role of Excitation/Inhibition (E/I) Balance in Auditory Hallucinations Using Electroencephalography (EEG) and Magnetic Resonance Imaging (MRI): a Case-control Study
Some people hear voices or sounds that other people cannot hear; these are called auditory hallucinations. The study aims to understand what is happening in the brain when this occurs and will use brain scans to learn more. Greater understanding should help develop better treatments in the future.
Read the detailed description
Psychotic disorders, including schizophrenia and bipolar disorder with psychotic features, are severe mental health conditions that significantly diminish quality of life and place a substantial economic burden on society. In England, the total societal cost of schizophrenia is estimated at £11.8 billion per year, with the public sector bearing approximately £7.2 billion of this cost. People with lived experience of psychosis (PWLEP) may experience a range of symptoms, including positive symptoms such as hallucinations and delusions, negative symptoms such as affective flattening, and cognitive impairments, including difficulties with attention, memory and executive function.
Auditory hallucinations, a common and disruptive symptom of psychotic disorders, are typically experienced as hearing voices and occur in approximately 75% of PWLEP. These voices are often intrusive and may be critical, threatening, or commanding, and can be associated with an increased risk of suicide. Whilst antipsychotic treatments, which primarily act through dopamine receptor antagonism, can be effective, they are often associated with significant side effects, and the response to antipsychotic treatment is insufficient in around 40% of patients. There is therefore an urgent need to better understand the mechanisms underlying auditory hallucinations to identify more effective treatment targets and develop novel therapies that act through mechanisms other than dopamine receptor antagonism.
A key avenue for understanding auditory hallucinations is examining disruptions in excitatory-inhibitory (E/I) balance, a fundamental mechanism in neural processing. Post-mortem and in vivo electrophysiological studies implicate dysregulated cortical microcircuits in psychosis, where excitatory pyramidal cells (signalling using glutamate) and inhibitory interneurons (signalling using gamma-aminobutyric acid or 'GABA') regulate neural activity. Interactions between these cells generate synchronised neural oscillations across different frequency bands, from low (delta, theta, alpha) to high (beta, gamma) frequencies. These oscillations, which are crucial for coordinating neural activity and supporting cognitive and perceptual function, can also serve as a measure of E/I balance and be assessed in humans using electroencephalography (EEG).
Previous studies have shown that resting-state cortical theta and gamma oscillations are increased, whilst beta oscillations and evoked gamma are reduced in people with psychosis, indicating altered E/I balance in the cortex. Dynamic causal modelling (DCM) is a validated computational technique for inferring E/I imbalance in both rodent models and humans, allowing a more precise estimate of E/I balance in the human brain to be obtained. Applying DCM to EEG and functional magnetic resonance imaging (fMRI) paradigms-including resting-state recordings, mismatch negativity (MMN), and the 40-Hz auditory steady-state response (ASSR)-has previously shown that pyramidal neuron disinhibition in the auditory cortex (primary auditory cortex and related regions) was associated with auditory perceptual symptoms, serving as a measure of hallucinations.
These findings have been demonstrated in those with chronic psychosis. The investigators now propose to measure E/I early in the presentation of a psychotic disorder to show whether this pathophysiology is related to symptoms demonstrated close to the onset of illness.
The aim of this study is to create a computational model of auditory hallucinations using cortical E/I balance in individuals with a psychotic disorder.
Primary Objective:
The principal research objective is to understand differences in brain signalling, specifically in E/I balance in those with auditory hallucinations using a computational model based on EEG measures such as ASSR relative to healthy volunteers without auditory hallucinations, and whether such measures predict changes in auditory hallucination over time.
Secondary Objectives:
The secondary research objectives include testing if levels of brain and blood substances and genetics are related to brain E/I balance in those with auditory hallucinations and healthy controls.
- Conditions
- Schizophrenia / Schizoaffective Disorder, Schizophrenia and Disorders With Psychotic Feature, Psychosis, SCHIZOPHRENIA 1 (Disorder), Schizophreni-form Disorder
- Keywords
- schizophrenia, EEG, E/I balance, electrophysiology, computational models, auditory hallucinations, MRI, psychosis, computational psychiatry, neuroimaging
- Medical subject headings
- Schizophrenia, Psychotic Disorders, Hallucinations
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| People with lived experience of psychosis (PWLEP) | Age 16-65 years with experience of auditory perceptual alterations as measured by validated scale and able to consent to the study. On stable dose of antipsychotic medication if using. No recent history of epilepsy or seizure within last 12 months. | |
| Control | Age 16-65 years with no relevant family history of schizophrenia and psychosis (as judged relevant by a study researcher) and able to consent to study. No recent history of epilepsy or seizure within last 12 months. |
What is being measured
The primary outcome is the main question the study is designed to answer.
E/I balance determined using the computational model based on the 40-Hz auditory steady-state response (ASSR) EEG response.
Computational model will be created after study end, using EEG data acquired at the baseline study visit.
Measured: Baseline
Secondary outcomes (5)
Mismatch Negativity (MMN): E/I balance determined using MMN amplitude and latency measured using EEG.
Measured: Baseline
Relationship between E/I balance and auditory perceptual symptom severity, assessed using the Auditory Perceptual Trait and State Scale.
Measured: Baseline
EEG Resting-State Activity: Power across frequency bands (delta, theta, alpha, beta, gamma) during resting-state EEG.
Measured: Baseline
Auditory Oddball P300: Amplitude of the P300 event-related potential in response to an auditory oddball, measured using EEG.
Measured: Baseline
fMRI Resting-State Connectivity
E/I balance determined using functional connectivity between key brain regions (e.g., auditory cortex, prefrontal cortex) assessed by resting-state fMRI.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2026
- Study startSep 2026 (estimated)
- Primary completionAug 2030 (estimated)
- Study completionAug 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Schizophrenia / Schizoaffective DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 146 participants (estimated)
Sponsor and investigators
- Lead sponsor
- King's College London
- Sponsor type
- University, hospital or other
- Collaborators
- University of Manchester, University College, London
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07820553
- Sponsor's protocol ID
- 368570
- Other IDs
- REC Approval Number:26/LO/0524
- Acronym
- CLARITY WP1
- Status last verified
- Sep 2026
- First submitted
- 8 Sep 2026
- Last updated
- 15 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Collected anonymised data may be shared with other researchers within and outside the UK as per open science agreements from the funder Wellcome.
Publications
Adams RA, Pinotsis D, Tsirlis K, Unruh L, Mahajan A, Horas AM, Convertino L, Summerfelt A, Sampath H, Du XM, Kochunov P, Ji JL, Repovs G, Murray JD, Friston KJ, Hong LE, Anticevic A. Computational Modeling of Electroencephalography and Functional Magnetic Resonance Imaging Paradigms Indicates a Consistent Loss of Pyramidal Cell Synaptic Gain in Schizophrenia. Biol Psychiatry. 2022 Jan 15;91(2):202-215. doi: 10.1016/j.biopsych.2021.07.024. Epub 2021 Aug 10.
PubMed 34598786
Study at a glance
From the registry record, last updated by the sponsor on 15 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Building a Computational Model of the Role of Excitation/Inhibition (E/I) Balance in Auditory Hallucinations Using Electroencephalography (EEG) and Magnetic Resonance Imaging (MRI): a Case-control Study
- ClinicalTrials.gov ID
- NCT07820553
- Acronym / sponsor ID
- CLARITY WP1 / 368570
- Conditions
- Schizophrenia / Schizoaffective Disorder, Schizophrenia and Disorders With Psychotic Feature, Psychosis, SCHIZOPHRENIA 1 (Disorder), Schizophreni-form Disorder
- Keywords
- schizophrenia, EEG, E/I balance, electrophysiology, computational models, auditory hallucinations, MRI, psychosis
- Study type
- Observational
- Recruitment status
- Not yet recruiting
- Enrolment
- 146 participants (estimated)
- Lead sponsor
- King's College LondonUniversity, hospital or other
- Collaborators
- University of Manchester, University College, London
- Study start
- Sep 2026 (estimated)
- Primary completion
- Aug 2030 (estimated)
- Study completion
- Aug 2030 (estimated)
- First posted
- 15 Sep 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Some people hear voices or sounds that other people cannot hear; these are called auditory hallucinations. The study aims to understand what is happening in the brain when this occurs and will use brain scans to learn more. Greater understanding should help develop better treatments in the future.
Detailed description
Psychotic disorders, including schizophrenia and bipolar disorder with psychotic features, are severe mental health conditions that significantly diminish quality of life and place a substantial economic burden on society. In England, the total societal cost of schizophrenia is estimated at £11.8 billion per year, with the public sector bearing approximately £7.2 billion of this cost. People with lived experience of psychosis (PWLEP) may experience a range of symptoms, including positive symptoms such as hallucinations and delusions, negative symptoms such as affective flattening, and cognitive impairments, including difficulties with attention, memory and executive function.
Auditory hallucinations, a common and disruptive symptom of psychotic disorders, are typically experienced as hearing voices and occur in approximately 75% of PWLEP. These voices are often intrusive and may be critical, threatening, or commanding, and can be associated with an increased risk of suicide. Whilst antipsychotic treatments, which primarily act through dopamine receptor antagonism, can be effective, they are often associated with significant side effects, and the response to antipsychotic treatment is insufficient in around 40% of patients. There is therefore an urgent need to better understand the mechanisms underlying auditory hallucinations to identify more effective treatment targets and develop novel therapies that act through mechanisms other than dopamine receptor antagonism.
A key avenue for understanding auditory hallucinations is examining disruptions in excitatory-inhibitory (E/I) balance, a fundamental mechanism in neural processing. Post-mortem and in vivo electrophysiological studies implicate dysregulated cortical microcircuits in psychosis, where excitatory pyramidal cells (signalling using glutamate) and inhibitory interneurons (signalling using gamma-aminobutyric acid or 'GABA') regulate neural activity. Interactions between these cells generate synchronised neural oscillations across different frequency bands, from low (delta, theta, alpha) to high (beta, gamma) frequencies. These oscillations, which are crucial for coordinating neural activity and supporting cognitive and perceptual function, can also serve as a measure of E/I balance and be assessed in humans using electroencephalography (EEG).
Previous studies have shown that resting-state cortical theta and gamma oscillations are increased, whilst beta oscillations and evoked gamma are reduced in people with psychosis, indicating altered E/I balance in the cortex. Dynamic causal modelling (DCM) is a validated computational technique for inferring E/I imbalance in both rodent models and humans, allowing a more precise estimate of E/I balance in the human brain to be obtained. Applying DCM to EEG and functional magnetic resonance imaging (fMRI) paradigms-including resting-state recordings, mismatch negativity (MMN), and the 40-Hz auditory steady-state response (ASSR)-has previously shown that pyramidal neuron disinhibition in the auditory cortex (primary auditory cortex and related regions) was associated with auditory perceptual symptoms, serving as a measure of hallucinations.
These findings have been demonstrated in those with chronic psychosis. The investigators now propose to measure E/I early in the presentation of a psychotic disorder to show whether this pathophysiology is related to symptoms demonstrated close to the onset of illness.
The aim of this study is to create a computational model of auditory hallucinations using cortical E/I balance in individuals with a psychotic disorder.
Primary Objective:
The principal research objective is to understand differences in brain signalling, specifically in E/I balance in those with auditory hallucinations using a computational model based on EEG measures such as ASSR relative to healthy volunteers without auditory hallucinations, and whether such measures predict changes in auditory hallucination over time.
Secondary Objectives:
The secondary research objectives include testing if levels of brain and blood substances and genetics are related to brain E/I balance in those with auditory hallucinations and healthy controls.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| People with lived experience of psychosis (PWLEP) | – | –Age 16-65 years with experience of auditory perceptual alterations as measured by validated scale and able to consent to the study. On stable dose of antipsychotic medication if using. No recent history of epilepsy or seizure within last 12 months. |
| Control | – | –Age 16-65 years with no relevant family history of schizophrenia and psychosis (as judged relevant by a study researcher) and able to consent to study. No recent history of epilepsy or seizure within last 12 months. |
Who may qualify
- Ages
- 16 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- PWLEP: people with auditory perceptual alterations able to get to the study site in London. Controls: people without psychosis or auditory perceptual alterations able to get to the study site in London.
Key inclusion criteria (12 listed)
- Age 16-65 years.
- A score of at least 3 on the state section of the Auditory Perceptual Trait and State scale (APTS).
- If using an antipsychotic drug, participants must be on a stable dose of any medication during the baseline measures.
- Sufficient understanding of the nature of the study and any hazards of participating in it, or suitable consultee who can understand this and provide an opinion of what the participant's wishes would be if the participant does not have capacity, if appropriate to do so.
- Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of, the entire study.
Key exclusion criteria (12 listed)
- Clinically relevant abnormal history, or laboratory values at the pre-study screening assessment or participation in other research studies that could interfere with the objectives of the study or the safety of the participant, as deemed significant for a study researcher.
- Impaired endocrine, cardiac, pulmonary, thyroid, haematological, hepatic, respiratory, neurological, immunological or renal function, or other major disease (e.g. cancer) deemed clinically significant at the time of the study.
- Recent history (i.e. in the last 12 months) of epilepsy or seizures.
- Homicidal ideation or intent, as judged by a researcher; suicidal ideation, with some intent to act, or suicidal behaviour, as judged by a researcher.
- History of drug or alcohol dependence (except for caffeine and nicotine and mild/moderate cannabis dependence) in the 3 months before study start.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
E/I balance determined using the computational model based on the 40-Hz auditory steady-state response (ASSR) EEG response.
Time frame: Baseline
Computational model will be created after study end, using EEG data acquired at the baseline study visit.
5 secondary outcomes
Mismatch Negativity (MMN): E/I balance determined using MMN amplitude and latency measured using EEG.
Time frame: Baseline
Relationship between E/I balance and auditory perceptual symptom severity, assessed using the Auditory Perceptual Trait and State Scale.
Time frame: Baseline
EEG Resting-State Activity: Power across frequency bands (delta, theta, alpha, beta, gamma) during resting-state EEG.
Time frame: Baseline
Auditory Oddball P300: Amplitude of the P300 event-related potential in response to an auditory oddball, measured using EEG.
Time frame: Baseline
fMRI Resting-State Connectivity
Time frame: Baseline
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Sep 2026.
- Results publication: PubMed 34598786Adams RA, Pinotsis D, Tsirlis K, Unruh L, Mahajan A, Horas AM, Convertino L, Summerfelt A, Sampath H, Du XM, Kochunov P, Ji JL, Repovs G, Murray JD, Friston KJ, Hong LE, Anticevic A. Computational Modeling of Electroencephalography and Functional Magnetic Resonance Imaging Paradigms Indicates a Consistent Loss of Pyramidal Cell Synaptic Gain in Schizophrenia. Biol Psychiatry. 2022 Jan 15;91(2):202-215. doi: 10.1016/j.biopsych.2021.07.024. Epub 2021 Aug 10.
- Individual participant dataSharing planned: Yes. Collected anonymised data may be shared with other researchers within and outside the UK as per open science agreements from the funder Wellcome.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Questions about this trial
What is this clinical trial studying?
An observational study of Schizophrenia / Schizoaffective Disorder and Schizophrenia and Disorders With Psychotic Feature, run by King's College London.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 15 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact CLARITY Study Contact (+447871777185, clarity@kcl.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
E/I balance determined using the computational model based on the 40-Hz auditory steady-state response (ASSR) EEG response. (time frame: Baseline). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07820553, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Sep 2026.