Multi-modal Assessment of Gamma-aminobutyric Acid (GABA) Function in Psychosis

NCT04004416 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: HUM00162597R01MH118634-01
• Study Type: interventional
• Target: 143
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to better understand mental illness and will test the hypotheses that, while viewing affective stimuli, patient groups will show increased blood oxygenation level dependent (BOLD) signal by fMRI after lorazepam. This study will enroll participants between the ages of 16 and 60, who have a psychotic illness (such as psychosis which includes conditions like schizophrenia, schizoaffective disorder, and mood disorders like bipolar disorder). The study will also enroll eligible participants between the ages of 18 and 60 without any psychiatric illness to compare their brains. The study will require participants to have 3-4 sessions over a few weeks. The initial assessments (may be over two visits) will include a diagnostic interview and several questionnaires (qols) to assess eligibility. Subsequently, there will be two separate functional magnetic resonance imaging (fMRI) sessions in which lorazepam or placebo will be given prior to the fMRI. During the fMRI, the participants will also be asked to answer questions. Additionally, the participants will have their blood drawn, vital signs will be taken, they will be asked to complete more qols, and women of childbearing potential will have a urine pregnancy test.

Conditions

Schizophrenia; Bipolar Disorder; Healthy; Psychosis; Schizophreniform Disorders; Schizo Affective Disorder; Major Depression With Psychotic Features

Outcome Measures

Primary Outcomes (1)

• Blood Oxygen Level Dependent (BOLD) Change in Medial Frontal Cortex While Viewing Affective Pictures

  Change in brain activity in the medial frontal cortex after being given lorazepam, a medication that changes the activity of GABAergic neurons. Results reflect the difference/change in brain signal between the lorazepam scan and the placebo scan. BOLD change in the dorsomedial prefrontal cortex (dmPFC) was summarized using MATLAB (MatrixLaboratory)'s SPM (Statistical Parametric Mapping) package for eigenvariate extraction, which extracts the first principal component of the voxel time series within an region of interest (ROI). The resulting values are in arbitrary units (AU) reflecting variance-normalized signal after temporal filtering and serial correlation correction, which removes absolute signal scaling. While AU values are not directly interpretable as percent signal change, they preserve relative differences in BOLD change across conditions and are appropriate for statistical comparison.

  Approximately 28 days

Other Outcomes (1)

• Levels of Negative Affect

  Approximately 28 days

Study Arms (4)

Healthy Controls

PLACEBO COMPARATOR

Other: Placebo and fMRI; Drug: Lorazepam and fMRI

Early Psychosis patients

EXPERIMENTAL

Other: Placebo and fMRI; Drug: Lorazepam and fMRI

Schizophrenia or Schizoaffective disorder patients

EXPERIMENTAL

Other: Placebo and fMRI; Drug: Lorazepam and fMRI

Bipolar disorder patients

EXPERIMENTAL

Other: Placebo and fMRI; Drug: Lorazepam and fMRI

Interventions

Placebo and fMRI OTHER

There will be two fMRIs done after the initial assessment and approximately 28 days apart. Females may need to have this scheduled to coincide with a certain phase of their menstrual cycle. A dose of Placebo will be given approximately 80-90 minutes prior to entering the fMRI scanner. Participants will complete assessments (vitals, questionnaires) and an optional blood draw prior to having each fMRI. Participants will be asked to rate pleasant/unpleasant pictures during their initial assessment visit and to view them during the fMRI.

Also known as: inactive medication

Bipolar disorder patients; Early Psychosis patients; Healthy Controls; Schizophrenia or Schizoaffective disorder patients

Lorazepam and fMRI DRUG

There will be two fMRIs done after the initial assessment and approximately 28 days apart. Females may need to have this scheduled to coincide with a certain phase of their menstrual cycle. A dose of Lorazepam (assigned to one of two dose levels between subjects: 0.01 mg/kg or 0.02 mg/kg) will be given approximately 80-90 minutes prior to entering the fMRI scanner. Participants will complete assessments (vitals, questionnaires) and optional blood draw prior to having each fMRI. Participants will be asked to rate pleasant/unpleasant pictures during their initial assessment visit and to view them during the fMRI.

Also known as: Ativan

Bipolar disorder patients; Early Psychosis patients; Healthy Controls; Schizophrenia or Schizoaffective disorder patients

Eligibility Criteria

• Age: 16 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Ability and willingness to give informed consent to participate;
• years old
• Meets DSM5 criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder type 1, with history of psychosis, major depressive disorder, with history of psychosis, brief psychotic disorder, or other specified/unspecified psychotic disorder; or, meets SIPS criteria for Presence of Psychotic Symptoms or Brief Intermittent Psychotic Syndrome (BIPS).
• Positive symptom onset ≤ 2 years
• No history of active substance use disorder in the past 2 months
• Not currently on an involuntary treatment order
• Not taking chronic narcotics, barbiturates, benzodiazepines
• Absence of suicidal thoughts with plans or intentions, as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
• No increases in psychotropic medication within the prior 4 weeks reflecting clinical instability and for half of the EP sample, not taking antipsychotic medication within the prior 4 weeks. Patients may take as needed doses of benzodiazepines as clinically prescribed, as long as those doses are not required within 5 half-lives of an fMRI session
• Ability to tolerate small, enclosed spaces without anxiety
• Vision equal to or better than 20/40 on a Snellen chart, with correction if necessary
• No metals, implants or metallic substances within or on the body that might cause adverse effects to the subject in a strong magnetic field, or interfere with image acquisition, e. g. aneurysm clips, retained particles (metal workers excluded), neurostimulators, foil-backed transdermal patches, carotid or cerebral stents, cerebral spinal fluid (CSF) shunts; magnetic dental implants, ferromagnetic ocular implants, pacemakers, automatic implantable defibrillators
• Size compatible with scanner gantry, e. g. men over 6 feet tall that weigh more than 250 pounds (lbs), men under 6 feet tall that weigh over 220 lbs, women over 5'11" tall that weigh more than 220 lbs, or women under 5'10" tall that weigh more than 200 lbs. Subjects of these weights or greater typically have difficulty fitting into the fMRI scanner properly.

You may not qualify if:

• If a woman of childbearing age, not pregnant or trying to become pregnant
• History of serious neurological illness or current medical condition that could compromise brain function, such as liver failure
• History of closed head injury, for example (e.g.) loss of consciousness \> \~5 min, hospitalization, neurological sequela
• Hypersensitivity to benzodiazepines or to components of the formulation, per judgment of the principal investigator (PI)
• Disorders affected by benzodiazepines, such as compromised respiratory function, e.g., chronic obstructive pulmonary disease, or acute, narrow angle glaucoma, per judgment of the principal investigator (PI)
• Schizophrenia/schizoaffective (SCZ) and bipolar affective disorder (BAD) patients:
• Ability and willingness to give informed consent to participate;
• years old
• Meets DSM5 criteria for schizophrenia, schizoaffective disorder, other specified/unspecified psychotic disorder, or bipolar disorder type 1, with history of psychosis bipolar affective disorder
• Duration of positive symptom onset \> 2 years
• No history of active substance use disorder in the past 2 months
• Not currently on an involuntary treatment order
• Not taking chronic narcotics, barbiturates, benzodiazepines
• Absence of suicidal thoughts with plans or intentions, as assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
• No increases in psychotropic medication within the prior 4 weeks reflecting clinical instability. Patients may take as needed doses of benzodiazepines as clinically prescribed, as long as those doses are not required within 5 half-lives of an fMRI session

Sponsors & Collaborators

• University of Michigan: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

MeSH Terms

Conditions

Schizophrenia; Bipolar Disorder; Psychotic Disorders

Interventions

Lorazepam

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Bipolar and Related Disorders; Mood Disorders

Intervention Hierarchy (Ancestors)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Stephan Taylor
• Organization: University of Michigan

sftaylor@med.umich.edu

(734) 936-4955

Study Officials

• Stephan Taylor, MD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Masking Details: Study coordinator and participant are blinded to medication administration.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry

Model Details: The two MRI sessions will be scheduled approximately 28 days apart. If you are a woman, we may need to schedule the scanning session to coincide with a certain phase of your menstrual cycle.

Study Record Dates

• First Submitted: June 28, 2019
• First Posted: July 2, 2019
• Study Start: January 16, 2020
• Primary Completion: February 28, 2025
• Study Completion: February 28, 2025
• Last Updated: June 17, 2026
• Results First Posted: June 17, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: De-identified data will be entered into the NDA within 1 year of the conclusion of the study.
• Access Criteria: No additional access restrictions will be placed on the de-identified data beyond those that are standard for the NDA.

Locations

US (1)