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

Multi-modal Assessment of GABA Function in Psychosis

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.

Study Overview

• Status: Completed
• Conditions: Healthy; Schizophrenia; Bipolar Disorder; Psychosis; Schizo Affective Disorder; Major Depression With Psychotic Features; Schizophreniform Disorders
• Intervention / Treatment: Other: Placebo and fMRI; Drug: Lorazepam and fMRI

Detailed Description

• Please note the collaborator (NIMH) is requesting that an NCT number be obtained prior to receiving the award number.
• Initial assessment(s) may be done via videoconference due to Covid.

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 56 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Early psychosis (EP) patients:

Inclusion Criteria:

• Ability and willingness to give informed consent to participate;
• 16-35 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.

Exclusion Criteria:

• 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:

Inclusion Criteria:

• Ability and willingness to give informed consent to participate;
• 16- 60 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
• 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.

Exclusion Criteria:

• 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)

Healthy control subjects:

Inclusion Criteria:

• Ability and willingness to give informed consent to participate
• 18- 60 years old
• No history of (h/o) past or current mental illness (except for simple phobias), but prior h/o substance abuse okay if in remission for greater than 5 years
• Not taking any medication, prescription or non-prescription, with psychotropic effects (birth control medications allowed)
• No first-degree family members with a history of a psychotic disorder (including bipolar disorder)
• 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.

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Healthy Controls	Other: Placebo and fMRI; 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.; Other Names: inactive medication; Drug: Lorazepam and fMRI; 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.; Other Names: Ativan
Experimental: Early Psychosis patients	Other: Placebo and fMRI; 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.; Other Names: inactive medication; Drug: Lorazepam and fMRI; 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.; Other Names: Ativan
Experimental: Schizophrenia or Schizoaffective disorder patients	Other: Placebo and fMRI; 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.; Other Names: inactive medication; Drug: Lorazepam and fMRI; 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.; Other Names: Ativan
Experimental: Bipolar disorder patients	Other: Placebo and fMRI; 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.; Other Names: inactive medication; Drug: Lorazepam and fMRI; 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.; Other Names: Ativan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of Negative Affect	Levels of negative affect were calculated from a PCA of self-report scales: Psychological Stress Index (PSI9; 9-item, Min=0, Max=36, higher=more stress), negative emotions from Modified Differential Emotions Scale (mDES; 8-item subscale, Min=0, Max=32, higher=more negative emotion), Beck Depression Inventory (BDI; 21-item, Min=0, Max=63, higher=more depression). Each measure was completed twice (pre-placebo and pre-drug). The PCA used the prcomp function in R (version 4.5.3), with variables from each scale centered and scaled to unit variance. The 1st principal component of PCA was used as index of general negative affect. This component explained 79% of the total variance across the 6 input measures. Individual component scores were extracted for each participant (Range Min=-3.352, Max=7.067, arbitrary units, higher values=more negative affect/worse outcome).	Approximately 28 days

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Stephan Taylor, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2020
• Primary Completion (Actual): February 28, 2025
• Study Completion (Actual): February 28, 2025

Study Registration Dates

• First Submitted: June 28, 2019
• First Submitted That Met QC Criteria: June 28, 2019
• First Posted (Actual): July 2, 2019

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Mood Disorders; Schizophrenia; Psychotic Disorders; Bipolar Disorder; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Benzodiazepines; Benzodiazepinones; Lorazepam
• Other Study ID Numbers: HUM00162597; R01MH118634-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The PI will share information about this/these trial(s) via timely registration, updates, and results reporting in ClinicalTrials.gov in accordance with NIH policy.

The PI will also upload data gathered in this proposal to an National Institute of Mental Health (NIMH)-designated central data, NIMH Data Archive (NDA), as prescribed by NOT-MH-15-012, working with NIMH program to determine the timing and extent of data sharing. This includes formulation of an enrollment strategy that will obtain the information necessary to generate a Global Unique Identifier (GUID) for each participant.

The consent form will include language indicating the intention to upload de-identified data into the central archive, and permission will be obtained from University of Michigan Institutional Review Board to do so. The budget includes a data manager to cover the costs of managing the data, building the data dictionary and harmonizing it with data structures.

• IPD Sharing Time Frame: De-identified data will be entered into the NDA within 1 year of the conclusion of the study.
• IPD Sharing Access Criteria: No additional access restrictions will be placed on the de-identified data beyond those that are standard for the NDA.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No