Biomarker Study of Acamprosate in Schizophrenia

Schizophrenia Clinical Trial

Official title:

Biomarker Study of Acamprosate in Schizophrenia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00688324
• Other study ID #: HP-00043248
• Secondary ID: R03AA019571
• Status: Completed
• Phase: Phase 4
• Start date: June 2008
• Est. completion date: February 2012

Study information

• Verified date: September 2019
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

NMDA receptors are brain receptors that are stimulated by glutamate. Poorly functioning NMDA receptors are thought to be involved in the pathology of schizophrenia. This hypothesis is based on the observation that PCP, which blocks the NMDA receptor, produces symptoms and cognitive impairments similar to schizophrenia. Efforts to enhance the function of the NMDA receptor with glycine and D-cycloserine have met with limited success. An alternative approach would be to use the drug acamprosate.

Acamprosate, FDA-approved for maintenance of sobriety after detoxification from alcohol, seems to act through modulation of the NMDA receptor. In the lab, acamprosate has been noted to act as an antagonist when the NMDA receptors are maximally stimulated but as an agonist when NMDA receptor stimulation is minimal. This "smart drug" action makes acamprosate appealing for use in schizophrenia. If acamprosate works as a smart drug in patients, then we would predict that it would enhance the function of NMDA receptors in schizophrenia and improve cognition and the symptoms of the illness. Additionally, acamprosate seems to modulate the NMDA receptor in novel ways distinct from glycine and D-cycloserine.

We will also see if the response to acamprosate differs based on whether participants do or do not have a past history of alcohol use disorders.

Description:

We propose to measure the response of symptoms and cognition in people schizophrenia given acamprosate or placebo. We hypothesize that symptoms and cognition will improve following two weeks of acamprosate. We will also use proton magnetic resonance spectroscopy (MRS) to examine the effect of acamprosate on glutamate & glutamine (Glu&Gln) brain levels in people with schizophrenia. We hypothesize that Glu&Gln concentrations in people with chronic schizophrenia will increase following two weeks of treatment with acamprosate.

The proposed study will consist of 50 individuals with chronic schizophrenia/schizoaffective disorder, 18-55 years old, from in/outpatient programs at the Maryland Psychiatric Research Center (MPRC). The dose of acamprosate will follow manufacturer recommendations with two 333mg tablets given three times per day. MRS will be acquired from areas involved in schizophrenia [dorsolateral-prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC)] at baseline and week two. Symptom ratings and cognitive testing will occur at baseline and be repeated at week two.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: February 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• DSM-IV diagnosis of schizophrenia/schizoaffective disorder

• Age 18-55 years

• Male or female

• Any Race/ethnicity

• Participants will be analyzed separately depending on whether they do or do not have a history of an alcohol use disorder

Exclusion Criteria:

• Pregnant/nursing females or females not using adequate birth control

• Documented history of mental retardation/severe neurological disorder/head injury with loss of consciousness

• DSM-IV diagnosis of substance dependence in previous six months/abuse in the previous three months (except nicotine)

• Serious suicidal risk in the previous six months

• History of renal failure/creatinine clearance of less than 50mL/min

• Current treatment with clozapine

• Contraindication to MRI scanning.

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

Intervention

Drug:
• Acamprosate
Acamprosate 333mg, ii tablets PO tid x 2 weeks

Locations

Country	Name	City	State
United States	Keypoint Community Mental Health Centers- Catonsville	Baltimore	Maryland
United States	Keypoint Community Mental Health Centers- Dundalk	Baltimore	Maryland
United States	Maryland Psychiatric Research Center	Baltimore	Maryland
United States	VA Maryland Health Care System	Baltimore	Maryland

Sponsors (3)

Lead Sponsor	Collaborator
University of Maryland, Baltimore	National Alliance for Research on Schizophrenia and Depression, National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Anterior Cingulate Cortex - Choline	Choline brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Anterior Cingulate Cortex (ACC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Anterior Cingulate Cortex - Creatinine	Creatinine brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Anterior Cingulate Cortex (ACC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Anterior Cingulate Cortex - Glutamate	Glutamate brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Anterior Cingulate Cortex (ACC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Anterior Cingulate Cortex - N-acetylaspartate	N-acetylaspartate (NAA) brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Anterior Cingulate Cortex (ACC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Anterior Cingulate Cortex - Myo-inositol	Myo-inositol brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Anterior Cingulate Cortex (ACC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Right Dorsal Lateral Prefrontal Cortex - Choline	Choline brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Right Dorsal Lateral Prefrontal Cortex (R DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Right Dorsal Lateral Prefrontal Cortex - Creatinine	Creatinine brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Right Dorsal Lateral Prefrontal Cortex (R DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Right Dorsal Lateral Prefrontal Cortex - Glutamate	Glutamate brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Right Dorsal Lateral Prefrontal Cortex (R DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Right Dorsal Lateral Prefrontal Cortex - N-acetylaspartate	N-acetylaspartate (NAA) brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Right Dorsal Lateral Prefrontal Cortex (R DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Right Dorsal Lateral Prefrontal Cortex - Myo-inositol	Myo-inositol brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Right Dorsal Lateral Prefrontal Cortex (R DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Left Dorsal Lateral Prefrontal Cortex - Choline	Choline brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Left Dorsal Lateral Prefrontal Cortex (L DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Left Dorsal Lateral Prefrontal Cortex - Creatinine	Creatinine brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Left Dorsal Lateral Prefrontal Cortex (L DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Left Dorsal Lateral Prefrontal Cortex - Glutamate	Glutamate brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Left Dorsal Lateral Prefrontal Cortex (L DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Left Dorsal Lateral Prefrontal Cortex - N-acetylaspartate	N-acetylaspartate (NAA) brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Left Dorsal Lateral Prefrontal Cortex (L DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Left Dorsal Lateral Prefrontal Cortex - Myo-inositol	Myo-inositol brain metabolite levels between those with and without a lifetime history of prior alcohol abuse/dependence in the Left Dorsal Lateral Prefrontal Cortex (L DLPFC) using Magnetic Resonance Spectroscopy (MRS). Metabolite concentration was calculated from the MRS signals and reported in "mM".	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)
Primary	Fractional Anisotropy Measured With Diffusion Tensor Imaging	Diffusion Tensor Imaging Frational Anisotropy (FA) Measures by Lifetime History of Alcohol Abuse/Dependence and Brain Hemisphere.	Completion of two scans
Secondary	BPRS - Symptoms of Psychosis Change in Scores	Symptoms of psychosis were measured with the Brief Psychiatric Rating Scale (BPRS). The items rated for psychosis are "Conceptual Disorganization", "Suspiciousness", "Hallucinatory Behavior", and "Unusual Thought Content". Each item score ranges from "1=Not Present" to "7=Very Severe".; Value at End of Study minus value at Baseline.	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)
Secondary	BPRS - Symptoms of Psychosis Total Score	The psychosis total score is calculated by adding the scores for scales #4 Conceptual Disorganization, #11 Suspiciousness, #12 Hallucinatory Behavior, and #15 Unusual Thought Content. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum psychosis score is 4 and the maximum psychosis score is 28. A higher score indicates a more severe psychosis rating.	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)
Secondary	SANS - Negative Symptoms of Schizophrenia Total Score	Negative symptoms of schizophrenia measured using the Scale for the Assessment of Negative Symptoms (SANS) Total Score. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)
Secondary	Cognitive Impairment	Cognitive tests will include the DigitSymbol Test (evaluating processing speed), California Verbal Learning Test (CVLT; evaluating verbal learning and episodic memory), and NBack (evaluating working memory).; Digit Symbol scaled scores range from 1 to 19, with the larger numbers indicating better performance.; On the CVLT, the delayed recognition score ranges from 0 to 16, with the larger numbers indicating better performance.; On the NBack test, subjects were asked to recall items 0-back, 1-back, and 2-back in a sequence. D-prime scores range from 0 to 8.6. Higher scores are better. As memory load increases from 0 to 1, from 1 to 2, D-prime scores are expected to be lower.	Change from Baseline (Treatment Week 0) to End of Study (Treatment Week 2)

External Links

•   Maryland Psychiatric Research Center