Biomarker Study of Acamprosate in Schizophrenia

Phase 4

Completed

Conditions: Schizoaffective Disorder
Schizophrenia

Interventions: Drug: Acamprosate

Registration Number: NCT00688324

Lead Sponsor: University of Maryland, Baltimore

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Arm	Acamprosate	All subjects will have baseline measures, receive acamprosate for 2 weeks, then have measures repeated.

Primary Outcome Measures

Name	Time	Method
Anterior Cingulate Cortex - N-acetylaspartate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Right Dorsal Lateral Prefrontal Cortex - Glutamate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Anterior Cingulate Cortex - Creatinine	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Right Dorsal Lateral Prefrontal Cortex - Creatinine	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Right Dorsal Lateral Prefrontal Cortex - N-acetylaspartate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Left Dorsal Lateral Prefrontal Cortex - Creatinine	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Left Dorsal Lateral Prefrontal Cortex - Glutamate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Anterior Cingulate Cortex - Myo-inositol	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Right Dorsal Lateral Prefrontal Cortex - Choline	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Left Dorsal Lateral Prefrontal Cortex - Choline	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Anterior Cingulate Cortex - Glutamate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Anterior Cingulate Cortex - Choline	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Right Dorsal Lateral Prefrontal Cortex - Myo-inositol	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Left Dorsal Lateral Prefrontal Cortex - N-acetylaspartate	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Left Dorsal Lateral Prefrontal Cortex - Myo-inositol	Baseline screening (Scan 1) and again after 2 weeks of Acamprosate treatment (Scan 2)	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".
Fractional Anisotropy Measured With Diffusion Tensor Imaging	Completion of two scans	Diffusion Tensor Imaging Frational Anisotropy (FA) Measures by Lifetime History of Alcohol Abuse/Dependence and Brain Hemisphere.

Secondary Outcome Measures

Name	Time	Method
BPRS - Symptoms of Psychosis Total Score	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)	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.
SANS - Negative Symptoms of Schizophrenia Total Score	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)	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.
BPRS - Symptoms of Psychosis Change in Scores	Baseline (Treatment Week 0) and End of Study (Treatment Week 2)	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.
Cognitive Impairment	Change from Baseline (Treatment Week 0) to End of Study (Treatment Week 2)	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.

Trial Locations

Locations (4): VA Maryland Health Care System
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Baltimore, Maryland, United States
Keypoint Community Mental Health Centers- Dundalk
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Baltimore, Maryland, United States
Maryland Psychiatric Research Center
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Baltimore, Maryland, United States
Keypoint Community Mental Health Centers- Catonsville
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Baltimore, Maryland, United States