Biomarker Study of Acamprosate in Schizophrenia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Biomarker Study of Acamprosate in Schizophrenia

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Acamprosate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>All subjects will have baseline measures, receive acamprosate for 2 weeks, then have measures repeated. | Drug: Acamprosate<br>* Acamprosate 333mg, ii tablets PO tid x 2 weeks<br>* Other names: Campral;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, schizoaffective disorder, glutamate, NMDA receptor, magnetic resonance spectroscopy, acamprosate