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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Acamprosate 333mg, ii tablets PO tid x 2 weeks
VA Maryland Health Care System
Baltimore, Maryland, United States
Keypoint Community Mental Health Centers- Dundalk
Baltimore, Maryland, United States
Keypoint Community Mental Health Centers- Catonsville
Baltimore, Maryland, United States
Maryland Psychiatric Research Center
Baltimore, Maryland, United States
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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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".
Time frame: 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.
Time frame: Completion of two scans
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Change from Baseline (Treatment Week 0) to End of Study (Treatment Week 2)
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