Biomarker Study of Acamprosate in Schizophrenia

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.

Eligibility Criteria:
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.