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Biomarker Study of Acamprosate in Schizophrenia

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ClinicalTrials.gov Identifier: NCT00688324
Recruitment Status : Completed
First Posted : June 2, 2008
Results First Posted : January 23, 2018
Last Update Posted : January 23, 2018
Sponsor:
Collaborators:
National Alliance for Research on Schizophrenia and Depression
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Information provided by (Responsible Party):
Robert W. Buchanan, University of Maryland

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Schizoaffective Disorder Drug: Acamprosate Phase 4

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Biomarker Study of Acamprosate in Schizophrenia
Actual Study Start Date : June 2008
Primary Completion Date : February 2012
Study Completion Date : February 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Single Arm
All subjects will have baseline measures, receive acamprosate for 2 weeks, then have measures repeated.
Drug: Acamprosate
Acamprosate 333mg, ii tablets PO tid x 2 weeks
Other Name: Campral



Primary Outcome Measures :
  1. Anterior Cingulate Cortex - Choline [ Time Frame: 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".

  2. Anterior Cingulate Cortex - Creatinine [ Time Frame: 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".

  3. Anterior Cingulate Cortex - Glutamate [ Time Frame: 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".

  4. Anterior Cingulate Cortex - N-acetylaspartate [ Time Frame: 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".

  5. Anterior Cingulate Cortex - Myo-inositol [ Time Frame: 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".

  6. Right Dorsal Lateral Prefrontal Cortex - Choline [ Time Frame: 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".

  7. Right Dorsal Lateral Prefrontal Cortex - Creatinine [ Time Frame: 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".

  8. Right Dorsal Lateral Prefrontal Cortex - Glutamate [ Time Frame: 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".

  9. Right Dorsal Lateral Prefrontal Cortex - N-acetylaspartate [ Time Frame: 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".

  10. Right Dorsal Lateral Prefrontal Cortex - Myo-inositol [ Time Frame: 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".

  11. Left Dorsal Lateral Prefrontal Cortex - Choline [ Time Frame: 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".

  12. Left Dorsal Lateral Prefrontal Cortex - Creatinine [ Time Frame: 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".

  13. Left Dorsal Lateral Prefrontal Cortex - Glutamate [ Time Frame: 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".

  14. Left Dorsal Lateral Prefrontal Cortex - N-acetylaspartate [ Time Frame: 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".

  15. Left Dorsal Lateral Prefrontal Cortex - Myo-inositol [ Time Frame: 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".

  16. Fractional Anisotropy Measured With Diffusion Tensor Imaging [ Time Frame: Completion of two scans ]
    Diffusion Tensor Imaging Frational Anisotropy (FA) Measures by Lifetime History of Alcohol Abuse/Dependence and Brain Hemisphere.


Secondary Outcome Measures :
  1. BPRS - Symptoms of Psychosis Change in Scores [ Time Frame: 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.


  2. BPRS - Symptoms of Psychosis Total Score [ Time Frame: 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.

  3. SANS - Negative Symptoms of Schizophrenia Total Score [ Time Frame: 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.

  4. Cognitive Impairment [ Time Frame: 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.




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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00688324


Locations
United States, Maryland
VA Maryland Health Care System
Baltimore, Maryland, United States, 21201
Keypoint Community Mental Health Centers- Dundalk
Baltimore, Maryland, United States, 21222
Keypoint Community Mental Health Centers- Catonsville
Baltimore, Maryland, United States, 21228
Maryland Psychiatric Research Center
Baltimore, Maryland, United States, 21228
Sponsors and Collaborators
University of Maryland
National Alliance for Research on Schizophrenia and Depression
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Investigators
Principal Investigator: Bernard A Fischer, M.D. Food and Drug Administration (FDA)

Additional Information:
Responsible Party: Robert W. Buchanan, Chief, Maryland Psychiatric Research Center, Outpatient Research Program, University of Maryland
ClinicalTrials.gov Identifier: NCT00688324     History of Changes
Other Study ID Numbers: HP-00043248
R03AA019571 ( U.S. NIH Grant/Contract )
First Posted: June 2, 2008    Key Record Dates
Results First Posted: January 23, 2018
Last Update Posted: January 23, 2018
Last Verified: October 2017

Keywords provided by Robert W. Buchanan, University of Maryland:
schizophrenia
schizoaffective disorder
glutamate
NMDA receptor
magnetic resonance spectroscopy
acamprosate

Additional relevant MeSH terms:
Schizophrenia
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Acamprosate
Alcohol Deterrents