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Anti-Inflammatory Treatment of Schizophrenia

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by University of Maryland
Sponsor:
Information provided by (Responsible Party):
Robert W. Buchanan, M.D., University of Maryland
ClinicalTrials.gov Identifier:
NCT01514682
First received: January 12, 2012
Last updated: November 5, 2014
Last verified: November 2014
  Purpose

Despite current antipsychotic treatment, the majority of people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. An alternative approach to the use of psychotropic agents for the treatment of persistent symptoms is the use of anti-inflammatory agents to reverse the pro-inflammatory state hypothesized to underlie the symptom and sign manifestations of the illness.

The investigators primary hypothesis is that add-on anti-inflammatory combination therapy will have significant beneficial effects on persistent positive symptoms and cognitive impairments.

The investigators secondary hypotheses are:

  1. add-on anti-inflammatory combination therapy will be associated with improvements in depressive and negative symptoms and a reduction in pro-inflammatory cytokines
  2. add-on anti-inflammatory combination therapy compared to placebo will not be associated with elevated adverse risk.

Condition Intervention
Schizophrenia
Drug: Anti-inflammatory Combination Therapy
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia

Resource links provided by NLM:


Further study details as provided by University of Maryland:

Primary Outcome Measures:
  • Change in persistent positive symptoms [ Time Frame: The BPRS positive item total score will be used to assess positive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]
    The Brief Psychiatric Rating Scale (BPRS)positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness.

  • Change in neuropsychological test performance [ Time Frame: MCCB will be administered at baseline and end-of-study ] [ Designated as safety issue: No ]
    The MATRICS Consensus Cognitive Battery (MCCB) composite score will be used to assess neuropsychological test performance.


Secondary Outcome Measures:
  • Side effects [ Time Frame: The SEC and vital signs will be assessed at baseline and every two weeks during the double-blind phase of the study. The EKG will be conducted at baseline and at week 12 (end-of-study) ] [ Designated as safety issue: Yes ]
    Side Effect Checklist (SEC); EKG; Vital Signs

  • Change in depressive symptoms [ Time Frame: The CDS total score will be used to assess depressive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]
    The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. The CDS was specifically designed to assess depressive symptoms in schizophrenia.

  • Change in negative symptoms [ Time Frame: The SANS total score will be used to assess positive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]
    The SANS total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, will be used to measure negative symptoms. The inappropriate affect, poverty of content of speech, and attention items are excluded because they lack construct validity and factor analytic study results suggest that these items are not closely related to negative symptoms. We will use a modification of the SANS that is appropriate for the assessment of negative symptoms in both inpatient and outpatient settings.

  • Change in pro-inflammatory cytokines [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ] [ Designated as safety issue: No ]
    The cytokine profile includes the following pro- and anti-inflammatory cytokines: IL-1β, IL-1RA, IL-2, sIL-2R, IL-6, IL-10, IL-12, IL-17, CRP, IFN-γ, TNF-α, and TGF-β.


Estimated Enrollment: 60
Study Start Date: June 2012
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo pills to be assigned using a permuted randomization system
Drug: Anti-inflammatory Combination Therapy
  1. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening
  2. fluvastatin: target dose 40 mg/day, administered in a single evening dose
  3. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose
Drug: Placebo
Non-medication pills; To be taken in morning and evening intervals.
Experimental: Anti-inflammatory Combination Therapy
Salsalate, statin and omega-3-fatty acid combination therapy
Drug: Anti-inflammatory Combination Therapy
  1. salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening
  2. fluvastatin: target dose 40 mg/day, administered in a single evening dose
  3. combined omega-3-fatty acid preparation of EPA and DHA; target dose EPA 2 gm/day and DHA 2 gm/day administered in a single evening dose

Detailed Description:

Schizophrenia has been hypothesized to be due, in part, to disruptions of normal immune system and inflammatory responses to viral or bacterial infections or other stimuli of these systems. Epidemiological and clinical studies have provided extensive evidence that perinatal exposure to infection contributes to the etiology of schizophrenia. The recent reports of associations between markers of single nucleotide polymorphisms located within the major histocompatibility complex on chromosome 6p22.1 and schizophrenia provide further support for etiological hypotheses of immune system dysfunction in schizophrenia.

There are a large number of reports that suggest that people with schizophrenia have altered cytokine levels, with one or more studies reporting elevated levels of the pro-inflammatory cytokines: IL-1β, IL-6, IL-12, CRP, IFN-γ, and TNF-α; and reduced levels of the anti-inflammatory cytokine: IL-10. In this study we examine the use of combination anti-inflammatory therapy as an intervention in patients with schizophrenia. We will use

  1. Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines;
  2. Omega-3-fatty acids eicosapentaenoic (EPA; 2 gm/day) and docosahexaenoic (DHA; 2 gm/day). Omega-3-fatty acids exert their anti-inflammatory effects through their oxygenation into resolvins or protectins, which are potent anti-inflammatory agents;
  3. Fluvastatin, 40 mgs/day. Fluvastatin is a lipid-lowering drugs, which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA). Fluvastatin may also exert anti-inflammatory effects independent of its lipid-lowering effects via a mechanism involving HMG-CoA inhibition and decreased NF-κB activation.

We have chosen to use combination therapy with three different classes of anti-inflammatory agents to address the potential benefit of this therapeutic approach for persistent positive symptoms and cognitive impairments. The three agents have unique anti-inflammatory mechanisms of action, which we believe offers the most robust evaluation of this therapeutic approach and maximizes the likelihood of eliciting pronounced therapeutic effects.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants will meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder.
  • Participants will be required to meet the following symptom criteria:

    1. BPRS total score of 45 or greater on the 18 item version (scale: 1-7) or a Clinical Global Impression (CGI) severity of illness item score of 4 (moderate) or greater.
    2. BPRS positive symptom item total score of 8 or greater and a score of 4 or more on at least one individual item.
  • Participants will be clinically stable, be treated with the same antipsychotic for at least 60 days and a constant therapeutic dose for at least 30 days prior to study entry.
  • Participants must be judged competent to participate in the informed consent process and provide voluntary informed consent

Exclusion Criteria:

  • Participants who meet DSM-IV-TR criteria for alcohol or substance dependence (except nicotine) within the last 6 months or DSM-IV-TR criteria for alcohol or substance abuse (except nicotine) within the last month will be excluded
  • Participants with a current infection or an organic brain disorder or medical condition, whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol will be excluded.
  • Participants with a history of: aspirin allergy, pre-existing tinnitus, tuberculosis, HIV, or hepatitis C; or autoimmune disease.
  • Participants who are currently treated with a statin, warfarin, dipyridamole, or other anti-coagulants.
  • Participant is currently treated with an omega-3-fatty acid preparation and cannot discontinue their use of the preparation for the duration of the study.
  • Female participant who is sexually active and not using any form of birth control such as oral contraceptives or IUDs.
  • Female participant who is pregnant or breastfeeding.
  • Participant with current/active peptic ulcer disease or gastritis (hematocrit levels ≤35); anemia or thrombocytopenia (platelet count ≤120).
  • Participant who is currently treated with a medication that can increase the risk of myopathy and rhabdomyolysis such as Fluconazole, Ketoconazole, Colchicine, Daptomycin, Erythromycin, or immunosuppressants that alter statin levels.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01514682

Contacts
Contact: Jennifer Osing, MA 410-402-6060 josing@mprc.umaryland.edu

Locations
United States, Maryland
Maryland Psychiatric Research Center Recruiting
Baltimore, Maryland, United States, 21228
Contact: Christine Brown    410-402-7878    cbrown@mprc.umaryland.edu   
Contact: Jennifer Osing    410-402-6060    JOsing@mprc.umaryland.edu   
Principal Investigator: Robert W Buchanan, MD         
Principal Investigator: William T Carpenter, MD         
Sponsors and Collaborators
University of Maryland
Investigators
Principal Investigator: Robert W Buchanan, MD University of Maryland
Principal Investigator: William T Carpenter, MD University of Maryland
  More Information

No publications provided

Responsible Party: Robert W. Buchanan, M.D., Chief, Maryland Psychiatric Research Center, Outpatient Research Program, University of Maryland
ClinicalTrials.gov Identifier: NCT01514682     History of Changes
Other Study ID Numbers: 11T-002
Study First Received: January 12, 2012
Last Updated: November 5, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Maryland:
schizophrenia
anti-inflammatory
salsalate
statins
omega-3-fatty acids

Additional relevant MeSH terms:
Schizophrenia
Mental Disorders
Schizophrenia and Disorders with Psychotic Features
Anti-Inflammatory Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014