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Anti-Inflammatory Treatment of Schizophrenia

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ClinicalTrials.gov Identifier: NCT01514682
Recruitment Status : Completed
First Posted : January 23, 2012
Results First Posted : March 29, 2018
Last Update Posted : November 4, 2019
Sponsor:
Information provided by (Responsible Party):
Robert Buchanan, University of Maryland, College Park

Brief Summary:

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 or disease Intervention/treatment Phase
Schizophrenia Drug: Anti-inflammatory Combination Therapy Drug: Placebo Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia
Actual Study Start Date : June 2012
Actual Primary Completion Date : April 17, 2017
Actual Study Completion Date : April 17, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Placebo Comparator: Placebo
Placebo pills to be assigned using a permuted randomization system
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




Primary Outcome Measures :
  1. Change in Persistent Positive Symptoms [ Time Frame: The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]
    The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating.

  2. Change in Neuropsychological Test Performance [ Time Frame: The MCCB was administered at baseline and end-of-study (Week 12). ]
    The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome.


Secondary Outcome Measures :
  1. Change in Depressive Symptoms [ Time Frame: The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]
    The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. Total score calculated by adding scores for scales #1-#9. Each scale ranges from "0=Absent" to "3=Severe". The minimum total CDS score is 0 and the maximum total CDS score is 27. A higher score indicates a more severe depression rating.

  2. Change in Negative Symptoms [ Time Frame: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]
    The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. Median SANS total score by treatment and week. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms.

  3. Change in Pro-inflammatory Cytokines [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ]
    Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.

  4. Change in C-Reactive Protein (CRP) [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ]
    Data was only available on 2 of the 9 cytokines (i.e., IL-2 and IL-8) and C-Reactive Protein (CRP). The baseline values for the other cytokines in the panel were below the level of detection.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
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; 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.

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): NCT01514682


Locations
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United States, Maryland
Maryland Psychiatric Research Center
Baltimore, Maryland, United States, 21228
Sponsors and Collaborators
University of Maryland, Baltimore
Investigators
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Principal Investigator: Robert W Buchanan, MD University of Maryland, College Park
Principal Investigator: William T Carpenter, MD University of Maryland, College Park
  Study Documents (Full-Text)

Documents provided by Robert Buchanan, University of Maryland, College Park:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Robert Buchanan, Chief, Maryland Psychiatric Research Center, Outpatient Research Program, University of Maryland, College Park
ClinicalTrials.gov Identifier: NCT01514682    
Other Study ID Numbers: HP-00051603; 11T-002
First Posted: January 23, 2012    Key Record Dates
Results First Posted: March 29, 2018
Last Update Posted: November 4, 2019
Last Verified: May 2017
Keywords provided by Robert Buchanan, University of Maryland, College Park:
schizophrenia
anti-inflammatory
salsalate
statins
omega-3-fatty acids
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Anti-Inflammatory Agents