Anti-Inflammatory Treatment of Schizophrenia

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

Detailed Description
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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 Salsalate, 4 gm/day. Salsalate is a potent inhibitor of nuclear transcription factor NF-κB activation. NF-κB is activated by pro-inflammatory cytokines; 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; 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.

Official Title
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Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Anti-inflammatory Combination Therapy
* Drug: Placebo


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo pills to be assigned using a permuted randomization system | Drug: Placebo<br>* Non-medication pills; To be taken in morning and evening intervals.<br>|
| Experimental: Anti-inflammatory Combination Therapy<br>Salsalate, statin and omega-3-fatty acid combination therapy | Drug: Anti-inflammatory Combination Therapy<br>* salsalate: target dose 4 gm/day, administered in two divided doses of 2 gm in the morning and 2 gm in the evening fluvastatin: target dose 40 mg/day, administered in a single evening dose 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Persistent Positive Symptoms | 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. | The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | 
| Change in Neuropsychological Test Performance | The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome. | The MCCB was administered at baseline and end-of-study (Week 12). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depressive Symptoms | 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. | The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | 
| Change in Negative Symptoms | 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. | Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. | 
| Change in Pro-inflammatory Cytokines | 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. | A cytokine profile will be collected at baseline and at week 12 (end-of-study). | 
| Change in C-Reactive Protein (CRP) | 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. | A cytokine profile will be collected at baseline and at week 12 (end-of-study). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schizophrenia, anti-inflammatory, salsalate, statins, omega-3-fatty acids