Anti-Inflammatory Treatment of Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional

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.
    

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.
    

Intervention name(s): Anti-inflammatory Combination Therapy; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; Non-medication pills; To be taken in morning and evening intervals.
Intervention MeSH terms: Anti-Inflammatory Agents
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: schizophrenia; anti-inflammatory; salsalate; statins; omega-3-fatty acids