Anti-Inflammatory Treatment of Schizophrenia

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.

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.