Anti-Inflammatory Treatment of Schizophrenia

NCT ID: NCT01514682

Last Updated: 2022-03-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2017-04-17

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.

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.

Conditions

Schizophrenia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Placebo

Placebo pills to be assigned using a permuted randomization system

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Non-medication pills; To be taken in morning and evening intervals.

Anti-inflammatory Combination Therapy

Salsalate, statin and omega-3-fatty acid combination therapy

Group Type: EXPERIMENTAL

Anti-inflammatory Combination Therapy

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Placebo

Non-medication pills; To be taken in morning and evening intervals.

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Maryland, Baltimore

OTHER

Sponsor Role: lead

Responsible Party

Robert Buchanan

Chief, Maryland Psychiatric Research Center, Outpatient Research Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert W Buchanan, MD

Role: PRINCIPAL_INVESTIGATOR

Maryland Psychiatric Research Center, University of Maryland School of Medicine

William T Carpenter, MD

Role: PRINCIPAL_INVESTIGATOR

Maryland Psychiatric Research Center, University of Maryland School of Medicine

Locations

Maryland Psychiatric Research Center

Baltimore, Maryland, United States

Countries

United States

References

Buchanan RW, Weiner E, Kelly DL, Gold JM, Chen S, Zaranski J, Blatt F, Wehring H, Carpenter WT. Anti-inflammatory Combination Therapy for the Treatment of Schizophrenia. J Clin Psychopharmacol. 2020 Sep/Oct;40(5):444-450. doi: 10.1097/JCP.0000000000001253.

Reference Type: DERIVED

PMID: 32796391 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

HP-00051603; 11T-002

Identifier Type: -

Identifier Source: org_study_id