Anti-Inflammatory Treatment of Schizophrenia
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia|
- Change in persistent positive symptoms [ Time Frame: The BPRS positive item total score will be used to assess positive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]The Brief Psychiatric Rating Scale (BPRS)positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness.
- Change in neuropsychological test performance [ Time Frame: MCCB will be administered at baseline and end-of-study ] [ Designated as safety issue: No ]The MATRICS Consensus Cognitive Battery (MCCB) composite score will be used to assess neuropsychological test performance.
- Side effects [ Time Frame: The SEC and vital signs will be assessed at baseline and every two weeks during the double-blind phase of the study. The EKG will be conducted at baseline and at week 12 (end-of-study) ] [ Designated as safety issue: Yes ]Side Effect Checklist (SEC); EKG; Vital Signs
- Change in depressive symptoms [ Time Frame: The CDS total score will be used to assess depressive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]The Calgary Depression Scale (CDS) total score will be used to measure depressive symptoms. The CDS was specifically designed to assess depressive symptoms in schizophrenia.
- Change in negative symptoms [ Time Frame: The SANS total score will be used to assess positive symptoms. The BPRS will be administered at baseline and every two week throughout the double-blind phase of the study. ] [ Designated as safety issue: No ]The SANS total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, will be used to measure negative symptoms. The inappropriate affect, poverty of content of speech, and attention items are excluded because they lack construct validity and factor analytic study results suggest that these items are not closely related to negative symptoms. We will use a modification of the SANS that is appropriate for the assessment of negative symptoms in both inpatient and outpatient settings.
- Change in pro-inflammatory cytokines [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ] [ Designated as safety issue: No ]The cytokine profile includes the following pro- and anti-inflammatory cytokines: IL-1β, IL-1RA, IL-2, sIL-2R, IL-6, IL-10, IL-12, IL-17, CRP, IFN-γ, TNF-α, and TGF-β.
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||March 2015|
|Estimated Primary Completion Date:||March 2015 (Final data collection date for primary outcome measure)|
Placebo Comparator: Placebo
Placebo pills to be assigned using a permuted randomization system
Drug: Anti-inflammatory Combination Therapy
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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01514682
|Contact: Jennifer Osing, MAfirstname.lastname@example.org|
|United States, Maryland|
|Maryland Psychiatric Research Center||Recruiting|
|Baltimore, Maryland, United States, 21228|
|Contact: Christine Brown 410-402-7878 email@example.com|
|Contact: Jennifer Osing 410-402-6060 JOsing@mprc.umaryland.edu|
|Principal Investigator: Robert W Buchanan, MD|
|Principal Investigator: William T Carpenter, MD|
|Principal Investigator:||Robert W Buchanan, MD||University of Maryland|
|Principal Investigator:||William T Carpenter, MD||University of Maryland|