Anti-Inflammatory Treatment of Schizophrenia
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|ClinicalTrials.gov Identifier: NCT01514682|
Recruitment Status : Completed
First Posted : January 23, 2012
Results First Posted : March 29, 2018
Last Update Posted : November 4, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Schizophrenia||Drug: Anti-inflammatory Combination Therapy Drug: Placebo||Not Applicable|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||50 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia|
|Actual Study Start Date :||June 2012|
|Actual Primary Completion Date :||April 17, 2017|
|Actual Study Completion Date :||April 17, 2017|
Placebo Comparator: Placebo
Placebo pills to be assigned using a permuted randomization system
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
- Change in Persistent Positive Symptoms [ Time Frame: The BPRS will be administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]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.
- Change in Neuropsychological Test Performance [ Time Frame: The MCCB was administered at baseline and end-of-study (Week 12). ]The MATRICS Consensus Cognitive Battery (MCCB) composite score by week ranging from -10-100 with a higher score indicating a better outcome.
- Change in Depressive Symptoms [ Time Frame: The CDS was administered at baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]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.
- Change in Negative Symptoms [ Time Frame: Baseline and every two weeks throughout the double-blind phase of the study, for up to 12 weeks. ]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.
- Change in Pro-inflammatory Cytokines [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ]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.
- Change in C-Reactive Protein (CRP) [ Time Frame: A cytokine profile will be collected at baseline and at week 12 (end-of-study). ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01514682
|United States, Maryland|
|Maryland Psychiatric Research Center|
|Baltimore, Maryland, United States, 21228|
|Principal Investigator:||Robert W Buchanan, MD||University of Maryland, College Park|
|Principal Investigator:||William T Carpenter, MD||University of Maryland, College Park|