Siltuximab in Schizophrenia

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A pathophysiological role for inflammation in schizophrenia has been one of the more enduring findings in the field. Recently, increased understanding of complex interactions between inflammation and the brain in other chronic diseases has better informed this relationship in schizophrenia. Several ...

A pathophysiological role for inflammation in schizophrenia has been one of the more enduring findings in the field. Recently, increased understanding of complex interactions between inflammation and the brain in other chronic diseases has better informed this relationship in schizophrenia. Several trials have found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs), in adjunct to antipsychotics, was associated with significant improvement in psychopathology in schizophrenia. Cytokines are key regulators of inflammation that exert effects in the periphery and the brain. Serum cytokine levels predicted response in two studies , and another study found a trend for improved cognition with adjunctive NSAID treatment. These findings provide important empirical support for a pathophysiological role for inflammation in some patients with schizophrenia. Two important limitations of these trials are that: a) the agents investigated have relevant off-target (i.e., non-immune) effects, and b) evidence of inflammation in the peripheral blood was not an inclusion criterion, which may have decreased the signal-to-noise ratio. Schizophrenia is associated with impaired cognition, which persists despite current treatments, and is an important determinant of quality of life and overall function. Converging lines of evidence suggest that interleukin-6 (IL-6) is a promising therapeutic target for cognitive impairment in schizophrenia. IL-6 is a cytokine produced by peripheral blood leukocytes, and central nervous system (CNS) microglia and astrocytes. The IL-6 gene is a risk factor for schizophrenia and may impact on serum IL-6 levels. Blood and cerebrospinal fluid (CSF) IL-6 levels are altered in schizophrenia. IL-6 levels are associated with psychopathology and cognition in schizophrenia. Serum IL-6 levels are also increased in prodromal psychosis, drug-naïve first-episode psychosis (FEP) and first-degree relatives of patients with schizophrenia. In populations outside of schizophrenia, higher serum IL-6 levels are associated with poorer cognition, cognitive decline, and smaller hippocampal volume. In FEP and chronic schizophrenia, IL-6 levels are a significant predictor of smaller left hippocampal volume. Evidence from animal studies also supports a putative role for IL-6 in the pathophysiology of schizophrenia. A single maternal injection of IL-6 during mouse pregnancy caused prepulse and latent inhibition deficits in the adult offspring. In rat prenatal immune activation models, adult offspring have increased serum IL-6 levels, at an age with homology to the usual age of onset of schizophrenia, that are modulated by antipsychotics. Ketamine-induced neuronal production of IL-6 is responsible for the activation of brain N=nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and dysfunction of fast-spiking parvalbumin-expressing interneurons. Along with our other previous work, our preliminary studies provide strong evidence that IL-6 is a novel therapeutic target for cognitive impairment in schizophrenia, and demonstrate the feasibility of the proposed trial. Briefly, in 64 patients with schizophrenia, the investigators found higher blood IL-6 levels were a significant predictor of greater impairment on the Brief Assessment of Cognition in Schizophrenia (BACS) after controlling for multiple potential confounding factors. In an 8-week open-label trial in 6 subjects, tocilizumab (an anti-IL-6 receptor monoclonal antibody), given in adjunct to antipsychotics, was well tolerated and associated with significant improvement in BACS verbal fluency at 4 weeks, BACS digit symbol coding at 2, 4, and 8 weeks, and BACS composite score at 4 and 8 weeks. In the first year following the submission, one clinical trial is planned. The investigators will conduct a 9-week randomized, double-blind, placebo-controlled trial to determine the safety, tolerability, and efficacy of siltuximab as an adjunct to antipsychotic medications in 30 stable outpatients with schizophrenia. Siltuximab has not been used before in the treatment of schizophrenia, and using it this way is experimental. The risks that have been found in people with multicentric Castleman's disease are known, but there may be unknown risks when used in schizophrenia. Clinically significant adverse drug reactions include anaphylaxis, renal failure, and pneumonia. Known side effects of siltuximab that are common include: swelling of the extremities, fatigue, itching, rash, weight gain, diarrhea, abdominal pain, and joint or limb pain. The most common side effect of the drug is nasopharyngitis, which occurs in 63% of subjects with long-term exposure to Siltuximab. Subjects with schizophrenia and schizoaffective disorder will be accessed from outpatient psychiatry clinic at Augusta University or other satellite collaborative sites. The study has 5 visits: screening, baseline, and weeks 3, 6, and 9. Subjects will be randomized equally to either siltuximab (n=15) or placebo (n=15), in adjunct to their current antipsychotic and other psychotropic medications. The study has 5 visits: screening, baseline, and weeks 3, 6, and 9. Subjects will be randomized equally to either siltuximab (n=15) or placebo (n=15), in adjunct to their current antipsychotic and other psychotropic medications. Subjects in the siltuximab group will receive an 11 mg/kg infusion at baseline, and weeks 3 and 6, as per the recommended dosing for multicentric Castleman's disease. Subjects in the placebo group will receive an infusion of normal saline (with the same packaging and volume as the siltuximab group) at baseline, and weeks 3 and 6. Subjects will be monitored for an additional 30 minutes following the completion of the infusion. Dr. Miller will monitor the subject throughout the infusion and the 30 minute post-infusion period. The investigators will contact the subjects by phone on days 1 and 7 after each infusion to assess for any infusion-related events. The investigators will assess cognition and psychopathology at baseline, and at weeks 3, 6, and 9. The investigators will also measure a multiplex panel of blood cytokines (including IL-6) and tryptophan catabolites at baseline, and at weeks 3, 6, and 9. At Screening, all subjects will be administered the evaluation to sign consent, informed consent, and the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (DSM) psychosis and affective disorders modules. The investigators will perform a medical history and physical exam, fasting labs (complete blood count [CBC], complete metabolic profile [CMP], hsCRP, lipid panel, urinalysis, and urine drug screen (UDS), hepatitis panel, HIV, rapid plasma reagin [RPR], and human chorionic gonadotropin [hCG] in females), a tuberculin skin test, and a 12-lead electrocardiogram. At Baseline, the investigators will perform the Positive And Negative Syndrome Scale (PANSS), BACS, and Clinical Global Impressions scale (CGI), Calgary Depression Scale (CDS) and Short Form Health Survey (SF-36) and draw blood for IL-6 and high-sensitivity c-reactive protein (hsCRP). At Week 3, 6, and 9, the investigators will perform an interval history, physical exam, PANSS, BACS, CGI, CDS, SF-36, and obtain fasting labs (CBC, CMP, lipid panel, hsCRP, urinalysis, UDS, and hCG in females). Different versions of the BACS will be used to avoid practice effects. Patients will be withdrawn if they meet any exclusion criterion at any time point.

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