Schizophrenia is a chronic, debilitating disorder with life-long consequences on affected individuals and families. Schizophrenia is also associated with impaired cognition or thinking, which persists despite currently available treatments, and is an important determinant of quality of life and overall function. Associations between immune system abnormalities and schizophrenia, in particular increased inflammation, are one of the more enduring findings in the field. Four of six trials found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) was associated with significant improvement in psychopathology (Muller et al., 2010a; Muller et al., 2010b). Serum cytokine levels predicted response in two studies (Laan et al., 2010; Muller et al., 2004), and another study found a trend for improved cognition (Muller et al., 2005) with adjunctive NSAID treatment. These findings provide important empirical support for a pathophysiological role for inflammation in a subset of patients with schizophrenia.
Cytokines are key regulators of inflammation that exert effects in the periphery and the brain. IL-6 is a cytokine produced by peripheral blood leukocytes, and central nervous system microglia and astrocytes. Serum IL-6 levels are increased in patients with schizophrenia, and two studies reported significant positive correlations between IL-6 and total psychopathology at baseline and following antipsychotic treatment (Miller et al., 2011). Schizophrenia is associated with impaired cognition, which persists despite current treatments, and is an important determinant of quality of life and overall function. In populations outside of schizophrenia, higher serum IL-6 levels are associated with poorer cognition, cognitive decline, and smaller hippocampal gray matter volume (Marsland et al., 2006; Marsland et al., 2008). In a first-episode psychosis sample, IL-6 messenger ribonucleic acid expression was a significant predictor of smaller left hippocampal volume (Mondelli et al., 2011).
Several other lines of evidence provide a theoretical background for targeting IL-6 in schizophrenia. Polymorphisms of the gene for IL-6 (Paul-Samojedny et al., 2010) and its receptor (Sun et al., 2008) have been associated with schizophrenia. In mice, a single maternal injection of IL-6 during pregnancy caused prepulse and latent inhibition deficits in the adult offspring (Smith et al., 2007). Prenatal maternal infections are a replicated risk factor for schizophrenia (Brown and Derkits, 2010). In a rat prenatal immune activation model, adult offspring have increased serum IL-6 levels, at an age with homology to the usual age of onset of schizophrenia, that are significantly decreased following treatment with haloperidol (Romero et al., 2007; Romero et al., 2010). Another animal study found that ketamine-induced neuronal production of IL-6 is responsible for the activation of brain NADPH-oxidase and subsequent dysfunction of fast-spiking parvalbumin-expressing interneurons (Behrens et al., 2008). These findings provide further support for a potential role of IL-6 in the pathophysiology of schizophrenia.
In our Preliminary Study, patients with schizophrenia, age 18-70 and taking non-clozapine antipsychotics, had a fasting blood draw for serum cytokines, and assessment of psychopathology, including cognition. Subjects were not taking NSAIDs, and had no history of immune disorders, illicit drug use in the past month, or antibiotic use in the past 2 weeks. In 39 patients, after controlling for potential confounding effects of age, sex, race, smoking, BMI, socioeconomic status, serum cortisol, psychotropic medications, intelligence quotient, and severity of psychopathology, higher serum IL-6 levels predicted greater cognitive impairment, measured by the Brief Assessment of Cognition in Schizophrenia (BACS) composite score, in a linear regression model (p=0.002, Figure 1). Higher IL-6 levels were also associated with significantly lower scores on the Verbal Memory (r=-0.40, p\<0.01) and Motor Speed (r=-0.42, p\<0.01) subtests of the BACS.
In the first year, one clinical trial is planned. We will conduct an 8-week open-label trial to determine the safety, tolerability, and efficacy of tocilizumab as an adjunct to antipsychotic medications in 10 stable outpatients with schizophrenia.
Tocilizumab 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 rheumatoid arthritis are known, but there may be unknown risks when used in schizophrenia. Clinically significant adverse drug reactions include anaphylaxis (0.4%), infections (0.1-7.8%), intestinal perforation, neutropenia (7.0%), and cardiac failure. Known side effects of tocilizumab that are common include: increase in hepatic enzymes (AST, ALT), hypertension, headache, neutropenia, infusion-related reactions, upper respiratory tract infections, and nasopharyngitis.
Less common side effects include: peripheral edema, dizziness, rash, increased total cholesterol and LDL, hypothyroidism, diarrhea, abdominal pain, mouth ulcerations, gastric ulcer, stomatitis, weight gain, gastritis, thrombocytopenia, leukopenia, increased bilirubin, conjunctivitis, nephrolithiasis, bronchitis, cough, dyspnea, herpes simplex. Rare side effects include: cellulitis, fungal infections, diverticulitis, gastroenteritis, herpes zoster, hypertriglyceridemia, malignancy (including breast and colon), multiple sclerosis, otitis media, pneumonia, sepsis, tuberculosis, urinary tract infections, and varicella.
Subjects with schizophrenia will be accessed from outpatient psychiatry clinic at Georgia Health Sciences University or other satellite collaborative sites. The study has 5 visits: screening, baseline, and 2, 4, and 8 weeks. At Screening, all subjects will be administered the evaluation to sign consent, informed consent, and the structured clinical interview for Diagnostic and Statistical Manual psychosis and affective disorders modules. We will perform a medical history and physical exam, fasting labs (CBC, Complete Metabolic Panel, lipid panel, urinalysis, and urine drug screen (UDS)), a tuberculin skin test, and a 12-lead electrocardiogram. At Baseline, we will perform the Positive and Negative Syndrome Scale, BACS, and Clinical Global Impressions scale (CGI), and draw blood for IL-6 and high-sensitivity c-reactive protein (hsCRP). All subjects will receive a 4 mg/kg infusion of tocilizumab, the recommended starting dose for adults with rheumatoid arthritis. We will contact the subjects by phone on day 1 and 7 after the infusion to assess for any infusion-related events. At Week 2 and 4, we will perform an interval history, physical exam, Positive and Negative Syndrome Scale, BACS, and CGI. Different versions of the BACS will be used to avoid practice effects. At Week 4, we will obtain fasting labs (CBC, Complete Metabolic Panel, lipid panel, IL-6, hsCRP, and UDS), and subjects will receive a 4 mg/kg infusion of tocilizumab, We will contact the subjects by phone day 1 and 7 after the second infusion to assess for any infusion-related events. At Week 8, we will perform an interval history, physical exam, and administer the Positive and Negative Syndrome Scale, BACS, CGI, and obtain fasting labs (CBC, Complete Metabolic Panel, lipid panel, IL-6, hsCRP, and UDS). Patients will be withdrawn if they meet any exclusion criterion at any time point.
