An Open-Label Trial of Tocilizumab in Schizophrenia

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.

Inclusion Criteria:

- male and female

- age 18-50

- capable of giving informed consent

- diagnosis of schizophrenia

- stable based on clinical judgement, no psychiatric hospitalizations in past 3 months,
and on the same psychotropic medications for >4 weeks

- taking a non-clozapine antipsychotic

Exclusion Criteria:

- imminent danger to self/others

- antibiotic use in the past 2 weeks

- current scheduled use of immunomodulatory agents

- history of an immune disorder

- illicit drug use in the past 30 days

- any unstable or untreated medical condition

- history of gastrointestinal ulcers, diverticulitis, malignancy, central nervous
system demyelinating disorder, seizure disorder, or tuberculosis

- low absolute neutrophil (<2000) or platelet (<100,000) count

- abnormal hepatic (AST or ALT >1.5 times the upper limit of normal) or renal (BUN or
creatinine>1.5 times the upper limit of normal) function

- any abnormal lab test result judged to be clinically significant

- active, chronic or recurrent infections

- pregnancy

- breastfeeding

- female and of child-bearing potential who is not using any contraception