In recent years, a steadily growing body of evidence has indicated an association between elevated levels of inflammation and psychiatric illness.

The word “association” is very important in this context: it means that, in schizophrenia, for example, some fraction of patients have significantly elevated markers of inflammation. But as to the key question of cause and effect, the jury is out. Does inflammation contribute to causation? Or does having the illness in some way cause inflammation levels to rise? Or are the two phenomena merely coincident?

A research team led by two BBRF grantees, Thomas W. Weickert, Ph.D., and his wife, Cynthia Shannon Weickert, Ph.D., has just reported in the journal Brain, Behavior and Immunity on the exploration of this specific question: in patients with schizophrenia with elevated levels of inflammation, would administering a drug to reduce the inflammation have any impact on reducing schizophrenia symptoms?

Dr. Thomas Weickert’s 2016 BBRF Independent Investigator award was devoted to testing a new anti-inflammatory treatment in schizophrenia. Dr. Cynthia Weickert, a 2004 BBRF Independent Investigator and 2001 and 1999 BBRF Young Investigator, conducted work in schizophrenia patients that suggested elevated immune system activity. The Weickerts are currently at SUNY Upstate Medical University and Neuroscience Research Australia; Dr. Cynthia Weickert has an appointment at the University of New South Wales, Australia. The team also included 2003 BBRF Young Investigator Roshel Lenroot, M.D., and 2008 BBRF Young Investigator Julia Lappin, MBChBN, MRCPsych.

Drs. Weikert and colleagues point out that the question has been tested before: will anti-inflammatory medicines help reduce symptoms in schizophrenia? Results, they note, have been inconsistent and inconclusive. There are many possible reasons, but one important reason one is that schizophrenia, like other psychiatric illnesses, is highly “heterogeneous”; symptoms differ in kind and severity across the full spectrum of patients. It is almost certain that causal mechanisms differ, as well. One implication is that what helps one patient or group of patients might not help another.

In their trial, Drs. Weickert and team exclusively recruited chronically ill schizophrenia patients with elevated markers of inflammation in their peripheral blood. It’s possible that prior tests of anti-inflammatories didn’t register significant positive results because many of the participants did not have elevated inflammation levels to begin with. The team wanted to test a specific anti-inflammatory medicine on patients they knew to have elevated inflammation levels.

Twenty-seven such patients were recruited for the study, which was conducted in Australia. To be included, a participant had to have at least two elevated markers of peripheral (bodily) inflammation, out of three such general markers tested. The markers indicated levels of: two cytokines (small proteins that help regulate immune system cells in the body), specifically, Interleukin 1-Beta (IL-1β) or IL-6; high-sensitivity C-reactive protein (hsCRP), a protein whose level correlates with immune activation; and a marker called NLR that measures the ratio in the blood of neutrophils to lymphocytes (two types of white blood cells).

The cohort was composed of 12 females and 15 males with a diagnosis of schizophrenia (18) or schizoaffective disorder (9). The average age was late-thirties; the average duration of illness was about 12 years; the typical participant had been hospitalized three times over the course of their illness, and was moderately overweight (BMI ~ 32).

Fourteen participants were assigned to receive a single injection under the skin of an approved medicine called canakinumab, a monoclonal antibody that blocks the activity of IL-1β. Thirteen participants received a placebo injection. All 27 continued to take the antipsychotic medicines they had been taking before the start of the trial.

Why the focus on blocking the activity of IL-1β? Levels of IL-1β are known to be elevated in a “substantial subgroup” of chronically ill schizophrenia patients, as evidenced in blood, cerebrospinal fluid, and brain tissue. Past studies have shown that elevated peripheral IL-1β levels correlate with impairment in attention, working memory, language, and episodic memory in schizophrenia patients. The Weickerts have previously found, moreover, elevated IL-1β expression in white blood cells in 40% of patents with chronic schizophrenia, as well as higher levels of IL-1β expression in cells of the prefrontal cortex in regions where new neurons are generated, and in the midbrain, in about an equal fraction of patients. The C-reactive protein marker was chosen because its level is elevated in 60% of patients admitted to hospital for a psychotic episode and 40% of chronically ill schizophrenia patients. Elevation in CRP has been liked with thinning of the cortex and problems with attention. Past clinical trials have demonstrated that injection of canakinumab quickly lowers peripheral CRP levels in peripheral blood.

Results of the trial, based on comparisons between the two groups of inflammatory marker levels in peripheral blood and symptom severity at baseline and at 4 and 8 weeks post-injection, showed that a single injection of the drug (150mg) “was effective in reducing a peripheral marker of inflammation [CRP].” Levels of CRP declined continuously for the first 4 weeks post-injection and were significantly reduced at all times through 8 weeks relative to baseline levels.

Markers of inflammation were lower; but did this correlate with a reduction in the severity of symptoms? Negative symptoms—various cognitive impairments experienced by all schizophrenia patients—were not impacted by canakinumab or by the placebo. But the drug did have an impact described as “statistically significant” on schizophrenia’s positive symptoms—hallucinations, delusions, and odd or intrusive thoughts.

Those in the canakinumab group “had a significant reduction in positive symptom severity score 8 weeks following the injection,” the team reported. While “the magnitude of the reduction would not generally be considered clinically robust,” they added, “it is important to note that most novel treatments do not reduce” these symptoms, particularly if the patients, as in this trial, continue to take their regular antipsychotic medicine throughout the trial. The team found that the in the canakinumab group, reduction in CRP levels at week 4 predicted the degree to which a patient’s positive symptoms would be reduced in severity at week 8. Reductions in CRP levels are also considered positive for general health, as elevated levels are strongly linked with heart disease.

Future trials to confirm or extend the team’s results will need to include many more patients with elevated inflammation markers, including those at earlier stages of schizophrenia and psychotic disorders. To be truly meaningful, any benefit in reducing symptoms would need to be sustained for much longer than the 8 weeks tested in this trial. To that end, the team hopes to test canakinumab in inflammation-affected patients with higher dosages of the medicine, and with longer treatment administration, including “top-up” or additional injections over time. Also, they noted, “treating people closer to the onset of the illness when inflammation has not been present for a long time may have the potential to show larger effects.”