Anti-inflammatories May Cut Negative Symptoms of Schizophrenia

Daniel M. Keller, PhD

April 10, 2015

VIENNA — Off-target actions of currently approved drugs have shown benefit on some symptoms of schizophrenia, a new research suggests.

Specifically, ondansetron and simvastatin showed modest effects in reducing negative symptoms and a trend toward a benefit on cognition in established disease.

Simvastatin is an HMG-CoA reductase inhibitor with anti-inflammatory properties, and ondansetron is a 5-HT3 (5-hydroxytryptamine = serotonin) receptor antagonist. Statins decrease levels of C-reactive protein, and 5-HT3 antagonists decrease the tumor necrosis factor-α response to immune activation in monocytes.

Bill Deakin, MD, PhD, from the University of Manchester, United Kingdom, reported on a 2-by- 2 design testing simvastatin (S; 40 mg/day) or ondansetron (O; 8 mg/day) separately or together against placebo (P) in a cohort of 302 patients aged 18 to 65 years with a stable schizophrenia-related diagnosis receiving their usual treatments. Patients were randomly assigned approximately equally to SP, OP, SO, or PP.

The treatment groups were well balanced in terms of age; sex; years of education; and Positive and Negative Syndrome Scale (PANSS) measures of negative, positive, general, and total scores.

Dr Deakin reported his results here at the European Psychiatric Association (EPA) 23rd Congress.

Results were similar at 3 and 6 months. At 6 months, 245 patients who had been adherent to study medications for at least 3 months were available for evaluation.

At 3 and 6 months, negative symptoms improved more in the three drug treatment groups than in the placebo-only group. From mean PANSS negative syndrome baseline scores of 17.4 to 18.0 in the four groups, a mixed-effects analysis of the 3- and 6-month data showed the scores of the adherent group of patients were reduced by approximately 1.9 with ondansetron (P = .003), 1.9 with simvastatin (P = .002), and 1.3 with the combination of the drugs (P = .007).

"There's no sign of an additive effect. That's clearly the result of the study," Dr Deakin said. "The difference is 2 points on the PANSS negative syndrome scale. It's probably not clinically important."

However, he proposed that if patients were stratified by sex, duration of illness, or the use of typical or atypical antipsychotic drugs, clearer effects might be revealed. He also speculated that the lack of an additive effect could be because the mechanism of action of the 2 drugs occurs through the same pathway.

There were no drug effects on positive symptoms. There was little evidence of effects on cognitive function, although ondansetron alone trended toward improving performance on the Coughlan verbal list learning (P = .083).

Dr Deakin reviewed some previous studies in schizophrenia using minocycline, which has anti-inflammatory properties. It, too, showed benefits on PANSS negative but not positive symptom scores in a handful of studies, and he and his colleagues are conducting another such study.

The rationale for the use of anti-inflammatory drugs in schizophrenia is supported by a finding that there is increased uptake of a positron emission tomography marker that binds to microglia in the anterior cingulate cortex of untreated patients with early psychosis, validating neuroinflammation as a target for treatment.

"Immune system alterations can give neurotransmitter abnormalities, for example, in the dopamine system and in the glutamate system, which is implicated in schizophrenia," session moderator Arjen Sutterland, MD, from the Academic Medical Centre in Amsterdam, the Netherlands, commented to Medscape Medical News.

He said the results on negative symptoms were "promising...because we don't have any answer to these negative symptoms in schizophrenia. That's a huge challenge for psychiatry, and of course, it has a big impact on the social functioning."

Although the effect sizes were small, Dr Sutterland said that these findings could possibly be improved if an approach using anti-inflammatory drugs is applied to subgroups of patients identified through the emerging research on biomarkers in schizophrenia.

He did not dismiss the 2-point difference on the PANSS negative symptom scale in this study as clinically irrelevant and proposed that even that small improvement could affect patients' overall social functioning.

He said it "still eludes" him why anti-inflammatory drugs affect only negative but not positive symptoms of schizophrenia.

Dr Deakin reports he has received honoraria or expenses and research funding from Lundbeck, Sunovion, and AstraZeneca. He has stock options in Lundbeck. Dr Sutterland has disclosed no relevant financial relationships.

European Psychiatric Association (EPA) 23rd Congress. Abstract #0071. Presented March 30, 2015.


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