Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan

Abstract

Increasing evidence suggests that inflammation contributes to the etiology and progression of schizophrenia. Molecules that initiate inflammation, such as virus- and toxin-induced cytokines, are implicated in neuronal degeneration and schizophrenia-like behavior. Using therapeutic agents with anti-inflammatory or neurotrophic effects may be beneficial for treating schizophrenia. One hundred healthy controls and 95 Han Chinese patients with schizophrenia were tested in this double-blind study. Their PANSS scores, plasma interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and brain-derived neurotrophic factor (BDNF) levels were measured before and after pharmacological treatment. Pretreatment, plasma levels of IL-1β and TNF-α were significantly higher in patients with schizophrenia than in controls, but plasma BDNF levels were significantly lower. Patients were treated with the atypical antipsychotic risperidone (Risp) only or with Risp+ dextromethorphan (DM). PANSS scores and plasma IL-1β levels significantly decreased, but plasma TNF-α and BDNF levels significantly increased after 11 weeks of Risp treatment. Patients in the Risp+ DM group showed a greater and earlier reduction of symptoms than did those in the Risp-only group. Moreover, Risp+ DM treatment attenuated Risp-induced plasma increases in TNF-α. Patients with schizophrenia had a high level of peripheral inflammation and a low level of peripheral BDNF. Long-term Risp treatment attenuated inflammation and potentiated the neurotrophic function but also produced a certain degree of toxicity. Risp+ DM was more beneficial and less toxic than Risp-only treatment.

Clinical trial registration: Protocol Record: HR-93-50;

Trial registration number: NCT01189006; URL: http://www.clinicaltrials.gov.

Fig 1

The plasma (A) TNF-α, (B) IL-1β, and (C) BDNF levels of healthy controls (n = 100) and patients with schizophrenia (SCZ) (n = 95) before treatment. *p < 0.05, **p < 0.01, ***p < 0.001 vs. healthy controls (t-test).

Fig 2

The plasma (A) IL-1β and (B) TNF-α levels and their change percentages (%) (C), (D) in patients with schizophrenia after 11 weeks of treatment with risperidone (Risp)+Placebo or Risp+add-on dextromethorphan (DM) (60 mg/day). Plasma samples were collected and analyzed at 0, 2, 4, 8, and 11 weeks. *p < 0.05, **p < 0.01, ***p < 0.001 vs. week 0 data within same group (repeated-measures ANOVA with Newman-Keuls post test).

Fig 3

(A) The plasma BDNF change percentages (%) after 11 weeks of treatment with risperidone (Risp)+Placebo or Risp+add-on dextromethorphan (DM) (60 mg/day). Plasma samples were collected and analyzed at 0, 2, 4, 8, and 11 weeks. *p < 0.05, **p < 0.01 vs. week 0 data within same group (repeated-measures ANOVA with Newman-Keuls post test) and (B) scatter plots of plasma BDNF levels with PANSS negative symptom scores in patients with schizophrenia (Pearson r = −0.233, p = 0.018). Linear regression and the Pearson product-moment correlation coefficient were used to analyze the correlation.

Fig 4

The change percentages (%) of (A) PANSS positive symptom scores and (B) PANSS negative symptom scores in patients with schizophrenia after 11 weeks of risperidone (Risp)+Placebo or Risp+add-on dextromethorphan (DM) (60 mg/day) treatment. *p < 0.05, **p < 0.01, **p < 0.001 vs. week 0 data within same group (repeated-measures ANOVA with Newman-Keuls post test).