SU63. Association Between Inflammatory Markers and Negative Symptoms in Individuals With Persistent Symptoms of Schizophrenia Treated With Clozapine

Abstract

Background: Negative symptoms of schizophrenia are characterized by absent or diminished behavior and include decreased motivation, social withdrawal, as well as poverty of speech, decreased emotional reactivity and psychomotor retardation. Importantly, negative symptoms have consistently been identified as those features of the disorder that are most predictive of functional impairment and poor outcome. Moreover, whereas antipsychotic medications are effective in treating positive symptoms (e.g., delusions and hallucinations), they are less effective in treating negative symptoms. One pathophysiologic pathway that may contribute to negative symptoms in schizophrenia is inflammation. There is a growing literature that inflammatory cytokines may be linked to negative symptoms in individuals with schizophrenia, and no one has explored this specific connection in patients on clozapine. Methods: Ten participants (9M,1F) with diagnoses of schizophrenia or schizoaffective disorder, all treated with clozapine, were included in this analysis. All subjects were recruited from the PSTAR (Persistent Symptoms: Treatment, Assessment and Recovery) Clinic, at Grady Memorial Hospital in Atlanta, Georgia. Inclusion criteria included evidence of persistent symptoms as measured by cutoff scores on the Positive and Negative Symptom Scale (PANSS), treatment with clozapine for at least three months, a documented clozapine level 4350 ng/ml, and no change in clozapine dose greater then 100mg at least one month prior to study enrollment. The following inflammatory markers were measured: high sensitivity c-reactive protein (hsCRP), interleukin (IL) 1beta, IL-6, IL-10, and tumor necrosis factor (TNF). Blood sampling for plasma inflammatory markers were completed at standardized times to control for circadian variations. Clinical rating scales to assess negative symptoms included the PANSS as well as the Scale for the Assessment of Negative Symptoms (SANS). To assess functional ability, the World Health Organization Disability Assessment Schedule (WHODAS 2.0) was also administered. Pearson correlation coefficients were calculated for the relationship among inflammatory markers and negative symptoms. Results: Mean clozapine dose in this analysis was 557.5mg (SD 128.05). Mean clozapine level was 759.8 mcg/L (SD 601.68). One subject had an hsCRP and IL-6 43SD from the mean concentration and that subject's hsCRP and IL-6 values were excluded from analysis. Mean hsCRP concentration (n =9) was 3.72 mg/L (SD 2.74). Mean IL-1beta concentration (n =10) was 0.67 pg/ml (SD 0.21). Mean IL-6 concentration (n =9) was 1.16 pg/ml (SD 0.18). Mean IL-10 concentration (n =10) was 0.44 pg/ml (SD 0.44). Mean TNF alpha concentration (n =10) was 5.71 pg/ml (SD 2.48). IL-1beta was significantly correlated with the passive/apathetic social withdrawal (r = 0.657, p = 0.039) and the disturbance of volition (r = 0.686, p = 0.029) items of the PANSS, as well as the avolition-impersistence at work or school (r = 0.644, p = 0.045), global rating of avolition-apathy (r = 0.751, p = 0.012), and the attention-social inattentiveness (r = 0.665, p = 0.036) items of the SANS. IL-10 was negatively correlated with the emotional withdrawal (r =-0.638, p = 0.047) and the passive/apathetic social withdrawal (r =-0.655, p = 0.04) items of the PANSS as well as the negative symptom total score of the PANSS (r =-0.792, p = 0.006). IL-10 was also negatively correlated with the total score of the WHODAS 2.0 (r =-0.792, p = 0.006). Conclusions: IL-1beta, a pro-inflammatory cytokine, was significantly correlated with items assessing negative symptom domains of avolition and social deficits. Moreover, IL-10, an anti-inflammatory cytokine, was negatively correlated with similar negative symptom items, including the negative symptom total score on the PANSS as well as the total score on a scale of real-world functional and role impairment. Though the sample size is small, these data suggest that inflammation may be relevant for these negative symptom domains. Indeed, administration of inflammatory stimuli has been reliably linked to deficits in reward processing and motivation via effects of inflammatory cytokines on regions of the basal ganglia, including the ventral striatum. Individuals with depression and increased inflammation also exhibit decreased functional connectivity in reward circuits in association with anhedonia. Future work should further explore the relationship between negative symptoms and inflammation in individuals with schizophrenia.