The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice

Abstract

Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it's active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly.

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

“…A unified mechanistic understanding of immune dysregulation has been difficult to decipher from these clinical reports because they are largely confounded by examining patients with psychiatric diagnoses and thus atypical inflammatory backgrounds. We previously reported global immune dysregulation with and without challenge, as measured by circulating cytokines and antibody levels using our preclinical murine model [54,55]. This current study bolsters these findings by identifying tissue-specific inflammatory dysfunction that could lead to NAFLD in the context of histopathologic findings consistent with its development.…”

“…One such protein that is not activated by phosphorylation, mannose-binding lectin (MBL1), was significantly overexpressed during both RIS and OLAN treatment. The downstream impact of MBL1 interactions include activation of numerous phosphorylation-dependent signaling cascades (e.g., NF-κB signaling), some of which were not seen as changes in total proteins but whose impact could be seen phenotypically in the current report ( Figure 1 ), in our prior reports demonstrating global immune dysregulation during AA treatment [ 54 , 55 ], and in several small-scale studies of patients taking AA medications [ 56 ]. Similarly, significantly depressed levels of cytochrome oxidase subunit VI B (COX6B) during both RIS and OLAN treatment would lead to profound changes in oxidative phosphorylation and metabolic rate that may not be reflected as level changes of downstream proteins because differentially phosphorylated states are not detected.…”

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

“…These included a range of viral and influenza-linked GO terms in amisulpride and volinanserin, and TNF and TGF-beta in risperidone. Consistent with this, a recent study showed a considerable global suppression of immune response in mice treated with risperidone, indicated by reduction in a number of cytokines during treatment [32]. Our findings suggest that this impact extends to other antipsychotics and so underscore the need to prioritise investigation of immune response in people with dementia.…”

Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations

“…Antipsychotics have been associated with immunosuppressive proprieties, such as decreased pro-inflammatory cytokine levels, blood dyscrasias, and altered production of antibodies [60,73,76,77]. The risk of neutropenia is about 1% for clozapine (3% in the elderly) and 0.1% for phenothiazines [36], while for other medications data are sparse [68].…”