Genetics of Antipsychotic-induced Side Effects and Agranulocytosis

Abstract

Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.

Risk of neutropenia in a clozapine-treated elderly population

“…This said, both older patients and patients with multiple comorbidities, as is often the case in the elderly, represent risk factors for the development of neutropenia and its complications (Dale, 2009). From a genetics perspective, several candidate genes have been implicated in the development of clozapineinduced agranulocytosis (Chowdhury et al, 2011), with a sequence variant (6672G>C) in the HLA-DQB1 identifying a subset of patients with an exceptionally higher risk (1,175%) than a control population (Athanasiou et al, 2011). While not specific to a geriatric population, these findings may be clinically useful in ascertaining the appropriateness of prescribing clozapine to a given individual based on his or her genetic make-up.…”

Genetics of antipsychotic drug outcome and implications for the clinician: into the limelight

“…A large-scale, retrospective study in 2012 by Lahdelma et al analyzed 163 Finnish patients with clozapine-induced agranulocytosis and reported that the highest risk is during the first year of treatment (135). There are a couple of theories surrounding clozapine-induced agranulocytosis; the first being that clozapine activates electrophilic nitrenium ions, which is the first step in agranulocytosis, and the second theory suggests an immune-mediated mechanism (136). A few gene variants have been clearly implicated in clozapine-induced agranulocytosis with the most promising being variants of the HLA-DQB1 region of the major histocompatibility complex (136).…”

“…There are a couple of theories surrounding clozapine-induced agranulocytosis; the first being that clozapine activates electrophilic nitrenium ions, which is the first step in agranulocytosis, and the second theory suggests an immune-mediated mechanism (136). A few gene variants have been clearly implicated in clozapine-induced agranulocytosis with the most promising being variants of the HLA-DQB1 region of the major histocompatibility complex (136). The 6672G !C marker of HLA-DQB1 was recently implicated in agranulocytosis and can help identify a small subset of individuals with extremely high-risk for agranulocytosis (137).…”

Clinical use of second-generation antipsychotics in children

“…Some specific genes have already been linked with the increased risk of adverse effects with SGAs, but there are no gene tests available yet in everyday clinical work (47,48). In the light of current evidence, screening and monitoring practices should thus be emphasized.…”