Treatment-resistant schizophrenia: current insights on the pharmacogenomics of antipsychotics

Abstract

Up to 30% of people with schizophrenia do not respond to two (or more) trials of dopaminergic antipsychotics. They are said to have treatment-resistant schizophrenia (TRS). Clozapine is still the only effective treatment for TRS, although it is underused in clinical practice. Initial use is delayed, it can be hard for patients to tolerate, and clinicians can be uncertain as to when to use it. What if, at the start of treatment, we could identify those patients likely to respond to clozapine – and those likely to suffer adverse effects? It is likely that clinicians would feel less inhibited about using it, allowing clozapine to be used earlier and more appropriately. Genetic testing holds out the tantalizing possibility of being able to do just this, and hence the vital importance of pharmacogenomic studies. These can potentially identify genetic markers for both tolerance of and vulnerability to clozapine. We aim to summarize progress so far, possible clinical applications, limitations to the evidence, and problems in applying these findings to the management of TRS. Pharmacogenomic studies of clozapine response and tolerability have produced conflicting results. These are due, at least in part, to significant differences in the patient groups studied. The use of clinical pharmacogenomic testing – to personalize clozapine treatment and identify patients at high risk of treatment failure or of adverse events – has moved closer over the last 20 years. However, to develop such testing that could be used clinically will require larger, multicenter, prospective studies.

Treatment resistant schizophrenia – review and a call to action

“…What if, at the early stages of antipsychotic treatment we could identify those patients likely to respond to clozapineand those likely to have adverse effects? The available neuroimaging and genetic biomarkers cannot yet reliably guide the early use of clozapine (Lally et al, 2016b, Samanaite et al, 2018. Of 379 investigated gene variants, only three (DRD3 Ser9Gly, HTR2A His452Tyr, and C825T GNB3) have independently replicated significant findings in clozapine response prediction.…”

Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders

“…It is well known that genetic and environmental factors contribute to the underlying cause of schizophrenia (SZ) [66–73]. Recently, it was shown that the mammalian brain suffers a global epigenomic reconfiguration during fetal to young adult development which could influence SZ onset specifically before the age of 20 [11].…”

Clozapine as a Model for Antipsychotic Development

“…To date, pharmacogenetic research has emphasized the major neurotransmitter systems involved in the pharmacodynamics and pharmacokinetics of antipsychotics. While issues with consistency exist in the findings [67][68][69][70], many of these associations could still be important. Several reasons may underlie the inconsistent results, such as different duration of clozapine treatment among the studies, different inclusion criteria for clozapine responders [23], and different ethnicities [71][72][73][74].…”