Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy

Abstract

The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.

Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment

“…Changes in miRNA expression may be a result of altered neuronal signaling (Eacker, Keuss, Berezikov, Dawson, & Dawson, ) or treatment with antipsychotics (Song et al, ; Swathy & Banerjee, ). Changes in expression of miRNAs that regulate 5‐HT pathway or are associated with SZ may affect the expression of 5‐HT pathway genes.…”

“…It is difficult to distinguish between similar epigenetic variations that can be either risk factors or caused by the therapy. However, some epigenetic variations are also present in close relatives of SZ patients or in untreated patients and are thus less likely to be a consequence of therapy (Ghadirivasfi et al, ; Swathy & Banerjee, ). Furthermore, there can be variations in tissues used and heterogeneity between different ethnic groups (Castensson et al, ; Dolzan et al, ; Piva et al, ; Raymond et al, ).…”

DNA Methylation Profiling in a Neuroblastoma Cell Line Exposed to the Antipsychotic Perospirone

“…toreduceclinicalsymptomscores [8,9],sideeffectsincludingextrapyramidal symptoms and metabolic syndrome development induced by perospirone were reported to be milder [6,9]. Sinceantipsychoticdrugsarereportedtoinfluenceepigenetic profiles,suchasDNAmethylation,andhistonemodifications [10], wehavebeensystematicallyexaminingtheeffectofantipsychotics on DNA methylation using cellular models [11][12][13]. Here, we report a comprehensive DNA methylation analysis of perospirone using the HumanMethylation450 BeadChip platform for better understanding of the pharmacological actions of perospirone.…”

Epigenetic Modifications in Schizophrenia and Related Disorders: Molecular Scars of Environmental Exposures and Source of Phenotypic Variability

“…Indeed, different genome-wide studies have limited overlap in terms of their results, and these unbiased approaches could replicate only a small fraction of the initial findings that were obtained from targeted (hypothesis-driven) epigenetic studies. The lack of reproducibility is most likely accounted for by a number of factors, including small sample size and study population bias (141), influence of chronic pharmacotherapy (142), and other confounders such as smoking (143), methodological differences in epigenetic screening (144), and heterogeneity of cell populations studied (145). The latter has emerged as an important source of data variability at both the gene transcriptional and epigenetic levels (145), which in turn can mask diagnostic differences or lead to spurious and irreproducible findings.…”