Molecular mechanisms of antipsychotics – their influence on intracellular signaling pathways, and epigenetic and post-transcription processes

Abstract

Purpose: The purpose of this paper is to describe some aspects of the intra-cellular mechanism of action of neuroleptics, drugs widely used in psychiatry in treatment of psychotic and affective disorders. The ability of neuroleptics to influence and modify the metabolic, energetic and structural processes of neurons, as well as their apoptosis, probably influence their therapeutic potential. The direct and indirect mechanisms of antipsychotics are discussed on the basis of epigenetic, intra-cellular and post-transcription processes.Views: Antipsychotic drugs facilitate chromatin remodeling, decreasing or increasing histone acetylation, and affect DNA methylation differently. Antipsychotics modulate the intracellular signaling cascades like the cyclic adenosine monophosphate (cAMP), AKT/glycogen synthase kinase-3 (GSK-3) pathway and mitogen-activated protein kinase (MAPK) in a variety of ways that contribute to their different clinical and side-effect profiles. Among the cellular processes involved in the activity of antipsychotics are energy and metabolism, protein synthesis and processing, cytoskeleton functions like microtubule dynamics, dendritic branching, and spine dynamics, as well as cell adhesion and synaptic activity. Finally, antipsychotics have the ability to modulate the expression of a large number of miRNAs, which is related to oxidative stress and metabolism. Conclusions: Despite the efficacy of antipsychotics in treating schizophrenia and bipolar disorders over the last several decades, their molecular mechanisms of action turn out to be very complex and have not yet been fully elucidated. Recent thinking about a more personalized and endophenotype-specific diagnosing and treatment requires a more advanced genomic and proteomic approach and seems to be the next step in the treatment of mental disorders.

Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia

“…GO keywords related to cellular communication and regulation were repeated in treatment effectiveness and resistance comparisons, reflecting the major mechanism of drug action ( 99 ). Notably, pathway and network analyses revealed a strong correlation between DMRs associated with an effective antipsychotic response and genes implicated in the ribosome pathway, providing more evidence to support the hypothesis that treatment efficacy may be influenced by epigenetic modulation of ribosome-related genes ( 100 ).…”