Antipsychotic Drug Responsiveness and Dopamine Receptor Signaling; Old Players and New Prospects

Abstract

Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.

A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing

“…GSK3B ranks among the most connected genes within Darkorange (Table S4), making it a potential hub of coexpression. These findings are consistent with prior reports implicating GSK3B variants in SCZ intermediate phenotypes (48)(49)(50).…”

“…Interestingly, mGlu5 acts via a pathway mediated by activation of phospholipase C and protein kinase C (46), a pathway also represented in Darkorange (PLCB1 and PRKCB). Similarly, many studies have implicated the Glycogene-Synthetase-Kinase-3beta (GSK3B) gene in emotion processing (47) and in SCZ (48). GSK3B ranks among the most connected genes within Darkorange (Table S4), making it a potential hub of coexpression.…”

A chromosomal connectome for psychiatric and metabolic risk variants in adult dopaminergic neurons

“…1, 7, 11, 20, and 22 interconnect to one of the top-scoring schizophrenia risk loci, MAD1L1 [56], which in context of reward-associated paradigms is associated with significant functional hypoactivation of the ventral midbrain and its prefrontal targets [88], to multiple genes each located within 40 kb from both BMI and SCZ risk sequences, such as, (i) chr. 11 DRD2 dopamine receptor, a critical antipsychotic drug target [89], (ii) chr. 1 GBN1 neurodevelopmental risk gene encoding a guaninenucleotide binding protein coupled to dopamine receptor systems [90], (iii) chrs.…”

Pharmacogenomics in Psychiatric Disorders

“…The most relevant PGx markers associations to main psychiatric pharmacotherapeutics, replicated by different case-control studies, are illustrated in Table 1 (Eum, Lee & Bishop, 2016;Lally et al, 2016;Leucht et al, 2013, Rampino et al 2019, Pardiñas et al, 2019Philips et al, 2018;Tauser, 2012;Zhang & Malhotra, 2011). The predicted responsivity to antipsychotics is 54% higher for Ins/Ins carriers; Del allele carriers had poor response to clozapine and to chlorpromazine in Han Chinese, as well as higher latency to olanzapine's and risperidone's efficacy in first episode of schizophrenia Taq1A SNP DRD2 A1 carriers more responsive to antipsychotics, although A2/A2 alleles correlated to greater response to therapy (smaller scores in PANSS a and BPRS b ); higher risk of the TD as ADR for A2/A2 genotype: one copy of the A2 allele increased the risk of TD with 30%, and A2/A2 genotype with 50%, respectively, relative to the A1 allele Ser9Gly SNP DRD3…”