Pharmacoepigenetics in schizophrenia: Predicting drug response

Table 1 Effects of antipsychotic drugs and environmental factors on the epigenetics of schizophrenia

Mechanism	Drugs/environmental factors	Result/summary	Ref.
DNA methylation	Clozapine	Clozapine increased methylation and gene expression	[69]
	Olanzapine	Olanzapine increased expression of histone deacetylase genes
	Risperidone	Risperidone activated some genes while suppressing others
	Haloperidol	Haloperidol caused the most substantial increase in gene expression and significant effects on histone modification
	Risperidone, olanzapine, clozapine	DNA methylation was highest in non-responders. Methylation levels may tend to decrease in treatment responders	[56]
	Clozapine	Methylation sites associated with schizophrenia were found to be hypermethylated, and dynamic epigenetic regulation was identified	[59]
	Various antipsychotics	Clozapine and olanzapine induced global hypermethylation, whereas risperidone and quetiapine led to hypomethylation in specific regions	[64]
	Risperidone	Good responders showed hypermethylation in genes linked to neuroplasticity and cognition. Poor responders exhibited hypermethylation in genes involved in drug metabolism and immune response	[67]
	Childhood trauma	Childhood trauma was shown to induce epigenetic changes in stress-related genes, potentially contributing to schizophrenia	[44]
	Cannabis	Cannabis use was found to increase DNMT enzymes that suppress GABA synthesis, potentially raising the risk of schizophrenia through epigenetic mechanisms	[39]
	Risperidone	Risperidone treatment was found to shift DNA methylation patterns in patients with schizophrenia closer to those of healthy individuals	[66]
	Various antipsychotics	Clozapine, haloperidol, and atypical antipsychotics increased methylation, whereas risperidone caused decreased CYP2D6 methylation, possibly affecting drug metabolism	[65]
	Haloperidol, risperidone	Haloperidol and risperidone were found to induce significant hypermethylation in CpG regions	[62]
	Various antipsychotics	While no significant changes in DNA methylation were detected, widespread differences in gene expression levels were observed	[70]
	Clozapine, various antipsychotics	The majority of schizophrenia-associated differentially methylated positions were hypermethylated. Significant clozapine-associated DMPs were identified, all showing hypermethylation	[60]
	Cannabis	Early exposure to cannabis disrupted dopaminergic and endocannabinoid systems through decreased DNA methylation in the DRD2 gene and increased expression of the CNR1 gene, leading to schizophrenia-like behaviors	[35]
	Cannabis	Cannabis use was found to increase DLGAP2 gene expression through hypomethylation, potentially raising the risk of neurodevelopmental disorders such as autism and schizophrenia	[38]
	Marijuana	Marijuana was shown to increase synaptic plasticity by increasing BDNF levels through DNA hypomethylation, leading to an increased risk of disease in individuals genetically predisposed to schizophrenia	[36]
	Aripiprazole	Methylation levels of the ANKK1 gene were identified as a potential biomarker for predicting aripiprazole treatment response	[68]
	Clozapine	While global methylation levels generally decreased, the specific increase in methylation of certain genes contributed to the therapeutic effects of clozapine in treatment-resistant schizophrenia	[58]
	Haloperidol, clozapine, olanzapine	These drugs caused increased global DNA methylation levels and expression of epigenetic genes, including DNA methyltransferases, methyl CpG binding proteins, and DNA demethylases	[18]
	Risperidone	Elevated methylation rate within the promoter regions of the CYP3A4 and CYP2D6 genes was observed	[91]
DNA methylation/miRNA	Haloperidol, clozapine, olanzapine	Haloperidol had the strongest effect on methylation, followed by clozapine and olanzapine, with miR-29b downregulation and increased expression of DNMT1 and DNMT3A contributing to the hypermethylation	[57]
DNA methylation/histone modification	Cannabis exocannabinoid	Cannabis caused DNA hypomethylation in DRD2, COMT, DLGAP2, STAT3, PENK genes and hypermethylation in DNMT3a/b, NCAM1, and AKT1 genes. It also increased histone acetylation and methylation	[37]
Histone-chromatin modification	Various antipsychotics	Haloperidol increased histone acetylation and modulated DRD2 gene methylation and expression in the striatum. Olanzapine increased histone acetylation at BDNF. Clozapine increased histone methylation at GAD1. Risperidone reduced H3K27ac levels in the striatum, impacting genes like DRD2 and inflammatory pathways. Quetiapine modified global H3K9me2 levels in the prefrontal cortex	[64]
	Various antipsychotics	In individuals receiving antipsychotic treatment, HDAC activity decreased, and histone acetylation increased, leading to an increase in gene expression	[74]
	Clozapine, haloperidol, risperidone	Clozapine reduced histone acetylation in the GRM2 gene and increased histone acetylation and methylation in the GRM3 gene	[77]
	Various antipsychotics	Antipsychotic use reversed schizophrenia-related epigenetic changes in some genes and caused new changes in others. Antipsychotics altered histone acetylation and methylation, especially in dopamine-related and glutamate-related genes	[78]
	Clozapine, risperidone, haloperidol	Clozapine altered histone acetylation and methylation at ADRA2A and ADRA2C promoters. By contrast, risperidone and haloperidol caused no significant changes in epigenetic markers or gene expression	[75]
	Clozapine	Clozapine caused decreased H3 acetylation and increased HDAC2 binding at the mGlu2 promoter, which led to suppressed gene expression through enhanced histone deacetylation. These effects were absent in HDAC2 knockout mice	[76]
ncRNAs (lncRNAs)	Atypical antipsychotics	Risperidone regulated dopamine signaling by increasing MIAT levels. Atypical antipsychotics generally normalized NEAT1 levels. LncRNAs such as MIAT and NEAT1 played central roles in the pathogenesis of schizophrenia	[79]
	Various antipsychotics	Antipsychotics decreased MEG3, PINT, and GAS5 levels. Antipsychotics can modulate the immune system by decreasing the level of MEG3. Risperidone may regulate the immune response by altering heterochromatin-related genes	[89]
ncRNAs (miRNAs)	Clozapine (used only for TRS patients)	MiR-675-3p levels were elevated in TRS patients, and clozapine further increased miR-675-3p levels in TRS patients. Clozapine also increased miR-675-3p levels in cell culture	[88]
	Haloperidol	Haloperidol caused downregulation of miR-137-3p and increased Nr3c1 mRNA expression	[86]
	Olanzapine	Olanzapine significantly reduced miR-195 levels in treatment-responsive patients, which was positively correlated with the total score of PANSS	[83]
	Clozapine	Clozapine counteracted NMDA blockade, improved cognitive function, normalized some miRNA levels - especially decreasing miR-184 - and modulated the estrogen signaling pathway, potentially relevant for treating schizophrenia in women	[87]
	Olanzapine, haloperidol	Olanzapine and haloperidol reduced the disease-related increase in miR-223 levels in neurons, reducing pressure on glutamate receptors and indirectly contributing to regulating glutamate receptor levels	[84]
	Haloperidol, clozapine	Haloperidol and clozapine increased miRNA-143 levels and suppressed NRG1 by blocking the D2 receptor, altering neuroplasticity and neurotransmission	[85]
	Haloperidol, clozapine, olanzapine	In vitro studies, the drugs downregulated miR-27a and increased the expression of ABCB1 and CYP3A4 genes. CYP2D6 was upregulated only by haloperidol. The downregulation of miR-27a and increased expression of ABCB1 were also observed in the clinical setting	[82]
Oxidative stress	Various antipsychotics	Long-term antipsychotic use may increase dopamine turnover and trigger free radical production and oxidative stress. Low DNA methylation may increase CYP2E1 gene expression, which may trigger the development of tardive dyskinesia by raising the level of oxidative stress	[92]

ABCB1: ATP-binding cassette sub-family B member 1; ADRA2C: Adrenergic alpha 2C receptor; ADRD2A: Adrenergic receptor alpha 2; AKT: Protein kinase B; ANKK1: Ankyrin repeat and kinase domain containing 1; BDNF: Brain-derived neurotrophic factor; CNR1: Cannabinoid receptor 1; COMT: Catechol-O-methyltransferase; CYP2D6: Cytochrome P450 2D6; DLGAP2: Discs-large associated protein 2; DMPs: Differentially methylated probes; DNMT: DNA methyltransferase; DRD2: DA receptor subtype 2; GABA: Gamma-aminobutyric acid; GAD1: Glutamate decarboxylase 1; GAS5: Growth arrest-specific transcript 5; GRM: Glutamate receptor; H3K27ac: H3 acetylation of lysine 27; HDAC: Histone deacetylase; MEG3: Maternally expressed gene 3; MIAT: Myocardial infarction associated transcript; miRNA: MicroRNA; NMDA: N-methyl D-aspartate; NCAM1: Neural cell adhesion molecule 1; NEAT1: Nuclear paraspeckle assembly transcript 1; NMDA: N-methyl D-aspartate; Nr3c1: Glucocorticoid receptor gene; NRG1: Neuregulin 1; PANSS: Positive and Negative Syndrome Scale; PENK: Proenkephalin; PINT: p53-induced transcript; STAT3: Signal transducer and activator of transcription 3; TRS: Treatment-resistant.