Table 5.

Pharmacological modulation of miRNAs in neuropsychiatric disorders.

Drug	Sample	MiRNA	Main findings	Targets	Reference
Antipsychotics
Haloperidol	Rat	Up-regulation: miR-199a, miR-128a, miR-128b	Three miRNAs were up-regulated in response to haloperidol treatment in rats as compared to untreated controls but None of these miRNAs was differentially expressed in their SCZ patient group	Not assessed	Perkins et al. (2007)
Haloperidol Clozapine	C57BL/6 mice	Down-regulation: miR-219	Dizocilpine is a NMDA-R antagonist that can rapidly produce schizophrenia-like behavioral Pretreatment with haloperidol and clozapine prevented dizocilpine-induced effects on miR-219.	It has been proposed that miR-219 negatively regulates the function of NMDA receptors	Kocerha et al. (2009)
Risperidone	SCZ patients receiving drug treatment = 40	Down-regulation: miR-365 and miR-520c-3p	Among the seven miRNAs screened, the expression levels of miR-365 and miR-520c-3p were significantly down-regulated after 1 year of risperidone treatment	Not assessed	Liu et al. (2013)
Haloperidol Olanzapine	Mouse	Confirmed with real-time PCR: Haloperidol: Down-regulation: miR-434-5p, miR-22 Olanzapine: miR-193	For the haloperidol treatment group, miR-434-5p and miR-22, and for the olanzapine group, miR-193 was down-regulated, But validation of the clozapine treatment group was conflicting (miR-329 and miR-342-5p were significant down-regulation by qPCR and up-regulated on the microarray).	Metabolic pathways were enriched in olanzapine and clozapine treatments, possibly associated with their weight gain side effects. Neurologically and metabolically relevant miRNA-gene interaction networks were identified in the olanzapine treatment group.	Santarelli et al. (2013)
Olanzapine Quetiapine Ziprasidone Risperidone	Plasma control subjects = 20 SCZ patients receiving drug treatment = 20	Down-regulation: miR-181b	Among 20 patients, each drug group has 5 patients. 9 miRNA that were reported to be associated with SCZ were selected and after six weeks of antipsychotic treatment, only the expression level of miR-181b had significantly decreased.	miR-181b might implicate several target genes associated with synaptic transmission, nervous system development disorders.	Song et al. (2014)
Aripiprazole Risperidone	Plasma SCZ patients receiving drug treatment and remitted = 79, SCZ patients receiving drug treatment but unremitted = 28	Down-regulation: miR-130b and miR-193a-3p	Among 107 SCZ patients who completed the 1-year follow-up, 79 achieved the remission criteria. The baseline levels of plasma miR-130b and miR-193a-3p between patients who remitted and those without remission were compared.	The validated downstream target genes for miR-13 0b include PDGFRA, RUNX3, ITGB1, PPARG, FMRl, and STAT3, and for miR-193a-3p they include ErbB4, S6K2, and MCL1. Classification of these genes: -SCZ susceptibility genes (PDGFRA, PPARG, ErbB4), -neurodevelopment-related genes (RUNX3, ITGB1, FMR1, STAT3), and -neuroprotective genes (S6 K2 and MCL1).	Wei et al. (2015)
Mood stabilizers
Lithium	Human whole blood BD patients = 5 Control subjects = 21	miR-134	miR-134 down-regulation in patients Increase in miR-134 levels after lithium treatment	Targeted genes/gene pathways: Limk-1, dendritic spine size regulation	Rong et al. (2011)
Lithium/VPA combination	Rat cerebellar granule cells	Down-regulation: miR-34a and miR-495 Up-regulation: miR-182, miR-147, and miR-222		The pathways associated with mood stabilizer-regulated miRNAs this study, are strongly associated with pathways implicated in neuropsychiatric diseases such as SCZ.	Hunsberger et al. (2013)
Lithium or VPA	Rat hippocampus	Down-regulation: let-7b, let-7c, miR-128a, miR-24a, miR-30c, miR-34a, and miR-221 Up-regulation: miR-144	Alteration in hippocampal miRNA levels following chronic treatment with lithium or valproate (VPA), and the predicted effectors of these miRNAs are also genetic risk candidates for bipolar disorder.	These miRNAs are involved in neurite outgrowth, neurogenesis, and signaling of PTEN, ERK, and Wnt/β-catenin pathways. The effectors of miRNAs targeted by both lithium and VPA treatments were CAPN6, DPP10, GRM7, ESRRG, FAM126A and THRB.	Zhou et al. (2009)
Lithium	Lymphoblastoid cell lines (LCLs) BD patients = 10 Unaffected siblings = 10	miR-34a, miR-152, miR-155, and miR-221	After derivation of LCLs from patients and their unaffected siblings, miR-221, miR-152, miR-155 and miR-34a up-regulated at treatment time-point days 4 and 16.		Chen et al. (2009)
Lithium/VPA combination	SH-SY5Y	Down-regulation: miR-30a-5p			Croce et al. (2014)
Lithium	SH-SY5Y	Down-regulation: miR-34a		Neuroprotective and anti-oxidant effects of lithium is found to related miR-34a expression.	Alural et al. (2015)
Antidepressants
Fluoxetine	Mouse brain	miR-16	After infusion of fluoxetine in mouse brain, a 2.5-fold increase in the level of miR-16 has been observed.	miR-16 was identified as a complementarity to the 3′ untranslated region of the SERT mRNA by Using in silico computational target prediction.	Baudry et al. (2010)
Fluoxetine	Human CSF MDD = 9 and Mouse hippocampus tissue	miR-16	After fluoxetine treatment, miR-16 levels decreased in mouse hippocampus. Also, after fluoxetine treatment, miR-16 targeting molecules BDNF, Wnt2, 15d–PGJ2 levels increased in human CSF samples.	They proposed miR-16 as regulator between SRI treatment and hippocampal neurogenesis. BDNF, Wnt2 and 15-deoxy-delta12, 14-prostaglandin J2 (15d–PGJ2) act synergistically on the hippocampus by decreasing miR-16 and increasing serotonin transporter (SERT) and bcl-2 levels.	Launay et al. (2011)
Escitalopram	Human whole blood MDD = 10	Up-regulation: miR-130b*, miR-505*, miR-29-b-2*, miR-26a/b, miR-22*, miR-664, miR-494, let7d/e/f/g, miR-629, miR-106b*, miR-103, miR-191, miR-128, miR-502-3p, miR-374b, miR-132, miR-30d, miR-500, miR-589, miR-183, miR-574-3p, miR-140-3p, miR-335, miR-361-5p Down-regulation: miR-34c-5p, miR-770-5p	28 miRNAs were up-regulated, and 2 miRNAs were strongly down-regulated after 12-week escitalopram treatment	miRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with neuronal brain function (such as neuroactive ligand-receptor interaction, axon guidance, long-term potentiation and depression).	Bocchio-Chiavetto et al. (2013)
Citalopram	Human whole blood	miR-1202	A decrease in miR-1202 levels in “depressed patients and increase in miR-1202 levels after 8 weeks of treatment	miR-1202 regulates the expression of the metabotropic glutamate receptor 4 (GRM4) gene and predicts antidepressant response at baseline.	Lopez et al. (2014a,b)
Ketamine	Rat hippocampus tissue	miR-206	18 miRNAs were significantly reduced, while 22 miRNAs were significantly increased. But researchers focused on miR-206 expression due to its modulator effect on BDNF expression.	miR-206 strongly modulated the expression of BDNF. miRNA target gene analysis referred the enrichments in several pathways associated with neuronal brain function, such as the neuroactive ligand-receptor interaction (miR-132-3p, miR-206, miR-181a-5p, miR-150-5p), amphetamine addiction (miR-497-5p, miR-29a-3p, miR-132-3p, miR-181 a-5p, miR-29c-3p), Wnt signaling pathway (miR-29a-3p, miR-98-5p), dopaminergic synapse (miR-132-3p, miR-181a-5p), ErbB signaling pathway (miR-221-3p), mTOR and TNF signaling pathway (miR-206, miR-132-3p)	Yang et al. (2014)
Citalopram	Human whole blood MDD = 18 Control = 18	miR-335	Down-regulation of miR-335 levels in MDD patients and up-regulated after citalopram treatment.	Regulatory loop between GRM4 and miR-335 has been observed. The expression of miR-335 was increased and GRM4 was decreased in the blood samples of MDD patients after citalopram treatment.	Li et al. (2015)