TABLE 3.

Summary of studies exploring comparison of DNAm status across different medications.

Studies	Genome Region analyzed	Sample size	treatment duration	Tissue	Platform	Main results
Schizophrenia
Melas et al., 2012	Global methylation	129 SCZ; 171 HC	NA	Blood	LUMA	• Haloperidol vs. other APs: higher (control-like) global DNAm (p < 0.001)
Nour El Huda et al., 2018	COMT CpG islands	138 SCZ; 132 HC	NA	Blood	Bisulfite conversion + PCR	• AAP vs. TAP: lower DNAm status (p = 0.004); AAP vs. Sulpiride: lower DNAm status (p = 0.004) • Risperidone vs. TAP: lower DNAm status (p = 0.049)
Bipolar disorder
D’Addario et al., 2012	BDNF Promoter region	49 BD I; 45 BD II; 52 HC	at least 1 months	PBMCs	Bisulfite conversion + RT-qPCR	• AD vs. AD-free: higher DNAm levels (p < 0.01, AD-free had a control-like DNAm levels); Li vs. other drugs: lower (control-like) DNAm levels (p < 0.05) • VPA vs. other drugs: lower (control-like) DNAm levels (p < 0.05)
Backlund et al., 2015	Global methylation	61 BD; 26 HC	at least 3 months	Blood	ELISA	• Li vs. HC: lower DNAm levels (p = 0.036) • Li + VPA vs. Li: higher DNAm levels (p = 0.011); • Li + AP vs. Li: higher DNAm levels (p = 0.071)
Burghardt et al., 2018	AKT1&AKT2 &AKT3 Promoter region	30 BD	at least 3 months	FSM	PCR + MS-HRM	• AAP vs. MSs: increase of AKT1 and AKT2 DNAm (p = 0.03; p = 0.02)
D’Addario et al., 2018	PDYN Promoter region	54 BD I; 45 BD II; 41 HC	at least 1 months	PBMCs	Bisulfite conversion + RT-qPCR	• Li or VPA vs. other drugs: lower (control-like) DNAm levels (p < 0.05)
Burghardt et al., 2019	Global methylation	28 BD; 13 HC	at least 3 months	FSM	LINE1	• AAP vs. HC: higher DNAm levels (p = 0.0004, q = 0.0048) • MSs vs. HC: higher DNAm levels (p = 0.12) • AAP vs. HC: higher DNAm levels (p = 0.0156, q = 0.037)
Major depressive disorder
Ryan et al., 2017	IL6 Promoter region	92 MDD; 288 HC	4 waves of follow-up	Buccal swabs	SEQUENOM MassARRAY	• AD use was associated with a mean 4.6% increase in CpG2 DNAm of IL6 (p = 0.017)
Schizophrenia & Bipolar disorder
Abdolmaleky et al., 2006	MB-COMT promoter region	40 SCZ; 35 BD; 40 HC	life times	Post-mortem brain	qMSP	• AP vs. drug-free: no differences • VPA did not specifically alter DNAm status
Abdolmaleky et al., 2011	HTR2A promoter region	35 SCZ; 35 BD; 35 HC	life times	Post-mortem brain	qMSP	• AP vs. drug-free: lower DNAm levels (p = 0.012) • drug-free vs. HC: higher DNAm levels in BD and SCZ and BD combined (p = 0.002 and p = 0.0027, respectively) • AAP vs. TAP: no differences
Abdolmaleky et al., 2014	5-HTT promoter region	35 SCZ; 35 BD; 35 HC	life times	Saliva; Post-mortem brain	qMSP	• AP vs. HC: no differences in both saliva and brain • drug-free vs. AP: higher DNAm levels in brain (p = 0.038) • drug-free vs. HC: higher DNAm levels in brain (p = 0.04)
Abdolmaleky et al., 2015	DTNBP1 Promoter flanking SP1 binding site	35 SCZ; 35 BD; 35 HC	life times	Saliva; Post-mortem brain	qMSP	• Drug-free vs. AP: higher DNAm status in BD (p = 0.045) • CAP vs. AAP + CAP: lower DNAm status in SCZ (p = 0.037) • CAP vs. AAP + CAP and AAP combined: decrease of DNAm status in SCZ (p = 0.017)
Bipolar disorder & Major depressive disorder
Dell’Osso et al., 2014	BDNF Exon I promoter	43 MDD; 111 BD; 44 HC	NA	Blood	Bisulfite conversion + PCR	• Li or VPA vs. other drugs: tended to decrease (control-like) DNAm levels (no.sig)
Carlberg et al., 2014	BDNF Exon I promoter	207 MDD; 59 BD; 278 HC	NA	Blood	MS-qPCR	For 165 MDD: • AD vs. AD-free: higher DNAm levels (p = 0.0019) • AD vs. HC: higher DNAm levels (p < 0.0001) • AD-free vs. HC: no differences

Luminometric Methylation Assay, LUMA; Methylation-sensitive High-resolution Melting, MS-HRM; Linear Interspersed Nuclear Element 1, LINE1; Enzyme-linked Immunosorbant Assay, ELISA; Antipsychotics, APs; Atypical Antipsychotics, AAPs; Typical Antipsychotics, TAPs; Classic Antipsychotics, CAPs; Mood Stabilizers, MSs; Valproate, VPA; Lithium, Li; Fasting skeletal muscle, FSM; Peripheral blood mononuclear cells, PBMCs; Quantitative methylation specific PCR, qMSP.