Table 3.

Key issues and suggestions for future research in pharmacoepigenetic studies of antidepressant response

Key Issues	Suggestions for future research
1. May be missing relevant genes/loci due to lack of epigenome-wide association studies of antidepressant response	● Conduct whole genome epigenetic studies in humans by leveraging consortia data in order to have the sample sizes needed for appropriate power.
2. Lack of replication of particular epigenetic marks	● Test for replication of epigenetic marks in large controlled clinical trials and determine validity of these marks by expert group
3. Inconsistent methods for measuring epigenetic marks	● Avoid methods known to have poor performance compared to other assays, such as enrichment bisulfite sequencing.
4. Use of blood given low concordance between brain and blood methylation patterns	● Use saliva or buccal samples given higher concordance with brain methylation patterns as compared to blood. ● If blood is used, limit to markers showing high concordance between brain and blood or generate iPSC-derived neurons. ● Blood may be appropriate when assessing pharmacokinetic genes.
5. Lack of studies assessing non-CpG dinucleotides and 5hmC	● Incorporate testing of non-CpG dinucleotides and 5hmC into future studies.
6. Lack of studies with a comparator arm	● Design studies to determine if differential response to antidepressants can be predicted by epigenetic marks.
7. Variability in treatment duration, covariates included in the models, and use of correction for multiple testing	● Standardize treatment duration and covariates in order to increase comparability between studies and correct for multiple testing.

Abbreviations: 5hmC – 5-hydroxymethylcytosine; iPSC – induced pluripotent stem cell