The epigenetic changes triggered by antidepressant intake and withdrawal: the PSSD connection

Updated: Mar 31

Post SSRI sexual dysfunction (PSSD) is a very treatment resistant condition with only the lucky few finding relief. This led us to suspect epigenetic changes causing methylation of certain gene promoters and recent studies have confirm our suspicion.

DNA methylation causes long-term repression of bodily functions depending on the genes affected, and this has repercussions to human health. In 2018, a very important study was published exploring Citalopram's effect on DNA methylation. It was discovered that within 30 days of treatment, out of a total of 626 gene promoters showed significant differential methylation, with 272 being hypomethylated and 354 being hypermethylated in treated versus control [1]

Not only did Citalopram methylated some gene promoters, it had also demethylated others, in a ratio of 43.4% to 56.5%, respectively.

DNA methyltransferase (DNMT):

DNMTs are a family of enzymes that catalyze the transfer of a methyl group to DNA, and when located in a gene promoter, DNA methylation acts to repress gene transcription. However, it should be noted that the effect of DNA methylation is context-dependent and methylation of repressor sites can increase transcription [2]. DNA methyltransferase inhibitors induce antidepressant-like effect in rodents. Tricyclic antidepressants can regulate DNA methylation in the PFC similar to DNMT inhibitors and this is an important mechanism for their antidepressant-like effects [3]. Using two potent DNMT inhibitors, Decitabine and Azacitidine, it was found that they have dose-dependent antidepressant effect through demethylation of hippocampal BDNF expression, whereas stress causes methylation of BDNF expression and depressive symptoms [4]

SSRI antidepressants treatment decreases cortical DNMT1 and DNMT3a mRNA expression and decreases DNMT enzymatic activity [5][6][7]. On the other hand, Fluoxetine treatment induces methyl binding protein expression (MeCP2 and MBD1) within multiple brain regions, including the dentate gyrus subregion of the hippocampus rich in GABAergic neurons. This effect is mediated through elevation of serotonin, as other serotonergic agents were able to trigger the same response [8].

Histone deacetylase (HDAC):

DNA expression is also regulated by acetylation and de-acetylation. HDAC inhibitors have been used to treat a variety of diseases and, likewise, administering HDAC inhibitors has antidepressant effects [9]. SSRI treatment has also been shown to reduce histone deacetylase HDAC-5 mRNA expression and acetylated histone H3 levels in multiple brain regions as well as increasing HDAC2 expression [8][10].


Judging by these effects, it's clear that 5HT signaling modulates DNA methylation and remodels chromatin structure in favor of an antidepressant effect by modulating various gene promoters including, but not limited to, TrkB, BDNF, and GR expression, altering baseline homeostasis. Upon withdrawal of these agents, the methylation state of many gene promoters and repressors would be changed in an unpredictable way, potentially giving rise to new symptoms (PSSD) in the unlucky few. Once withdrawn, methyltransferase enzymes would work normally again, potentially causing rebound methylation.

Low dose SSRI reinstatement helps offset some of PSSD symptoms in many patients. Perhaps it does so in virtue of recovering the previous baseline, introduced through DNMT-inhibition of dividing cells. DNA methylation is a reversible process, but it depends on passive demethylation of dividing cells after inhibition of DNMTs. Unfortunately, this is not the case for non-dividing neurons. However, active demethylation of neurons has been detected, giving a reason for having hope for complete recovery [11].


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