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222 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
TBC1D22A in bipolar disorder; hypomethylation of TBC1D22A in schizophrenia)
(Sugawara et al. 2018).
Twin studies of bipolar disorder provide additional insights into the epigenetic
profiles of mood disorders. Among 11 pairs of monozygotic twins discordant for bi
polar disorder, differential DNA methylation was found within blood samples in the
gene encoding ST6GALNAC1, which was hypomethylated in the affected twin com
pared with the unaffected sibling (Dempster et al. 2011). Similar to the findings regarding TBC1D22A, the ZNF659 gene (which encodes ZNF385D) was found to be
hypomethylated in the twin pairs with bipolar disorder but hypermethylated in twin
pairs with schizophrenia. Differential methylation of the peptidylprolyl isomerase
E-like (PPIEL) pseudogene in lymphoblastoid cells has also been observed in bipolar
disorder–discordant twin-pair analyses (Kuratomi et al. 2008). Follow-up analyses
have indicated decreased DNA methylation of PPIEL in patients with bipolar II dis
order compared with healthy control subjects and patients with bipolar I disorder, indicating a potential relationship between DNA methylation and specific symptom
profiles.
Hypermethylation of the SLC6A4 gene has been observed in lymphoblastoid cells
of patients with bipolar disorder in a twin-pair and a case-control analysis (Sugawara
et al. 2011). This effect has also been observed in the postmortem frontal cortex of patients with bipolar disorder. Interestingly, the impact of SLC6A4 DNA methylation on
the expression of the serotonin transporter depends on the SLC6A4 genotype (Suga
wara et al. 2011), illustrating the interdependency of genetic and epigenetic factors.
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DNA Methylation in the Brain in Bipolar Disorder
Within the prefrontal cortex, patients with bipolar disorder have been found to have
decreased DNA methylation of KCNQ3 (which encodes for a voltage-gated potas
sium channel) in comparison with matched control subjects (Kaminsky et al. 2015).
Differential DNA methylation of the serotonin receptor type 2 (HTR2A) gene between
patients with bipolar disorder and healthy control subjects has been observed in the
frontal cortex. This epigenetic profile in bipolar disorder is significantly impacted by
medication history, with valproate use associated with hypomethylation (Abdol
maleky et al. 2011). Hypomethylation of the membrane-bound catechol-O-methyl-
transferase (MB-COMT) gene has been observed in the frontal cortex of patients with
bipolar disorder compared with healthy control subjects (Abdolmaleky et al. 2006),
and the DNA methylation status of both MB-COMT and HTR2A is also observed in
saliva samples of patients with bipolar disorder (Ghadirivasfi et al. 2011; Nohesara et
al. 2011).
Similar to MDD, the BDNF gene exhibits differential DNA methylation in patients
with bipolar disorder, with increased DNA methylation of the BDNF promoter in the
frontal cortex in a sample of patients compared with matched control subjects (Rao et
al. 2012). Within blood samples, this association between bipolar disorder and BDNF
hypermethylation has been replicated; however, the differential DNA methylation
and expression of BDNF were restricted to patients with bipolar II disorder (D’Addario et al. 2012).
Bipolar disorder is associated with indices of premature aging, including decreased
cognitive functioning, increased cardiovascular risk, and decreased gray matter vol-
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223 Epigenetics of Mood Disorders
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ume (Fries et al. 2020b). Analyses of hippocampal tissue from postmortem brains of
patients with bipolar disorder and matched nonpsychiatric control subjects indicated
epigenetic age acceleration in the patients based on genome-wide DNA methylation
levels (Fries et al. 2020a). However, this effect was observed only in the hippocampus
of older patients and was not observed in the cerebellum (Fries et al. 2017), although
some evidence suggests that the cerebellum is generally slower to age compared with
other brain regions (Horvath et al. 2015).
Histones and Noncoding RNA in Bipolar Disorder
The expression of HDAC4 mRNA is increased during depressive states in patients
with bipolar disorder compared with control subjects, whereas the expression of
HDAC6 and HDAC8 is decreased during both depression and remission (Hobara et
al. 2010). In genome-wide association analyses aimed at identifying common pathways across MDD, bipolar disorder, and schizophrenia, genes involved in histone
methylation emerge as a convergent gene cluster in these forms of psychiatric illness.
Within the frontal cortex of postmortem bipolar disorder brain samples, increased
global histone (H3) acetylation and phosphorylation are observed (Fries et al. 2020b).
A broad characterization of miRNA expression in the prefrontal cortex indicates that
approximately 19% of the variance in expression can be accounted for by a diagnosis
of bipolar disorder and its associated decreased expression of miRNAs (Moreau et al.
2011). The association between bipolar disorder and altered histone and miRNA pro
files likely has broad implications for gene expression and may also provide insights
into treatment response.
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Epigenetic Effects of Treatment of Mood Disorders
A consistent theme within the literature on epigenetic variation in mood disorders is
the utility of using epigenetic profiles to predict treatment responsiveness and the
epigenetic effects of pharmacological treatments with proven antidepressant or mood
stabilizing effectiveness. This theme is particularly relevant to compounds such as
valproate and sodium butyrate, which are used extensively in preclinical studies to
modify histone acetylation and DNA methylation, with consequences for gene ex
pression and behavior (Nicolini and Fahnestock 2018; Schroeder et al. 2007).
In addition to the previously noted effects of paroxetine, citalopram, and imipramine
on histones (Iga et al. 2007) and miRNAs (Lopez et al. 2014), differential DNA meth
ylation may be a significant predictor of treatment response. Comparison of antidepressant responders and nonresponders indicates that DNAmethylation within BDNF
is associated with treatment response, such that nonresponders have significantly
lower BDNF DNA methylation in blood samples (Tadić et al. 2014). Pharmacological
treatments for patients with bipolar disorder, including quetiapine and valproate, can
induce genome-wide changes in DNA methylation (Houtepen et al. 2016). Analyses
of DNA methylation in blood samples from patients with bipolar disorder after at
least 1 month of treatment using the Illumina 450K array indicate altered DNA methylation levels (compared with baseline) when controlling for immune cell type composition of the blood sample.
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224 The APA Publishing Textbook of Mood Disorders, Second Edition
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Among patients with bipolar disorder, compared with control subjects, global
DNA methylation levels in leukocytes were decreased in patients treated with lith
ium monotherapy, whereas hypermethylation was observed in patients treated with
a lithium combination therapy (lithium+valproate) (Backlund et al. 2015). mRNA
levels of the prodynorphin (PDYN) gene were significantly downregulated, and the
PDYN promoter was hypermethylated; this effect on PDYN DNA methylation was
not observed if the patients were being treated with lithium, which is associated with
decreased DNA methylation at the PDYN promoter (D’Addario et al. 2018). Effects of
BPD treatments have also been observed on measures of histone acetylation (Sharma
et al. 2006) and miRNA expression (Lim et al. 2016), confirming the broad epigenetic
effects of pharmacotherapies that ameliorate bipolar disorder symptoms.
Epigenetic Effects of Stress and Trauma
Early life adversity and later life trauma and stress are established predictors of psychiatric illness. These exposures also induce robust epigenetic changes in both the periphery and the brain that may account for some of the observed epigenetic differences
between patients with MDD, patients with bipolar disorder, and healthy control sub
jects. For example, in blood samples from monozygotic twin pairs, differential DNA
methylation of BDNF and NR3C1 was found to account for approximately 20% of the
relationship between childhood trauma and depressive symptoms in adulthood (Peng
et al. 2018). Elevated DNA methylation within NR3C1 is also observed in the hippo-
campus among individuals with a history of childhood maltreatment (McGowan et al.
2009). Adult trauma is also associated with altered DNA methylation in the periphery,
and these epigenetic changes, combined with a history of childhood adversity, can pre
dict posttraumatic stress symptomatology (Boks et al. 2016).
Interactions between genetic polymorphisms within MDD and bipolar disorder
candidate genes and childhood adversity or adult trauma are also observed in analyses
of the epigenome. Comparison of individuals with a diagnosis of MDD with healthy
control subjects indicates that among patients with MDD who have the high-risk allele
of the glucocorticoid receptor regulator FK506 binding protein 5 (FKBP5) gene, child
hood adversity predicts lower levels of DNA methylation within FKBP5 in white blood
cells (Tozzi et al. 2018). Moreover, among participants with MDD and control sub
jects, reduced FKBP5 DNA methylation levels were associated with reduced gray
matter in the inferior frontal orbital gyrus, suggesting a link between peripheral
FKBP5 DNA methylation and neurodevelopmental processes.
Analyses of polymorphisms within SLC6A4 have indicated that, compared with
individuals who have the LL alleles, individuals with the S-allele show increased
global DNA methylation associated with early life stress, chronic stress, and recent
depressive symptoms (Duman and Canli 2015). Among individuals with the L-allele
of the monoamine oxidase A (MAOA) gene, history of childhood adversity is a signif-
icant risk factor for depression, and decreased DNA methylation within MAOA in saliva samples is associated with MDD (Melas et al. 2013). Although disentangling the
epigenetic effects of childhood adversity from those associated with MDD or bipolar
disorder symptoms, lifestyle, and medication history is challenging, this growing
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body of literature provides a more integrative viewpoint on risk and resilience for
psychiatric disorders.
Conclusion
Epigenetic mechanisms play a fundamental role in basic biological processes that has
broad implications for health and development. In the case of mood disorders such
as MDD and bipolar disorder, epigenetic processes may be a contributor to disrupted
neurodevelopmental trajectories in response to childhood adversity, a significant predictor of treatment response, a mechanism of treatment effects, and a molecular link
between mental health and physical health and longevity. With increasing tools to
profile the human epigenome, our understanding of the role of epigenetics in mood
disorders is poised to expand. Future work in this area should consider study designs
that are genetically informed, account for exposures from the physical and psychoso
cial environment that can impact the epigenome, and provide a detailed analysis of
patient medication history.
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PART IV
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Somatic Interventions for
Mood Disorders
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CHAPTER 14
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Tricyclics, Tetracyclics,
and Monoamine
Oxidase Inhibitors
Matthew Macaluso, D.O., DFAPA
Like many established treatments in psychiatry, monoamine oxidase
inhibitors (MAOIs) and tricyclic antidepressants (TCAs) were serendipitously dis
covered. MAOIs were discovered after World War II when compounds with a hydrazine base were developed (isocarboxazid) from excess rocket fuel and used to treat
tuberculosis and, later, depression. Iproniazid, which was developed for tuberculosis
in the 1950s, has known MAOI properties and resulted in improved mood for
patients being treated for tuberculosis. Although hepatotoxicity limited iproniazid’s
use as an antidepressant, the development of other MAOIs led to their widespread
use in the 1950s through the 1970s (Hillhouse and Porter 2015).
As with MAOIs, TCAs were serendipitously discovered in the late 1950s in efforts to
produce more effective antipsychotic drugs. TCAs were created from chlorpromazine
by substituting sulfur for an ethylene bridge and modifying the phenothiazine ring.
These modifications led to the development of imipramine, the first TCA. The antidepressant properties of imipramine were discovered by the Swiss psychiatrist Kuhn
(1958), who was studying imipramine as an antipsychotic. Kuhn observed that imipramine did not have effects on psychosis but instead was useful in treating depression.
Prior to the discovery of these drugs, the major treatments for depression included
psychotherapy, psychoanalysis, hospitalization, sleep deprivation, or even psychosurgery in severe cases. The discovery of TCAs and MAOIs changed how the treatment of depression was conceptualized because effective medications were now
available. During the heyday of the TCAs and MAOIs, depression was characterized
as melancholic or nonmelancholic, a designation that influenced the choice of antidepressant. In addition, consideration was given to whether the patient’s depression
would respond to serotonergic versus noradrenergic antidepressants.
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