Major depressive disorder (MDD) affects up to 17% of the world’s population. The WHO estimates it will be the second most costly disease to world governments by 2020. As devastating as it is to those who suffer from it, and to their loved ones, relatively little is known about its exact causes, and while diagnosis and treatment have advanced greatly over the past twenty years, far too many people continue to slip through the cracks (only about 50% of patients experience full remission). The emerging disciplines of epigenetics and epigenomics offer new hope for ameliorating a variety of incompletely understood conditions. As with other biological phenomena, our grasp is becoming more nuanced as new discoveries are made.
The heritability of MDD is between 31 and 42%, substantially lower than that of schizophrenia or BPD, and to date researchers have failed to find genetic loci that correlate strongly to clinical depression. Monozygotic twin concordance is approximately 50%. This means major depression cannot be entirely explained through conventional genetic analysis. As I mentioned in The Epigenetics of Schizophrenia, scientists have speculated that changes in gene expression are stochastically modulated. Thus, along with obvious contributors like childhood trauma, essentially random changes in the epigenome explain why the phenotypes of two identical twins raised in the same household can dramatically diverge. A complete model of MDD would account for its varied symptomatology including, but not limited to, anhedonia, irregular sleep patterns, changes in appetite, and abnormal circadian rhythms.
These particular disturbances have led researchers to implicate the hypothalamus, an ancient brain structure responsible for many basic bodily functions, as well as the hippocampus, which has been linked again and again with MDD. The hippocampus is a brain structure crucial to the movement of short-term memories to long-term storage (which is why damage to it can result in the inability to retain new information). Damage to the hippocampus from increased glucocorticoid production is partially, if not largely, responsible for the cognitive deficits observed in MDD patients. Normally poor performance on psychometric tests is viewed as a behavioral side effect of depression but, as Austin, Goodwin and Mitchell noted in 2001, “a small number of studies indicate persistent cognitive impairment upon recovery in mood disorder, as noted above. These findings are reported in all age groups, although more frequently in older subjects.” Although the notion that impairment is the result of neurology (since cognitive problems can linger longer after remission) and not the byproduct of low motivation is gaining credibility in the form of data gleaned from functional neuroimaging, it is far from universally accepted.
In postmortem examinations, unmedicated people with MDD have lowered levels of BDNF (Brain-Derived Neurotrophic Factor) and those taking an antidepressant have elevated levels. Selective serotonin reuptake inhibitors (SSRIs) have been used with some success and the changes to the expression of this particular protein is probable explanation for part of their efficacy. “BDNF promotes the survival and differentiation of 5-HT neurons. Conversely, administration of antidepressant selective serotonin reuptake inhibitors enhances BDNF gene expression,” according to Martinowich and Lu. In other words, there is a synergy between these two systems. Bupropion, better known as Welbutrin, is classified as a weak norepinephrine-dopamine reuptake inhibitor (NDRI). Yet, in spite of its radically different pharmacology, bupropion is frequently used with success. In other words, the problems, and the solutions, do not rest exclusively with either BDNF or serotonin.
According to Massart, the monoamine hypothesis has “dominated” our understanding of depression and, moreover, recent evidence suggests “hyperactivity of the HPA axis is not a simple consequence or an epiphenomenon of depression, but a risk factor predisposing the patient to the development of depression.” One of the “most enduring and replicated findings in biological psychiatry is activation of the hypothalamic-pituitary-adrenal (HPA) axis” in a particular MDD subpopulation. The HPA axis is awoken by stress. When this occurs the hypothalamus secretes hormones that stimulate the release of adrenocorticotropin hormone (ACH). This eventually results in the production of cortisol, a well-known and often maligned steroid hormone. For these reasons cortisol, ACTH and CRH levels after the administration of dexamethasone (a synthetic corticosteroid) are used as a measure of HPA activity. If cortisol does not decrease the next day the patient is deemed DST nonsuppressive. An analysis of over 150 studies determined 67% of MDD patients fall into this category. Clinically depressed people also show a blunted ACTH response to CRH.
Michael Meaney performed a set of widely-cited experiments showing that the offspring of mothers who received low levels of maternal care and grooming are predisposed to anxiety compared to those whose mothers received high levels of care. In other words, the anxious or depressed phenotype rooted in the trauma of their own lives is passed on to their children. Neglected rats show decreased glucocorticoid receptor mRNA expression in their hippocampi. Their GR promoters are also acetylated. Maternal care (or lack thereof) can influence the ways in which the HPA axis functions (or malfunctions) for the rest of one’s life and, more shocking, how well one’s children and grandchildren cope under duress. Murgatroyd and Spengler famously postulated lasting behavioral changes stemming from unpleasant life events are due “persistent epigenetic programming” laid down during a critical window of development. Their culprit was the protein methyl-CPG binding protein MeCP2, resulting in hypomethylation of the AVP gene.
Histones are proteins responsible for the packaging of DNA and thus play a role in the regulation of gene expression. Histone deacetylase inhibitors (HDACi) do precisely what their name implies. Both systemic and intracerebral administration of HDACis were shown, either alone or alongside conventional antidepressants, to alleviate depression symptoms in animals. There are many types of histone acetylases and HDACis. Their interactions with the body are, as one would expect, quite complex. For instance, HDACi (MS275) infused into the amygdala alleviates social avoidance while doing nothing for anhedonia. However, do not fret, when injected into the hippocampus of rats, MS275 treats anhedonia, but only anhedonia.
Continued research into this area will allow researchers to map out the ways in which specific changes to the epigenome affect the phenotype and what treatments are best for whom. Depression, like so many other complex diseases, will be defeated through the advancement of personalized medicine.
Alonzi, Adam. “The Epigenetics of Schizophrenia.” What Is Epigenetics. What Is Epigenetics, 8 Dec. 2014. Web. 08 Dec. 2014.
Arana GW, Ross JB, Ornsteen M. The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Arch Gen Psychiatry. 1985;42:1193–1204.
Austin, Marie-Paule, Philip Mitchell, and Guy M. Goodwin. “Cognitive deficits in depression Possible implications for functional neuropathology.” The British Journal of Psychiatry 178.3 (2001): 200-206.
Covington, Herbert E., et al. “Antidepressant actions of histone deacetylase inhibitors.” The Journal of Neuroscience 29.37 (2009): 11451-11460.
Dwoskin, Linda P., et al. “Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent.” CNS drug reviews 12.3‐4 (2006): 178-207.
Holsboer F, von Bardeleben J, Wiedemann K, et al. Serial assessment of corticotropin-releasing hormone response after dexamethasone in depression: implications for pathophysiology of DST nonsuppression. Biol Psychiatry. 1987;22:228–234.
Lee B. H., Kim Y. K. 2010. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Invest. 7, 231–235. doi: 10.4306/pi.2010.7.4.231
Duman, Ronald S., and Lisa M. Monteggia. “A neurotrophic model for stress-related mood disorders.” Biological psychiatry 59.12 (2006): 1116-1127.
Izzo, Annalisa, and Robert Schneider. “Chatting histone modifications in mammals.” Briefings in functional genomics 9.5-6 (2010): 429-443.
Martinowich K., Lu B. 2008. Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33, 73–83. doi: 10.1038/sj.npp.1301571.
Massart, Renaud, Raymond Mongeau, and Laurence Lanfumey. “Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression.” Philosophical Transactions of the Royal Society B: Biological Sciences 367.1601 (2012): 2485-2494.
McGowan, Patrick O., et al. “Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.” Nature neuroscience 12.3 (2009): 342-348.
Murgatroyd, Chris, and Dietmar Spengler. “Epigenetic programming of the HPA axis: early life decides.” Stress 14.6 (2011): 581-589.
Reddy, M. S. “Depression: The disorder and the burden.” Indian journal of psychological medicine 32.1 (2010).
Schroeder, Marc, et al. “Epigenetics and depression: current challenges and new therapeutic options.” Current opinion in psychiatry 23.6 (2010): 588-592.
Sun, HaoSheng, Pamela J. Kennedy, and Eric J. Nestler. “Epigenetics of the depressed brain: role of histone acetylation and methylation.” Neuropsychopharmacology 38.1 (2012): 124-137.
WHO. “Mental Health: A Call for Action by World Health Ministers.” 54th World Health Assembly (2001): n. pag. World Health Organization. Web.