Background.Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the ‘gold standard’ for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic–pituitary–adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life.Method.In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored.Results.Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges.Conclusions.The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

A and Guo, L (2017) The effect of morphine upon DNA methylation in ten regions of the rat brain. Epigenetics, 12 (12 AbstractMorphine is one of the most effective analgesics in medicine. However, its use is associated with the development of tolerance and dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided insight into mechanisms possibly underlying addiction. In this study, we sought to identify epigenetic changes in ten regions of the rat brain following acute and chronic morphine exposure. We analyzed DNA methylation of six nuclear-encoded genes implicated in brain function (Bdnf, Comt, Il1b, Il6, Nr3c1 and Tnf) and three mitochondrially-encoded genes (Mtco1, Mtco2 and Mtco3), and measured global 5-methylcytosine (5-mc) and 5-hydroxymethylcytosine (5-hmc) levels. We observed differential methylation of Bdnf and Il6 in the pons, Nr3c1 in the cerebellum, and Il1b in the hippocampus in response to acute morphine exposure (all p<0.05). Chronic exposure was associated with differential methylation of Bdnf and Comt in the pons, Nr3c1 in the hippocampus and Il1b in the medulla oblongata (all p<0.05). Global 5-mc levels significantly decreased in the superior colliculus following both acute and chronic morphine exposure, and increased in the hypothalamus following chronic exposure. Chronic exposure was also associated with significantly increased global 5-hmc levels in the cerebral cortex, hippocampus and hypothalamus, but significantly decreased in the midbrain. Our results demonstrate, for the first time, highly localized epigenetic changes in the rat brain following acute and chronic morphine exposure. Further work is required to elucidate the potential role of these changes in the formation of tolerance and dependence.

Case reportMr M, a 53-year-old White man, had a 25-year history of recurrent, refractory psychotic depression (World Health Organization ICD-10 revision F33.3) that necessitated over 30 hospital admissions. Identifiable triggers were lacking and remission rarely achieved. Excepting childhood anxiety, he was well adjusted before first presentation. Drug or Alcohol misuse did not feature. Treatments of adequate dose and duration included: antidepressants from every major class, alone and in combination; lithium and carbamazepine augmentation; antipsychotics (first and second generation, oral and parenteral) including clozapine, which was stopped due to neutropenia; numerous electroconvulsive therapy (ECT) courses, approximating 600 stimulus deliveries; psychosurgery twice (bilateral anterior capsulotomy in 1996 and anterior cingulotomy in 1999), both producing unsustained responses. Postsurgical absence seizures responded to lamotrigine, but his depression did not. He remained out of hospital periodically with the support of his family and a combination of regular medication, as required chlorpromazine and maintenance ECT.In July 2012, he was admitted electively during maintenance ECT (135 bilateral stimulus deliveries) whilst taking nortriptyline (300 mg daily), amisulpride (300 mg daily), chlorpromazine (300 mg daily) and lamotrigine (100 mg daily). ECT caused marked cognitive impairment but when stopped, in November 2012, his psychotic depression worsened. He described -with horror -seeing and hearing a "foul-smelling dark man" and could not understand why others did not. This multimodal hallucination was mood congruent, and involved threats to kill the patient's family unless he committed suicide. He often mistook the ward for his home, required physical contact to ensure that staff were 'real' and had vivid dreams of being burned or drowned.Rivastigmine was prescribed (4.2 mg/day transdermal patch) off-licence in January 2013. His hallucinations lessened and resolved fully within a month; his mood improved concurrently. Drugs with anticholinergic properties were withdrawn during this period. Regrettably, intolerable side effects emerged: sialorrhoea, uncontrolled by hyoscine or ipratropium bromide 0.03% spray, resulted in aspiration pneumonia. Donepezil Acetylcholinesterase inhibitors in treatment-resistant psychotic depression Chris Smart, Hamish McAllister-Williams and David Andrew CousinsAbstract: Dopamine receptor antagonists can be effective in psychotic depression but response is not assured. Visual hallucinations may arise from a dysregulation of brain cholinergic systems and acetylcholinesterase inhibitors (AChEIs) can treat such hallucinations in dementia with Lewy bodies (DLB). AChEIs have been used in schizophrenia with some success but their efficacy and tolerability in psychotic depression is unclear. This striking case illustrates AChEIs specifically targeting multimodal hallucinations in treatment-resistant depression. To our knowledge it is the first case report to do so. It highlights the val...