Early-life adversities represent risk factors for the development of bipolaraffective disorder and are associated with higher severity of the disorder.This may be the consequence of a sustained alteration of thehypothalamic–pituitary–adrenal (HPA) axis resulting fromepigenetic modifications of the gene coding for the glucocorticoid receptor(NR3C1).

To investigate whether severity of childhood maltreatment is associated withincreased methylation of the exon? 1FNR3C1 promoter in bipolar disorder.

A sample of people with bipolar disorder (n = 99) wereassessed for childhood traumatic experiences. The percentage ofNR3C1 methylation was measured for eachparticipant.

The higher the number of trauma events, the higher was the percentage ofNR3C1 methylation (β = 0.52, 95% CI0.46–0.59, P<<0.0001). The severity ofeach type of maltreatment (sexual, physical and emotional) was alsoassociated with NR3C1 methylation status.

Early-life adversities have a sustained effect on the HPA axis throughepigenetic processes and this effect may be measured in peripheral blood.This enduring biological impact of early trauma may alter the development ofthe brain and lead to adult psychopathological disorder.

Adverse drug reactions are important determinants of non-adherence to antidepressant treatment but their assessment is complicated by overlap with depressive symptoms and lack of reliable self-report measures.

To evaluate a simple self-report measure and describe adverse reactions to antidepressants in a large sample.

The newly developed self-report Antidepressant Side-Effect Checklist and the psychiatrist-rated UKU Side Effect Rating Scale were repeatedly administered to 811 adult participants with depression in a part-randomised multicentre open-label study comparing escitalopram and nortriptyline.

There was good agreement between self-report and psychiatrists' ratings. Most complaints listed as adverse reactions in people with depression were more common when they were medication-free rather than during their treatment with antidepressants. Dry mouth (74%), constipation (33%) and weight gain (15%) were associated with nortriptyline treatment. Diarrhoea (9%), insomnia (36%) and yawning (16%) were more common during treatment with escitalopram. Problems with urination and drowsiness predicted discontinuation of nortriptyline. Diarrhoea and decreased appetite predicted discontinuation of escitalopram.

Adverse reactions to antidepressants can be reliably assessed by self-report. Attention to specific adverse reactions may improve adherence to antidepressant treatment.

There have been conflicting reports on whether the length polymorphism in the promoter of the serotonin transporter gene (5-HTTLPR) moderates the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). We hypothesised that the pharmacogenetic effect of 5-HTTLPR is modulated by gender, age and other variants in the serotonin transporter gene.

To test the hypothesis that the 5-HTTLPR differently influences response to escitalopram (an SSRI) compared with nortriptyline (a noradrenaline reuptake inhibitor).

The 5-HTTLPR and 13 additional markers across the serotonin transporter gene were genotyped in 795 adults with moderate-to-severe depression treated with escitalopram or nortriptyline in the Genome Based Therapeutic Drugs for Depression (GENDEP) project.

The 5-HTTLPR moderated the response to escitalopram, with long-allele carriers improving more than short-allele homozygotes. A significant three-way interaction between 5-HTTLPR, drug and gender indicated that the effect was concentrated in males treated with escitalopram. The single-nucleotide polymorphism rs2020933 also influenced outcome.

The effect of 5-HTTLPR on antidepressant response is SSRI specific conditional on gender and modulated by another polymorphism at the 5' end of the serotonin transporter gene.