Depression (Major Depressive Disorder)

Definition

Major Depressive Disorder (MDD) is a mood disorder characterized by persistent depressed mood, anhedonia, and associated cognitive and somatic symptoms causing significant functional impairment. Diagnosis follows DSM-5 / ICD-11 criteria requiring ≥5 symptoms for ≥2 weeks, including depressed mood or loss of interest.

Symptoms

Persistent depressed mood
Anhedonia (loss of interest or pleasure)
Changes in weight or appetite
Insomnia or hypersomnia
Psychomotor agitation or retardation
Fatigue or loss of energy
Feelings of worthlessness or excessive guilt
Impaired concentration or indecisiveness
Recurrent thoughts of death or suicidal ideation

Subtypes

Melancholic features
Atypical features
Psychotic features
Peripartum onset
Seasonal pattern (SAD)
Treatment-resistant depression (TRD)

Heritability and Etiology

Depression is only ~40% heritable (lower than SCZ or bipolar disorder), which underscores the critical role of environmental and epigenetic factors. Stressful life events are a major vulnerability factor. (Source: Nestler 2016)

Epigenetic Mechanisms

Histone deacetylation in NAc, hippocampus, PFC: HDAC inhibition produces antidepressant-like effects in rodent models. Suggests that reduced histone acetylation (hypoacetylation) is part of depression pathophysiology. (Hypothesis — confirmed in animal models, limited human data.)
H3K9me2 loss in NAc: Chronic social defeat stress reduces G9a/GLP methyltransferases, lowering this repressive mark. This is maladaptive; fluoxetine restores it at specific loci (Camkiia, Ras). (Established in animal models; corroborated at some loci in humans.)
H3K27me3 at Rac1 and BDNF: Increased repressive methylation reduces expression; dendritic spine changes follow. (Corroborated in human postmortem tissue.)
Dnmt3a upregulation in NAc: Chronic stress increases DNMT3a expression; DNMT inhibition has antidepressant effects. (Animal model finding; mechanism in humans not established.)
CRF demethylation in PVN: Susceptible mice show decreased DNA methylation at Crf promoter, increasing CRF and HPA-axis hyperactivity. Reversed by imipramine. (Animal model.)
Developmental epigenetics: Early life adversity (prenatal stress, maternal separation, low maternal care) causes lasting epigenetic changes at Nr3c1, BDNF, Avp, altering lifetime stress vulnerability. (Both animal and human evidence.)

Brain Regions Implicated

Nucleus accumbens (NAc)
Hippocampus
Prefrontal cortex (PFC)
Amygdala
Paraventricular nucleus of hypothalamus (PVN)