Aetiology

The aetiology of depression remains poorly understood. Integrative models, taking into account biological and social variables, most effectively reflect the complex aetiology. It is considered likely that there is substantial heterogeneity amongst causative factors across individuals with depression.[28]

There is evidence for familial risk for depression, but specific genetic factors are still under investigation.[50]​ Genetic risk is thought to be polygenic, resulting from the combined small effects of a large number of common genetic variants.[51][52][53][54]

Gene-environment interaction will probably help explain susceptibility to depression; however, the evidence is mixed. Variants of several genes have been associated with depression in the subset of individuals with depression who have experienced significant life stress.[55][56]​​ It has been postulated that exposure to adverse life events in early life may lead to epigenetic modifications affecting gene expression, which may predispose to depression.[57] With or without a known genetic component, stressful life events, personality, and sex may also play a modifying role in depression risk. In particular, adversity or maltreatment during critical periods in early life has been demonstrated to substantially increase the risk of later development of depression, and is also associated with a less favourable course of illness, including an increased risk of recurrent depression.[58][59] Traumatic experiences in adulthood, including intimate partner violence and gender-based violence, also increase the risk of depression.[26]

Previous substance use (particularly cannabis and tobacco) is associated with an increased risk of depression, although this link is not necessarily causal.[60]

Meta-analysis evidence suggests an association between lifestyle habits (including low levels of physical activity and unhealthy dietary pattern) and the development of depression, although it has not been established whether this link is causal.[61][62]​​[63]

The role of the gut microbiome in the aetiology of depression is an area of active research. Studies have shown differences in the composition of gut microbiota, with associated differences in gut amino acid metabolism, between people with depression and healthy controls.[64][65]

Pathophysiology

The pathophysiology of depression remains unclear. Abnormal concentrations of neurotransmitters, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and abnormalities of second messenger systems have all been identified as being possibly involved in the pathophysiology of depression.

Pathophysiological theories of monoaminergic neurotransmitters and depression attempt to link the known mechanisms of action of antidepressants to evidence concerning the role of specific neurotransmitters and clinical manifestations of depression. For example, abnormalities in dopamine may be related to impaired motivation and concentration, low levels of noradrenaline (norepinephrine) and dopamine may play a role in the fatigue and hypersomnia, and impaired noradrenaline and serotonergic regulation may contribute to physical symptoms.[66][67][68]​​ In particular, the role of serotonin in the development of depression has been much-studied, but remains incompletely understood. Older explanations that attribute depression to a 'deficiency of serotonin' are now widely regarded as overly simplistic and misleading. A large, widely reported umbrella review challenged the role of serotonin in depression, although these findings have been questioned by other experts, citing possible methodological weaknesses.[69][70] Perhaps the most resilient experimental evidence for the hypothesis that low serotonin is associated with depression comes from studies using the tryptophan depletion method - effectively depleting bodily tryptophan and therefore serotonin by ingesting a cocktail containing all amino acids except tryptophan. This method tends to temporarily restore depressive symptoms in patients who have recovered from major depression. The effect appears to be limited to those in recovery from depression, not in volunteers without depression, so the role of serotonin in causing depression, if any, appears complex.[71][72]

HPA axis dysregulation has been demonstrated in people with depression. Morning cortisol secretion is not suppressed by administration of low-dose dexamethasone at bedtime in many people with depression.[73][74]

Gut microbiota alterations are hypothesised to influence mood by production of metabolites and bacterial components that affect neurotransmission in the central nervous system; animal models offer tentative evidence in support of this theory.[64][65][75]

Systemic inflammation has been proposed as one potential causative factor in the pathogenesis of depression; of note, there is some evidence that previous childhood maltreatment increases the risk of systemic inflammation in adults.[76]

Across an analysis of neuroimaging studies from 20 sites internationally, adults with major depression had thinning in regions of the orbitofrontal, cingulate, insular, and temporal cortices, and reduction in hippocampus volume.[77][78][79] Structural and functional abnormalities in fronto-limbic networks were also detected in neuroimaging studies of treatment-naive patients with depression.[80][81]​ However, findings vary substantially across individuals, underscoring clinical heterogeneity. Depression is postulated to be the result of dysfunction across interconnected networks in the brain, and the aim of much current research is to explore neural systems, rather than individual brain regions.[82]

Classification

International classification of diseases, eleventh edition (ICD-11)​[2]​

ICD-11 depressive disorders are subdivided into single-episode and recurrent types, with designations for severity of the most recent episode and, in severe cases, the presence or absence of psychosis (hallucinations or delusions).

Additionally, ICD-11 includes under the depressive disorder category a diagnosis of dysthymic disorder and a new one for mixed anxiety and depressive disorder

Diagnostic and statistical manual of mental disorders, fifth edition, text revision (DSM-5-TR)[1]

DSM-5-TR divides depressive disorders into:

  • Disruptive mood dysregulation disorder

  • Major depressive disorder (including major depressive episode)

  • Persistent depressive disorder (previously known as dysthymic disorder)

  • Premenstrual dysphoric disorder

  • Substance-/medication-induced depressive disorder

  • Depressive disorder due to another medical condition

  • Other specified depressive disorders

  • Unspecified depressive disorder

  • Unspecified mood disorder.

These types of depression are distinguished based on the length and number of symptoms in addition to sad mood and/or anhedonia, the degree of functional impairment, and the severity of symptoms. Additionally, depressive symptoms as part of cyclothymia or bipolar disorder may also be seen.

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