The multifaceted nature of depression

According to the World Health Organisation (WHO, 2020), depression is a highly prevalent disorder with more than 300 million people affected globally. Unlike mood changes that people experience from time to time, depression may develop into a debilitating, potentially fatal illness. Causes of depression are complex, not entirely identified, and influenced by multiple sources including highly heterogeneous genetic and biological factors as well as psychosocial and environmental influences. Several models have been proposed to explicate the origins of depression, based on biological, psychological and environmental influences. 

Biological theories

One of the well-established biological theories which shed light on the aetiology of depression is the cytokine theory. Cytokines, which act primarily as cell signalling substances regulating inflammation in the immune system, may incite and aggravate depression. This was robustly supported by evidence of depression-like conditions that were induced by proinflammatory cytokines. Among other famous theories elucidating the causes of depression are the corticosteroid receptor (CRH) hypothesis of dysregulated hypothalamus–pituitary–adrenal (HPA) axis, resulting from stress and raised levels of stress hormones, and the monoaminergic theory of depression.

Genetic influences

A large body of evidence from family and twin studies points to genetic contributions to causes of depression. A meta-analysis by Sullivan, Neale and Kendler (2000) reports the estimated heritability of depression at about 37% and reveals that the risk of depression in children of individuals suffering from depression is elevated threefold.

Numerous candidate genes have been explored to establish possible genetic links to depression; however, no solid genetic associations are defined, implying that depression is a complex heterogeneous illness, and the synchronised action of various genes and their interaction with each other and with the environment governs the onset and development of depression.

Environmental causes

Converging evidence suggests that environmental exposures, such as exposure to air contamination, may contribute to the onset of depression. Air contaminants can affect the activity of serotonergic and dopaminergic neurons and inflammatory cytokines, alter the morphology of the hippocampal neurons and cause oxidative stress in the striatum and prefrontal cortex.

Psychosocial causes

A female preponderance in depression has been established by Wang et al. (2016) who highlighted that socioeconomic status and the severity of depression are negatively related. Among the psychosocial factors, stressful severe life events especially in early life undoubtedly contribute to the onset of depression as has been confirmed in many studies. A fourfold increased risk of depression was associated with women who were sexually or physically abused in childhood compared with women without such experiences.

Furthermore, the attachment theory of Bowlby (1977) claims that disrupted affectional bonds between children and caregivers have been the key contributors to psychopathology, including depression and anxiety.

Gene-environment interaction

Despite the higher risk of depression in individuals with adverse childhood experiences, responses of people to the same type of adversity are different, which is indicative of the co-influence of genetic factors. Caspi (2003) has been among the first to establish an interaction between genes and environment (GxE interaction) and to identify a critical relationship between the serotonin gene (5-HTTLPR), stress and depression. Caspi reported that individuals with the short allele of the 5-HTTLPR gene were remarkably susceptible to the adverse effects of childhood stress such as neglect or abuse.

Other possible pathways

Beck (2008) suggested that the pathway to depression starts with genetic susceptibility. He posited that hyperreactivity of the amygdala caused by the 5-HTTLPR polymorphism triggers negative bias and cognitive reactivity. Subsequently, this leads to the formation of dysfunctional beliefs and negative interpretations of experiences, which affect the HPA-axis and ultimately cause depression.

Another possible cause of depression can be explained by the developmental pathway from early conduct problems to adult depression.


Antidepressant medications have been known to alleviate symptoms of depression, especially in severe cases. Psychotherapeutic interventions have also been shown effective, either alone or combined with pharmacology. The major challenge, however, is 30% of treatment-resistant individuals.


Depression is a common disorder that impedes psychosocial functioning and markedly decreases the quality of life. This complex condition results from gene-environment interaction. Uncertain origins and an unpredictable trajectory of depression often pose challenges for health care professionals. Further research into the female preponderance may shed more light on the genesis of depression. Better insight into the aetiology of depression may be especially beneficial for the development of treatment for the treatment-resistant population.

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