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 alterations that everyone can experience from time to time, depression may develop into the 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 origins of depression, based on biological, psychological, and environmental influences. 

Biological theories

One of the well-established biological theories which sheds 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 statement 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 into causes of depression. A meta-analysis of 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. It seems highly plausible that the synchronised action of various genes and their interaction with each other and with 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 recently confirmed by Wang et al. (2016), highlighting that socioeconomic status and the severity of depression are negatively related. Among psychosocial factors, stressful severe life events, especially in early life, undoubtedly contribute to the onset of depression as confirmed in many studies. A fourfold increased risk of depression was associated with women who had been sexually or physically abused in childhood compared to those without such an experience.

Attachment theory of Bowlby (1977) may be a valuable basis to explore causes of depression – it claims that disrupted affectional bonds between children and caregivers are the key contributors to the development of psychopathology, including depression and anxiety.

Gene-environment interaction

However, despite the higher risk of depression in individuals with stressful childhood experiences, responses of people to the same type of adversity are different and this may be indicative of the co-influence of genetic factors. Caspi (2003) was among pioneers to establish an interaction between genes and environment, GxE interaction. He identified an important relationship between the serotonin gene (5-HTTLPR), stress, and depression. Individuals with the short allele of the 5-HTTLPR gene are remarkably susceptible to the adverse effects of childhood stress such as neglect or abuse.

Other possible pathways

Beck (2008) proposed the pathway to depression starts with genetic susceptibility. He posited that hyperreactivity of 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.

One more 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 illness that restricts psychosocial functioning and markedly decreases quality of life. It is a complex disorder resulting from the interaction of genes and environment. 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 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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