It is probable that a number of pathways lead to MDD and causation of depression is probabilistic, not deterministic (51). Since the 1950s, the risk factors and pathogenesis of depression have been studied from a neurochemical perspective. Both biological, psychological, sociological, genetic and environmental mechanisms are present in the pathogenesis of depression (39).
Low socio-economic status (SES), short education, low income, disability, unemployment and marital status (being divorced or widowed) are associated with an elevated prevalence of MDD (2,29). Lifestyle factors, such as smoking, may independently increase the risk of MDD (52). Growing evidence indicates that physical inactivity is an independent risk factor for depression, and physical exercise may be protective for mental health (27). Childhood maltreatment and trauma in early life are also independent predictors of MDD. However, the influence of these risk factors is modulated by numerous other factors, such as genetic background, temperament, received care, age and reconstructive factors in later life (53). Interestingly, traumas and early experiences of heightened stress may cause long-term neuroendocrinological changes, which may represent adaptations (54). These neurobiological changes tend to increase the risk of depression in later life, especially during stressful life events (54,55). In addition to these functional changes, differences in brain structure have also been reported (54).
Table 1. The ICD-10 criteria for diagnostic of clinical depression (F32). (41) Criteria for depressionSymptomsState of depressionNumber of symptoms A. Symptoms have lasted at least for two weeksKey symptoms:Persistent sadness or low mood Severe depression≥7, all 3 key symptoms B. Symptoms include at least two key symptomsLoss of interest or pleasure C. Altogether at least four symptoms (incl. key symptoms) is considered clinical depression
Fatigue or low energyModerate depression5-6 Other symptoms:Disturbed sleep Poor or increased appetiteMild depression4 Low self-confidence Poor concentration or indecisiveness Not depressed<4 Agitation or slowing of movements Guilt or self-blame Suicidal thoughts or acts Abbreviations: ICD, International Classification of Diseases
Susceptibility to depression is at least partly heritable, but the magnitude of genetic factors is still unknown. Approximations of heritability in MDD vary from 31% to 42%, which is substantially lower than in bipolar disorder or schizophrenia (39,51). Heritability may play a greater role when depression is severe, recurrent or has begun in early age (56).
Susceptibility to depression is explained by multiple genes (39,51). There is also a gene-environmental interaction in depression; for example, a polymorphism in the promoter region of the serotonin transporter gene moderates the influence of stressful life events on depression (57).
There are several theories of the pathogenesis of depression, and these theories are not separate, but highly connected (58). The most common biological candidates of interest have been monoamines, adenoreceptors, the dopaminergic system, the function of the hypothalamus-pituitary-adrenal gland (HPA) axis, corticosteroids, neurotrophins and atrophy or resynthesization of neuronal cells (58,59). The following sections present the hypotheses of monoamines, inflammation, stress and neurogenesis, which are the most promising candidates to explain the association between diet and depression.
2.4.1 Monoamine hypothesis
The monoamine hypothesis, an earlier major theory of depression, is based on the presumption that abnormalities in the metabolism of the neurotransmitters serotonin and noradrenaline may cause depression (39). The serotonergic and noradrenergic systems are capable of modulating the brain areas involved in behavior, sleep, eating, feelings and thoughts. Especially the role of serotonin has been supposed to be central in the pathogenesis of depression. According to this theory, depression could be defeated by returning the serotonin levels in the central nervous system (CNS) back to normal (39).
However, the monoamine hypothesis has been argued to be an insufficient approach to the etiology of depression, since typical monoamine-based antidepressant treatments have not been efficient enough, and the advantages of antidepressants to mood are seen only after several weeks of administration, not immediately (60).
2.4.2 Inflammation hypothesis
The first findings of the role of inflammation and cell-mediated immune activation in depression were reported already in the 1990s (61). Today, low-grade inflammation is believed to play an important role in the development of depression (62,63). Cytokines, secreted by macrophages as a result of the activation of sympathetic nervous system in stress, are proteins with either pro-inflammatory or anti-inflammatory effects (64).
Depressed patients have been observed to have high blood C-reactive protein (CRP) levels, as well as elevated levels of plasma pro-inflammatory cytokines, like interleukin 1, interleukin-6, interleukin-2 and tumor necrosis factor-α (58,62,63). It has also been suggested that the serotonergic disturbances in depression could be a consequence of cell-mediated immune activation (62), and pro-inflammatory cytokines reduce the functions of neurotransmitters in CNS (64). The inflammation theory supports the bi-directional relationships between depression and other non-communicable diseases, such as obesity, T2D and CVD (33,65).
2.4.3 Stress hypothesis
The stress hypothesis suggests that prolonged mental stress causes depression by hyperactivity of the HPA axis (66). Chronic mental stress disturbs the regulation of the HPA axis and causes chronic inflammation (67). Nevertheless, not all individuals who encounter acute or prolonged mental stress become depressed. Approximately half of the depressed patients have hyperactivity of the HPA axis (68) and elevated levels of cortisol are also common (39). It is possible that chronic mild elevations of cortisol levels have a pathogenic role in depression (39). In depressed patients, the ability of cortisol to restrict the activity of HPA axis is reduced, which further reinforces the hyperactivity of the HPA axis
(64). In addition, hypersecretion of corticotrophin-releasing hormone and impairment in responsiveness to glucocorticoids are typical in depression (58). Interestingly, the biological manifestations of mental stress are similar to depression at the biological level (69).
Cytokine effects on behavior are believed to be related in part to their effects on neuropeptide and neurotransmitter functions, synaptic plasticity and neuroendocrine function (66). Specifically, cytokines accelerate the HPA axis and thus reinforce the secretion of cortisol (67,70).
2.4.4 Neurogenesis and neural network hypothesis
Depression has been linked to impaired neurogenesis and information-processing dysfunction within neural networks (71,72). Hypersecretion of cortisol elevates the activation of type II glucocorticoid receptors, which in turn increases the activity of the neurotransmitter glutamate in CNS and may lead to the loss of neurons in hippocampus, a center of mood and memory (64). The challenges in adaptation of neural networks to environmental conditions possibly predispose to MDD (71,72). Brain-derived neurotrophic factor (BDNF) is a critical mediator of activity-dependent neuronal plasticity in the cerebral cortex and deficit of neurotrophic factors have been suggested to cause mood disorders (71). Peripheral levels of BDNF have been found to be decreased in depressed patients (58,73). The network hypothesis suggests that it is not the level of neurotrophins including BDNF alone and directly, but together with environmental conditions that guides neuronal networks to adapt better to the environment (71). The network hypothesis is also related to other hypotheses of depression as low-grade inflammation status and endothelial dysfunction both prevent the expression of BDNF (74).
In summary, the pathogenesis of depression is multifactorial and only partly understood.
There are plenty of biological changes involved in depression. Nevertheless, regardless of several candidates, there is no certain positive biomarker of depression (75). The magnitude of multiple factors in the prevention and the therapeutic potential of other pathways are under investigation.