What Causes Depression? A Brief Synopsis of Its Multifactorial Etiology

What Causes Depression? A Brief Synopsis of Its Multifactorial Etiology

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Tricia L. da Silva, MA
Graduate student, Institute of Medical Science, University of Toronto

Arun V. Ravindran, MB, PhD, FRCPC, FRCPsych
Professor of Psychiatry, University of Toronto
Chief, Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health

Photograph courtesy of Matthew Wu

Among mental illnesses, depression is the leading cause of disability worldwide and is projected to be the second highest contribution to the global burden of disease by the year 2020, second only to heart disease.(1) It has an estimated lifetime prevalence worldwide of 7-19%, and tends to occur more frequently in women than in men.(2) This highly common mental illness causes significant personal, social and occupational/academic impairment, and there is also substantial cost to society in terms of lost worker productivity and health care resource utilization, which have been estimated at $80-100 billion USD annually.(1)

Depression can manifest in several different forms: unipolar, bipolar, atypical, melancholic, persistent (chronic), postpartum, psychotic, and seasonal.(3) Common symptoms include affective symptoms (such as low mood, irritability, anxiety, and suicidality), cognitive symptoms (i.e. difficulties with concentration, decision making and motivation) and neurovegetative symptoms (changes in appetite, sleep, energy and sexual functioning, and psychomotor changes). However, differences in some phenomenology, such as circumstances of onset, presence of concurrent psychosis, direction of neurovegetative changes, and chronicity, do distinguish between forms of depression.

A wide range of pharmacological and psychological treatments have been developed to treat depression.(4) But in spite of appropriate treatment, about 20-40% of patients are resistant to treatment or experience subsyndromal symptoms, with resulting impact on their functioning and well-being.(5) This is a clinical concern as unremitted depression is associated with higher rates of relapse, poorer quality of life, and increased mortality rates.(5) As a result, there is increasing drive to find more effective treatments and to enhance long-term outcomes for both patients and society.

However, clinicians and researchers also concur that, in order to identify potential new treatments, a better understanding of the etiology of depression is urgently needed. No single cause has been identified for depression, and it is generally agreed that the multiple factors are contributary; these may be biological, psychosocial, or environmental in nature, and likely interact in triggering and maintaining depression. A brief review of some of the key factors is presented below.

Biological factors
Family and twin studies confirm the significant contribution of genetic factors to onset of depression, with heritability estimated at 30-40%.(6) As it is a genetically complex disorder, a wide range of genes are thought to be involved in the pathophysiology of depression, and among them, the serotonin transporter gene and the tryptophan hydroxylase genes (involved in the synthesis of serotonin) are thought to be particularly relevant.(6)
Altered activity of neurotransmitter systems and the hypothalamic-pituitary-adrenal (HPA) axis have also been implicated in depression. Neurotransmitters (e.g. serotonin, norepinephrine, and dopamine) moderate mood, as well as the physiological and cognitive symptoms of depression, while the hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the stress response and regulation of mood/emotion.(6,7) Altered monoaminergic and HPA axis activity have been shown to be associated with depression, but the type of association may vary in different subtypes of depression.(6,7)

Monoaminergic activity may also play a role in depression in another way. Patients with other medical illnesses, e.g. heart disease, stroke, Parkinson’s Disease, and Alzheimer’s Disease, often present with clinical depression, as well.(8) Similarly, a number of medications used to treat physical and mental illnesses have been noted to induce depression.8 It has been proposed that the emergence of depression in these contexts is likely mediated by the monoaminergic neurotransmitter systems.(8)

Hormonal abnormalities have also been linked to depression. Adrenocorticotropic hormone (ACTH), thyroid hormones, and estrogen all modulate neurotransmitter activity.(6,8) Cushing’s Disease (characterized by ACTH overproduction) and thyroid hormone deficiency are known to present with depression-like symptoms.(6) Further, fluctuation in estrogen levels over the lifespan has been proposed as a possible risk factor for depression in women.(6,8) Alterations in estrogen levels (e.g. at the start of the menstrual cycle, in the postnatal period or during (peri)menopause) is said to result in monoamine changes and to increase their vulnerability to depression.(8)

Psychological factors
The cognitive theory of depression suggests that maladaptive cognitive processes, reflected in a self-perpetuating cycle of negative thoughts/interpretations (about the self, life, and the future), emotions and behaviors, may play a key role in depression.(9) Indeed, those with a negative outlook have been found to report lower mood following a negative event than others, and a negative mind-set has also been noted in depressed individuals.(9) Whether a negative cognitive bias is a cause or result of the illness is still a matter of debate, but its association with depression is the basis for cognitive therapy, a proven effective treatment for depression.

Related to this, certain personality traits are also seen as increasing vulnerability to depression. Individuals who display high levels of neuroticism (i.e. a tendency toward negative mood states such as anxiety, envy, jealousy, moodiness), have been found to be more prone to developing depression.6 In contrast, those high in extroversion or openness to experience appear less likely to do so.

Learned helplessness is another proposed causative model for depression. It is thought that repeated exposure to stress reduces personal sense of control over such events in vulnerable individuals, inducing to a sense of helplessness and perceived lack of self-efficacy, and in turn, inability or lack of motivation to avoid stress.10 Learned helplessness has been found to correlate with depression and impaired performance and also to predict changes in depression over time.(10)

The ability to cope with stress also plays a role in depression. Maladaptive (emotion-focused) coping style predicts depression and stress, while adaptive (problem-focused) coping is associated with lower incidence of these symptoms, as well as better resilience and functioning.(11)

Social/Environmental factors
Stressful life events are a widely accepted social/environmental contributor to depression, and depressed individuals report an increase in both major and minor life events and ‘daily hassles’.(6) Childhood abuse (particularly sexual abuse) or neglect, experience of trauma (to self or others), bereavement, or major life transitions (e.g. going to university, losing a job, ending a romantic relationship) have all been correlated with depressive onset.(6) Poverty, as well as other adverse social determinants, such as physical illness, poor working conditions or lack of social support, are also associated with increased risk of depression.(8)

Among other social factors, marital status may be a protective influence for men, as higher rates of depression have been reported in single men than married men.8 For women, having children at a young age, being at home with several children, and lack of adequate social support, all appear to increase risk of depression.

Multifactorial Interaction in Contribution to Depression
The biological, psychosocial and environmental factors described above do not act in isolation. They interact to increase the overall vulnerability to depression, which may also contribute to subtype, severity and chronicity. Some such interactions are described below.

For example, neurotic individuals may be more likely to experience negative life events, either because they perceive events more negatively, or act/react in a way that worsens situational impacts on them, which increases their risk of depression.(6) Neuroticism also appears to predict the type and incidence of negative life events experienced. Similarly, childhood abuse has been correlated with higher neuroticism, more negative events experienced in adulthood, and higher rates of depression.(6) These phenomena demonstrate a “nature-nurture” contribution to depression, as temperament is heritable to a large degree.

In a similar vein, emotional neglect and abuse has been noted to produce a permanent sensitization of the HPA axis in very young children.(6) By extension, such neglect/abuse also has a permanent (deleterious) effect on the activity of neurotransmitter systems involved in mood regulation. Together, these neurobiological changes negatively influence stress reactivity and emotional response, thereby intensifying experiences of stressors and risk of depression. However, it is also of note that the base reactivity of the HPA axis at birth is genetically determined, and post-birth experiences serve to heighten or reduce its sensitivity.(6) As a result, some individuals may have a predisposition to stress sensitivity and depression that is exacerbated (not triggered) by negative childhood experiences. This overlapping gene-environment interaction can have profound lifelong consequences for vulnerable individuals.

In addition, children of depressed parents have been found to exhibit more negative self-perceptions, hopelessness and pessimism in response to interpersonal conflicts than other children, perhaps reflecting a learned response to stressors.(6) Since maladaptive coping styles and cognitive outlooks are both strongly linked to depression,(9-11) the interaction between genetic vulnerability (based on family history) and learned negativity (via modeling) may further heighten risk of depression.

Multiple factors (biological, psychological, social/environmental) contribute to increased vulnerability to depression,(6-8) which often results in significant functional impairment in both the short-and long-term outcomes, and also higher risk of early mortality.(1) Further exploration of these factors will help greatly to improve patient management and treatment (both pharmacological and psychological), as well as in prevention strategies.


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