What are the possible causes of clinical depression? The fact is, despite decades of research into this question, scientists at the U.S. National Institute of Mental Health and research universities around the world still don’t really know the cause of depression.

It is generally believed that all mental disorders — including clinical depression — are caused by a complex interaction and combination of biological, psychological, and social factors. This theory is called the bio-psycho-social model of causation and is the most generally accepted theory among mental health professionals and researchers of the cause of disorders such as depression.

More recent research also points to the overlooked importance of the gut’s microbiome — the types and quantities of important bacteria that live in our digestive systems. It appears that the health or imbalance of certain bacteria may contribute to or even cause mood disorders like depression.

Some types of major depression run in families, suggesting that a biological vulnerability can be inherited. This seems to be the case more so with certain types of mental illness, such as bipolar disorder and schizophrenia (NIMH, 2019).

Studies of families in which members of each generation develop bipolar disorder — one component of which is clinical depression — found that those with the illness have a somewhat different genetic makeup than those who do not get ill. However, the reverse is not true: Not everybody with the genetic makeup that causes vulnerability to bipolar disorder will have the illness. Apparently additional factors, possibly stresses at home, work, or school, are involved in its onset.

In some families, major depression also seems to occur generation after generation — which points to both genetic and parental factors (as parents generally teach their children the same coping skills and psychological coping techniques they themselves learned). However, it can also occur in people who have no family history of depression. Whether inherited or not, major depressive disorder is often associated with changes in brain structures or brain function.

People who have low self-esteem, who consistently view themselves and the world with pessimism, or who are readily overwhelmed by stress, are prone to depression. Whether this represents a psychological predisposition or an early form of the illness is not clear.

Gene x Environment Model of Depression

What researchers do have are a lot of different models and theories about what causes depression. Muneer (2018) suggests one such model (above) about how sets of genes that have been implicated in the cause of this condition might interact with other factors, such as the environment, that leads to depression. In this theory, all of these components either predispose a person for depression, protect them from depression, or put them at greater risk for being diagnosed with it:

  • Candidate gene sets: 5-HTTLPR, CB1, TPH2, CREB1, BDNF, COMT, GIRK, HTR1A, HTR2A.
  • Personality/temperamental factors (predisposing toward depression): neuroticism, rumination, stress vulnerability, impulsivity, negative cognitive style.
  • Personality/temperamental factors (protective against depression): openness, trust, acceptance, stress coping.
  • External factors: early life events, provoking life events, seasonal changes, social support.
  • Internal factors: hormones, biological rhythm generators, comorbid disorders

In recent years, researchers have shown that physical changes in the body can be accompanied by mental changes as well. Medical illnesses such as stroke, a heart attack, cancer, Parkinson’s disease, and hormonal disorders can cause depressive illness, making the sick person apathetic and unwilling to care for his or her physical needs, thus prolonging the recovery period. Also, a serious loss, difficult relationship, financial problem, or any stressful (unwelcome or even desired) change in life patterns can trigger a depressive episode. Very often, a combination of genetic, psychological, and environmental factors is involved in the onset of a depressive disorder.

While we don’t yet know the exact cause of clinical depression, it’s important to realize that even without understanding its specific causes, a person can still receive effective treatment.