Neurobiological mechanisms in major depressive disorder

Neurobiological mechanisms in major depressive disorder

Nearly 1 in 5 people will experience a major depressive episode at some point in their lives. In this review, we discuss data describing how genes, psychosocial adversity in childhood, and ongoing or recent psychosocial stress may impact multiple neurobiological systems relevant to major depressive disorder. Major depressive disorder may be caused by the cumulative effects of these 3 factors on the brain.


A major depressive episode is characterized by a low mood or an inability to experience pleasure (anhedonia), or both, for more than 2 weeks, combined with several cognitive and vegetative symptoms and the occurrence of distress or impairment. A diagnosis of major depressive disorder can be made if a person suffers at least 1 such episode (without ever experiencing mania)Neurobiological mechanisms in major depressive disorder. However, most people with major depressive disorder have multiple episodes. Importantly, several medical illnesses such as diabetes, heart disease, autoimmune disorders and pain are common comorbid diagnoses. The relation between major depressive disorder and these chronic and disabling conditions appears to be bidirectional because one may influence the prognosis of the other.

Investigations into the neurobiology of major depressive disorder have traditionally focused on the monoamine neurotransmitters serotonin and norepinephrine. The monoamine hypothesis initially posited that depressed individuals are likely to have low levels of these neurotransmitters because various antidepressant drugs acutely increase their levels. However, even though monoaminergic antidepressants are generally used for first-line treatment, they do not exert their clinical benefit immediately and for some people they do not provide any benefit at all. We review the neurobiological research that may help explain this.

A revised monoamine hypothesis

Studies on the pathophysiology of major depressive disorder tend to focus on people who are currently depressed. Although informative, data derived from such studies often do not allow for a distinction to be made between cause and effect. These studies also do not allow researchers to distinguish between core mechanisms responsible for the disease and epiphenomena. For example, the finding that the rate of serotonin synthesis may be low in depressed patients can be explained in multiple ways. A reduction in serotonin synthesis may result in depression, depression may result in a reduction in serotonin synthesis, or a third factor may be responsible for both lowering serotonin synthesis rates and triggering depression Neurobiological mechanisms in major depressive disorder.

Experimental studies involving patients whose depression is currently in remission may help clarify the role of serotonin in major depressive disorder. Indeed, one of the few areas of investigation with studies including such patients is concerned with the effects of experimental serotonin manipulations on mood. In most of these studies, patients ingest a tryptophan-deficient amino acid mixture that transiently decreases serotonin levels in the brain, because serotonin is derived from tryptophan Patients taking medications at the time of study may experience a brief relapse, especially if they are taking drugs that affect the serotonin system. Patients not taking any medications are also likely to experience a brief relapse of symptoms during tryptophan depletion, especially if their depression has been in remission for only a few months. This suggests that a lowering of serotonin levels may result in depression Neurobiological mechanisms in major depressive disorder.

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