The exact pathogenesis of major depressive disorder is not fully understood. However, it is thought that major depressive disorder is the result of decreased levels of serotonin, norepinephrine, and dopamine.

• The exact pathogenesis of major depressive disorder is not completely understood; however, following etiologies have been suggested to play a role in the development of major depressive disorder.
  • 1. Neurotransmitters
    • Serotonin: Serotonin depletion has been most commonly shown to be associated with depression. ^[1] For this reason, serotonergic agents are first-line treatment of major clinical depression.
    • Norepinephrine: Abnormal norepinephrine metabolites have been shown in blood, urine, and CSF in patients with major depressive disorder. ^[2] Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine) increase both serotonin and norepinephrine levels and are used as the firs-line treatment of major depressive disorder.
    • Dopamine: Major depressive disorder may be associated with decreased dopaminergic activity. ^[3] It has been suggested that patients with major depressive disorder may have dysfunctional masolimbic dopamine pathway and/or hypoactive dopamine D1 receptors. Reduced dopamine concentrations with drugs (e.g. reserpine) or certain pathologic conditions (e.g. Parkinson’s disease) have been linked to symptoms of depression. In addition, drus increasing dopamine concentrations, such as amphetamine, bupropion, and tyrosine can reduce depressive symptoms.
  • 2. Psychosocial
  • 3. Cognitive: Cognitive theory of Aaron Beck describes a triad of 1) negative self-view 2) negative interpretation of experience and 3) negative view of future. Closing </ref> missing for <ref> tag
  • 4. Learned helplessness: Based on this theory, depression is linked to an individual’s inability to control events.
  • 5. Stressful life events: Stressful life events may result in permanent neuronal alterations, subsequently predisposing an individual to mood disorders. The most often associated life event linked to the development of depression is losing a parent before age 11.