What is the pathophysiology of depression?

Updated: Sep 02, 2020
  • Author: Louise B Andrew, MD, JD; Chief Editor: Barry E Brenner, MD, PhD, FACEP  more...
  • Print


Depression is thought to involve changes in receptor-neurotransmitter relationships in the limbic system, as well as the prefrontal cortex, hippocampus, and amygdala. Serotonin and norepinephrine are thought to be the primary neurotransmitters involved, but dopamine has also been related to depression.

Typically, neurotransmitters are passed from neuron to neuron; subsequently, either they are reabsorbed into the neuron—where they are either destroyed by an enzyme or actively removed by a reuptake pump and stored until needed—or they are destroyed by monoamine oxidase (MAO) located in the mitochondria.

A decrease in the functional balance of these neurotransmitters causes certain types of depression (ie, decreased norepinephrine causes dullness and lethargy, and decreased serotonin causes irritability, hostility, and suicidal ideation).

Environmental factors, including coexisting illnesses or substance abuse, may affect neurotransmitters and/or have an independent influence on depression.

Alterations in the balance of neurotransmitters and/or their function include the following:

  • Impaired synthesis of neurotransmitters

  • Increased breakdown or metabolism of neurotransmitters

  • Increased pump uptake of neurotransmitters

In addition to localizable brain chemical changes, it is likely that gene-environment interactions, as well as endocrine, immunologic, and metabolic mediators, play a part in the development of depression. [11]

Studies have revealed a strong link between depression and migraine with aura, which is explained at least in part by genetic factors. [12] In addition, a reciprocal link exists between obesity and depression. [13]

Bipolar disorder has a prominent depressive component but is a different clinical entity from depression. There is a possible defect on chromosome II or X, but current genetic research is inconclusive.

Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!