The malaise theory of depression: major depressive disorder is sickness behavior and antidepressants are analgesic

Med Hypotheses. 2000 Jan;54(1):126-30. doi: 10.1054/mehy.1999.0986.


The malaise theory of depression constitutes a re-conceptualization and re-definition of major depressive disorder (MDD). It is proposed that the state or emotion of malaise should be considered the core symptom of depression, rather than sadness of mood. The syndrome of MDD is identified as a consequence of inappropriate sickness behavior mediated by immune activation including abnormalities in cytokines. Antidepressants are suggested to exert their specifically beneficial effects through an analgesic effect on the core dysphoric symptoms of malaise. These ideas are consistent with a substantial body of published literature and lead to a wide range of testable predictions.

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Cytokines / physiology
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / physiopathology*
  • Humans


  • Antidepressive Agents
  • Cytokines