Psychopharmacology 3e Web Box 18.2 - Pharmacology in Action: Stress–Diathesis Model of Depression

Nemeroff and colleagues (1998) developed a model of mood disorders called the stress–diathesis model of depression, which refers to the interaction between early experience (stresses such as abuse or neglect) and genetic predisposition (diathesis). In essence, they propose that the genetic character of depression is expressed in lowered monoamine levels in the brain or in increased reactivity of the HPA axis to stress. These factors create a lower threshold for depression. In addition, they believe that negative, stressful events early in life may lower the threshold even further, leaving the individual more vulnerable to depression as an adult. To test the model, one would have to show that early stress not only produces immediate activity of the HPA axis but also causes persistent activation of CRF-containing neurons. If such were the case, these individuals would respond more strongly to stress as adults than control subjects.

The design to test the model used newborn rats that were stressed by being removed from their mothers for brief periods daily for 10 days of their first 21 days of life. They were then allowed to grow up under standard conditions. The results showed that as adults, the deprived rats had elevations in stress-induced ACTH and cortisol and increased CRF in the brain. A permanent increase in CRF gene expression explains the increase in CRF production. Despite the higher levels of CRF, the studies also found increased CRF receptor density, which might be expected to produce long-term enhancement of stress and CRF-induced depression. More recently, other researchers in the same group observed that antidepressant drug treatment prevented the increase in CRF and reduced the fearful behaviors (e.g., freezing in novel situations) normally exhibited by the rats. When treatment was terminated, all the abnormalities returned. How the blocking of 5-HT reuptake with the antidepressant modifies the CRF axis is not immediately evident but is certainly the focus of future research.

The implications of this type of research are very clear. Several million children are abused or neglected in the United States each year. Based on the animal evidence, we would expect these children to be exposed to events that permanently modify their developing brains, leaving them more vulnerable to stress and depression as adults.

The research also suggests a new direction for antidepressant drug development and therapeutic regimens. The reemergence of biological abnormalities after termination of drug treatment suggests that treatment may need to be continued indefinitely to prevent the recurrence of depressive episodes. Also, the potential to develop a new class of antidepressants that block CRF receptors could lead to a new therapeutic approach to the treatment of at least some patients with depression.



Nemeroff, C. B. (1998). The neurobiology of depression. Sci. Am., 278, 42–49.