Letters to the Editor
Hypothalamic–Pituitary–Adrenal Function and Preventing Major Depressive Episodes
Dear Editor:
Depression is associated with dysregualtion of the hypothalamic–pituitary–adrenal (HPA) axis (1,2). HPA axis dysfunction can produce repeated episodes of hypercortisolemia in depression. Prolonged exposure to elevated cortisol levels may be neurotoxic, especially for brain regions rich in corticosteroid receptors, and may mediate neuronal vulnerability to stressors. Recurrent depression is associated with atrophy of the hippocampus and amygdala (3,4) and the prefrontal cortex (5). Gradual deterioration of hippocampal feedback inhibition of the HPA axis, owing to down-regulation of glucocorticoid receptors from repeated stress, has been demonstrated (6). A recent study has found that an increase in the number of major depressive episodes (MDEs) increases cortisol responses to fenfluramine administration (7). A study of first-episode patients identified memory impairment on neuropsychological testing but no hippocampal volume loss, whereas multiple-episode patients in the same study had both memory impairment and volume loss (8). The results of these and other studies underline the importance of preventing recurrent MDEs.
Antidepressants prevent recurrent MDEs and have a neuroprotecive effect (3,4,9). However, the prevention of MDEs should not be exclusively focused on antidepressive medications. Different types of psychological therapy, social help, vocational rehabilitation, light therapy, exercise, and complementary and alternative treatments may help to prevent recurrent MDEs. For example, mindfulness-based cognitive therapy (MBCT), a group intervention designed to train patients who have recovered from recurrent depression to disengage from dysphoria-activated depressogenic thinking, may prevent relapse or recurrence of depression in patients with a history of 3 or more MDEs (10).
Relapse and recurrence rates for patients with major depression and comorbid psychiatric and medical disorders are greater than rates among patients with depression alone (9). For example, personality disorders may substantially contribute to relapse and recurrence of depression. Therefore, it is important to treat comorbid conditions such as alcohol and substance abuse, personality disorders, and physical illnesses.
References
1. Gold PW, Drevets WC, Charney DS. New insight into the role of cortisol and the glucocorticoid receptors in severe depression. Biol Psychiatry 2002;52:381–5.
2. Sher L, Mann JJ. Psychiatric pathophysiology: mood disorders. In: Tasman A, Kay J, Lieberman JA, editors. Psychiatry. Chichester (UK): John Wiley & Sons, 2003, p 300–15.
3. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry 2003;160:1516–8.
4. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 2003;54:338–52.
5. Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M, and others. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997;386:824–7.
6. McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995;5:205–16.
7. Sher L, Oquendo MA, Galfalvy HC, Cooper TB, Mann JJ. Age effects on cortisol levels in depressed patients with and without a history of posttraumatic stress disorder, and healthy volunteers. J Affect Disord. Forthcoming.
8. MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, and others. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA 2003;100:1387–92.
9. Segal ZV, Pearson JL, Thase ME. Challenges in preventing relapse in major depression. Report of a National Institute of Mental Health workshop on state of the science of relapse prevention in major depression. J Affect Disord 2003;77:97–108.
10. Teasdale JD, Segal ZV, Williams JM, Ridgeway VA, Soulsby JM, Lau MA. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. J Consult Clin Psychol 2000;68:615–23.
Leo Sher, MD
New York, New York
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