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From Chemical Imbalance to Neurogenesis

Posted by plosmedicine on 30 Mar 2009 at 23:50 GMT

Author: 'David' 'Antonuccio'
Position: Professor
Institution: University of Nevada School of Medicine
Submitted Date: February 15, 2006
Published Date: February 22, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

Jeff Lacasse and Jonathan Leo offer a cogent critique of the theory that depression is caused by a chemical imbalance related to serotonin (Leo & Lacasse, 2005). The lack of support for this theory may be one reason physicians do not typically order lab tests of serotonin levels in depressed patients. However, the chemical imbalance theory of depression may be morphing into the neurogenesis theory of depression, i.e., the notion that there is a deficiency of neurons in the hippocampus of the brain and that antidepressants work by helping the brain generate new neurons thought to affect mood (for example, Malberg et al., 2000; Santarelli et al., 2003). While the neurogenesis hypothesis may be a reasonable hypothesis, there are at least two questions that must be answered to understand how neurogenesis might affect depression. One is to explain what role neurogenensis might play in the positive response of many depressed patients who are randomly assigned to receive a placebo, a group that does about 82% as well as those randomly assigned to receive an antidepressant (Kirsch et al., 2002). Another question has to do with whether neurogenesis is always a good thing and whether it might even be harmful under some circumstances.


Lacasse, J., Leo, J. (2005). Serotonin and depression: A disconnect between the advertisements and the scientific literature. PLoS Med, 2 (12), e395.

Kirsch, I., Moore T.J., Scoboria, A., & Nicholls, S.S. (2002), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment. 5:Article 23. Available at:

Malberg, J.E. et al., (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. The Journal of Neuroscience, 20, 9104-9110.

Santarelli, L. et al., (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805-809.

Competing interests declared: University of Nevada School of Medicine; Reno V.A. Medical Center; author of smoking cessation book Butt Out; past recipient of NIDA and NCI funding for smoking cessation research; past recipient (1995) of funding from Marion Merrill Dow for research on the nicotine patch; workshops on the treatment of depression; expert witness