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Emerging Perspectives: New Stories of How Genes and Life Events Interact in Depression

Conflicting findings might eventually lead to elegant, more accurate explanations of how the serotonin system is involved in depression.

A new story about the genesis of depression has greatly excited the psychiatric community. Evidence supporting this story indicates that individuals with at least one short (s) allele of the promoter region linked to the serotonin transporter (5-HTTLPR) have greater vulnerability to depression in the face of adverse life events than do individuals with two long (l) alleles. Data from several studies identify well-known brain areas that could be involved in the interaction between adverse events and genetic vulnerability; for example, in response to fearsome faces, individuals with an s allele have increased activation of the amygdala,¹ an area already implicated in depression pathophysiology. Most investigators have thought that individuals with an s allele might express less serotonin-transporter protein, and that this difference might confer added vulnerability to depression.

However, the story is still emerging, as seen in the January issue of the American Journal of Psychiatry. Two research papers add fresh information that complicates the story, and the authors and other commentators discuss intriguing hypotheses about how these contradictory findings might eventually form the basis of an augmented, more accurate model.

The first set of findings was no surprise. In a PET study of six brain regions (amygdala, anterior cingulate, hippocampus, midbrain, putamen, and thalamus) in 25 medication-free subjects with current episodes of DSM-IV major depression and 43 healthy comparison subjects, those with depression were found to have less binding potential in the amygdala and midbrain than controls. The authors’ interpretation was that depressed patients have fewer serotonin-transporter sites. The finding was more pronounced in antidepressant-naïve patients than in antidepressant-experienced patients.²

The surprise came when the researchers genotyped the same subjects with a triallelic classification (the s allele and two polymorphisms of the l allele, one of which has been associated with low expression of the serotonin transporter). However, no differences were found in serotonin-transporter binding potential among genotypes or in allelic frequencies in depression and control groups.³

Comment: There might be several ways to reconcile these findings with the emerging story. The authors and editorialists suggest that the alleles might not be directly related to binding potential in adults, but might have had an impact at earlier developmental periods (e.g., possibly by altering patterns of neurogenesis or methylation, perhaps in interaction with early-life stress).⁴ The editorialists also note that serotonin-transporter levels might have different effects on serotonin-transporter–mediated processes involving presynaptic inhibitory 5-HT_1A autoreceptors in midbrain pathways than on serotonin-mediated pathways in the amygdala and prefrontal cortex — clearly, we need to learn more. Finally, at least 10 allelic variants have now been identified for 5-HTTLPR, and all deserve study. What might have been a simple and elegant story may ultimately prove to be elegant, but not quite so simple.

— Joel Yager, MD

Published in Journal Watch Psychiatry January 25, 2006

Citation(s):

1. Hariri AR and Brown SM. Serotonin. Am J Psychiatry 2006 Jan; 163:12.

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• Medline abstract (Free)

2. Parsey RV et al. Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 2006 Jan; 163:52-8.

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3. Parsey RV et al. Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 2006 Jan; 163:48-51.

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• Medline abstract (Free)

4. Sibille E and Lewis DA. SERT-ainly involved in depression, but when? Am J Psychiatry 2006 Jan; 163:8-11.

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• Medline abstract (Free)