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Warren D. Taylor, MD; David C. Steffens, MD; Martha E. Payne, MPH, RD; James R. MacFall, PhD; Douglas A. Marchuk, PhD; Ingrid K. Svenson, PhD; K. Ranga R. Krishnan, MD

Arch Gen Psychiatry. 2005;62:537-544.

Context  Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) influence transcription and may play a role in the pathogenesis and course of depression. Recent research demonstrates that specific polymorphisms may be associated with differences in hippocampal volumes in subjects with depression.

Objective  To examine associations between 5-HTTLPR genotype and hippocampal volumes in elderly control subjects and elderly subjects classified as having early or late onset of depression.

Design  Cohort study examining baseline characteristics.

Participants  Subjects were community dwelling and 60 years or older. Using a definition of early-onset depression as depression first occurring at 50 years or younger, we examined 72 subjects with early-onset depression, 63 subjects with late-onset depression, and 83 healthy control subjects.

Main Outcome Measures  All subjects underwent genotyping for the 5-HTTLPR and underwent brain magnetic resonance imaging. Analyses of hippocampal volumes were controlled for total cerebral volume, age, and sex.

Results  The interaction between diagnosis and 5-HTTLPR genotype was statistically significant for the right hippocampus (P = .04). Subjects with late-onset depression who were homozygous for the long (L) allele (L /L genotype) had significantly smaller right hippocampal volumes than did L /L subjects with early-onset depression (P = .046) or L /L control subjects (P = .01). Post hoc analyses showed that later age of depression onset was associated with smaller hippocampal volumes in subjects with the L /L genotype, but earlier age of onset was associated with smaller hippocampal volumes in subjects who were homozygous for the short (S) allele (S/S genotype).

Conclusions  Subjects with late-onset depression who were homozygous for the L allele exhibited smaller hippocampal volumes than other groups. Genotype also mediated the effect of age of onset on hippocampal volumes. Our findings differ from previous work; however, we examined an older and larger cohort of subjects than previous studies. Possible explanations for these findings include interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses, each of which may affect hippocampal volumes.

Author Affiliations: Departments of Psychiatry (Drs Taylor, Steffens, and Krishnan and Ms Payne), Radiology (Dr MacFall), and Molecular Genetics and Microbiology (Drs Marchuk and Svenson), Duke University Medical Center, Durham, NC.

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