Substantial evidence supports a role for dysfunction of the serotonin
transporter in the pathogenesis of major depression. Several studies have
found reciprocal interactions between the serotonergic system and both brain-derived
neurotrophic factor and glutamate, which are known to modulate or affect hippocampal
To examine the influence of a polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene on hippocampal
volumes in patients with major depression and healthy controls.
Baseline investigation of a prospective magnetic resonance imaging study
with a 4-year follow-up period.
We examined 40 inpatients with major depression as well as 40 healthy
controls matched for age, sex, and handedness.
Main Outcome Measures
Subjects underwent high-resolution magnetic resonance imaging. Furthermore,
genotyping for the 5-HTTLPR biallelic polymorphism
was performed, which consists of a 44–base pair insertion (L allele) or deletion (S allele).
Patients with the L/L homozygous genotype had
significantly smaller hippocampal gray matter (left hemisphere: P = .003; right hemisphere: P = .01) and white
matter volumes (left hemisphere: P = .001; right
hemisphere: P = .002) than controls with this genotype.
No significant differences were found between patients and controls with the L/S or S/S genotype. Moreover,
patients with the L/L genotype had significantly
smaller hippocampal white matter volumes than those with the L/S or S/S genotype (P =
These findings suggest that homozygosity for the L allele is associated with decreased hippocampal volumes in patients
with major depression but not in healthy controls. A possible explanation
is that the interaction between the serotonergic system and neurotrophic factors
as well as excitatory amino acid neurotransmission may affect hippocampal