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Reduced Hippocampal Volumes Associated With the Long Variant of the Serotonin Transporter Polymorphism in Major Depression
Thomas Frodl, MD;
Eva M. Meisenzahl, MD;
Peter Zill, MD;
Thomas Baghai, MD;
Dan Rujescu, MD;
Gerda Leinsinger, MD;
Ronald Bottlender, MD;
Cornelius Schüle, MD;
Peter Zwanzger, MD;
Rolf R. Engel, MD;
Rainer Rupprecht, MD;
Brigitta Bondy, MD;
Maximilian Reiser, MD;
Hans-Jürgen Möller, MD
Arch Gen Psychiatry. 2004;61:177-183.
Background 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 morphologic characteristics.
Objective 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.
Design Baseline investigation of a prospective magnetic resonance imaging study with a 4-year follow-up period.
Patients 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).
Results 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 = .03).
Conclusions 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 morphologic characteristics.
From the Departments of Psychiatry (Drs Frodl, Meisenzahl, Zill, Baghai, Rujescu, Bottlender, Schüle, Zwanzger, Engel, Rupprecht, Bondy, and Möller) and Radiology (Drs Leinsinger and Reiser), Ludwig-Maximilians-University of Munich, Munich, Germany.
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