The principal finding of this study is that depressed elderly individuals with low serotonin transporter expressing 5-HTTLPR alleles (S carriers or S') have more microstructural white matter abnormalities in frontolimbic and other regions and are less likely to achieve remission of depression than L homozygotes. To our knowledge, this is the first study to demonstrate an association between 5-HTTLPR allele status and microstructural frontolimbic white matter abnormalities in depression. The depressed subjects of this study had more microstructural white matter frontolimbic abnormalities than normal controls. This observation suggests that our sample was similar to those of studies that documented microstructural white matter abnormalities in depressed patients (Nobuhara et al., 2006
The mechanisms by which low transcribing 5-HTTLPR allele status may lead to low remission rate are unclear. However, some abnormalities in serotonin-related functions have been documented in S carriers compared to L homozygotes. These include blunted neuroendocrine response to serotonin function probes (Reist et al., 2001
), lower platelet serotonin uptake (Greenberg et al., 1999
) lower concentrations of the serotonin metabolite 5-hydroxy-indolo-acetic acid (Williams et al., 2003
) and lesser decrease in right and greater decrease in left cortical metabolism in response to citalopram administration in S carriers compared to the LL subjects (Smith et al., 2004
). These findings parallel the differences found in comparing depressed elderly patients to age-matched controls (Smith et al., 2002
5-HTTLPR polymorphisms may influence brain structures. Steffens et al observed that depressed elderly patients with SL genotype have more total brain lesions and white matter lesions than depressed L and S homozygotes (Steffens et al., 2008b
). In our sample, only one of the S allele carriers was an S homozygote. Thus the association between S allele status and reduced fractional anisotropy was mainly due to our SL subjects and thus consistent with the Steffens et al report. Moreover, S-allele elderly carriers with major depression had lower caudate nucleus volume than L homozygotes (Hickie et al., 2007
). Finally, non-depressed S carriers had reduced gray matter in the perigenual cingulate and amygdala and increased sensitivity in processing fearful stimuli (Pezawas et al., 2005
The relationship of low serotonin transporter expressing alleles to microstructural white matter abnormalities may be multi-determined. Serotonin signaling is a regulator of adult neurogenesis (Gould, 1999
) and is influenced by the serotonin transporter. Low serotonin transporter expressing 5-HTTLPR alleles account for more than 30% of the variance in depression severity directly and by increasing the impact of life events (Zalsman et al., 2006
). The S allele increases the likelihood of developing depression in the presence of stress (Caspi et al., 2003
). S-allele carrier status interacts with waking cortisol and is associated with impaired memory and lower hippocampal volume (O'Hara et al., 2007
). These observations suggest that the S allele confers increased vulnerability to hyperactivity of the hypothalamic-pituitary-adrenal axis. Finally, some 5-HTTLPR polymorphisms are associated with increased risk for vascular disease. SL-allele status increased cholesterol, triglycerides and risk for heart disease, angina, and heart attacks in individuals aged 50–70 years (Comings et al., 1999
). Moreover, cardiac events including cardiac death, revascularization, heart failure, reinfarction, arrhythmia, and unstable angina were more frequent after acute myocardial infarction in S-allele carriers than in L homozygotes (Nakatani et al., 2005
). This effect was in part mediated by depressive symptoms.
In our sample, taking vascular risk factors into consideration did not change the relationship of S carrier status to FA abnormalities. Vascular risk factors have an indirect relationship with cerebrovascular damage (Wolf et al., 1991
). Therefore, the association between S carrier status and FA abnormalities may be due to factors other than vascular. Alternatively, S carrier status may promote vascular damage regardless of presence or absence of vascular risk factors.
FA differences between S-allele careers and L homozygotes were most pronounced in depressed patients compared to controls. This finding suggests that the S allele may interact with factors associated with geriatric depression to promote FA abnormalities above and beyond those of normal subjects. These interactions are likely complex. First, low transporter expressing alleles may increase neuronal vulnerability to hypothalamic-pituitary-adrenal axis (HPA) hyperactivity or to vascular changes occurring during depression, thus leading to microstructural white matter abnormalities. Second, S carriers are more likely to have compromised cerebrovascular integrity than L homozygotes (Comings et al., 1999
; Nakatani et al., 2005
) and thus present more microstructural white matter abnormalities. Finally, microstructural white matter abnormalities in S-allele carriers may result from a combination of cerebrovascular compromise (a state predisposing to depression) (Alexopoulos, 2005
) and increased sensitivity to hypercortesolemia of the S allele carriers during depressive episodes.
The small number of subjects does not permit an examination of whether the association between S-allele status and low remission rate is mediated by frontolimbic white matter abnormalities. However, similar structural brain abnormalities have been associated with poor outcomes of late life depression. We reported that low FA in several corticolimbic white matter areas predict low remission rates in depressed elderly patients treated with citalopram (Alexopoulos et al., 2002
) and escitalopram (Alexopoulos et al., 2008
). Similarly, white matter hyperintensities have been associated with chronicity of geriatric depression (Simpson et al., 1998
) although negative findings also exist (Salloway et al., 2002
). Basal ganglia lesions predicted failure to respond to antidepressants (Patankar et al., 2007
). Finally, lesions in subcortical grey matter predict poor outcome of geriatric depression over a 5 year period (Steffens et al., 2005
Some of the metabolic changes in corticolimbic systems occurring during depression are restored with improvement of depression. Remission of depression is associated with metabolic increases in dorsal cortical regions (Drevets, 2000
). In contrast, decreases in ventral limbic and paralimbic structures, i.e. subgenual cingulate, ventral mid- and posterior insula, hippocampus and hypothalamus occur during remission (Mayberg et al., 1999
). ACC metabolic abnormalities occurring during depressive episodes are normalized during remission (Mayberg et al., 1999
). Rostral ACC hypermetabolism subsides after response to antidepressants (Mayberg et al., 1997
), ECT (Nobler et al., 2001
), or sleep deprivation (Smith et al., 1999
), and cognitive behavioral therapy (Goldapple et al., 2004
). A potential explanation of our findings is that some of the corticolimbic abnormalities of S-allele carriers interfere with the reciprocal neocortical-subcortical regulation and contribute to poor antidepressant response. Another contributor to non-remission may be the increased amygdala activation in response to negative stimuli reported in S allele carriers (Munafo et al., 2008
). Amygdalar hyper-reactivity may be another source of neocortical-subcortical imbalance (Hariri et al., 2006
) added to microstructural abnormalities of S allele carriers and complicating re-equilibration.
The findings of this study should be viewed in the context of its limitations. These include the small number of subjects, the lack of random sampling, the subject selection bias inherent in imaging studies (healthier patients are likely favored), the fixed dose of the antidepressant, and the absence of long-term follow-up. It is likely that some subjects may have remitted if treated with higher dosages of escitalopram or longer treatment was offered. However, the only two non-remitted subjects who exited the trial prematurely received escitalopram for 9 and 11 weeks. Moreover, there were no significant differences at baseline between remitters and non-remitters in variables associated with prediction of treatment resistance. The absence of population stratification is also a limitation of the present study but the small sample size of this study prevents a meaningful application of currently available methods for the identification of and correction for population substructure. Finally, our observations may be influenced by the large number of comparisons, as voxelwise analysis increases the risk of Type I error. To address this potential problem, we used a white matter mask to reduce the number of comparisons. We also applied a rather conservative threshold and cluster size requirement for additional protection over Type I error.
While this study found a relationship between S allele carriers and low remission rate following treatment with an SSRI, the literature suggests that the effect size of this relationship is small (Munafo et al., 2008
). Overall, SSRIs are well tolerated and effective in the elderly (Solai et al., 2001
), including patients with post-stroke depression (Starkstein et al., 2008
). Furthermore, a recent study has shown that prophylactic use of the SSRI escitalopram in stroke patients reduced the incidence of depression over 12 months of treatment compared to placebo (Robinson et al., 2008
). A theoretically, appealing observation is that paroxetine was shown to decrease beta-thromboglobulin and platelet factor 4 suggesting that it may reduce platelet aggregation and perhaps exert a protective effect on vasculature (Pollock et al., 2000b
). Moreover, paroxetine was shown to decrease platelet serotonin, an effect most pronounced in S allele carriers (Abdelmalik et al., 2008
). Nonetheless, use of SSRIs does not reduce the progression of white matter lesions in older adults over a period of 5 years (Steffens et al., 2008a
). These findings suggest that the risk-benefit of using SSRIs in depressed elderly S allele carriers needs further evaluation.
This study suggests that elderly S-allele carriers with major depression have both a low remission rate and microstructural white matter abnormalities in several areas including areas of frontolimbic networks. Microstructural abnormalities in these areas have been associated with low remission rates of geriatric depression (Alexopoulos et al., 2008
). It remains unclear whether the risk for chronicity of geriatric depression in S-allele carriers is mediated by frontolimbic compromise along with other mechanisms. Nonetheless, these observations can be used as the basis of studies aiming to identify the relationship of the S allele to impairment in specific frontolimbic functions interfering with response of geriatric depression to antidepressants.