Poststroke depression and 5-HTTLPR

Subsequent to the seminal paper in 2003 by Caspi et al,1 who reported that a 44 base pair insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTT) gene (SLC6A4) moderated the relationship between stressful life events (SLEs) and depression, over 50 studies have sought to replicate this specific gene-environment interaction. In Caspi et al's original work, carriers of the short (s), transcriptionally less active, allele of a common genetic variant often referred to as the 5-HTT-linked polymorphic region (5-HTTLPR) exhibited more depressive symptoms and suicidality in response to environmental adversity and childhood maltreatment.

Poststroke depression (PSD) has been estimated to affect at least 30% of stroke survivors at any time during follow-up.2 PSD has been linked to clinically adverse outcomes such as increased mortality3 and poorer long-term functional recovery.4 The pathogenesis of PSD still remains undetermined. Various lines of evidence suggested that 5-HTTLPR polymorphism may be implicated in PSD. The association of PSD with abnormalities in central serotonergic responsiveness5 and the fundamental role of 5-HTT gene expression in regulating serotonergic signalling6 led to the hypothesis that the moderating effect of 5-HTT functional polymorphism on a major life event like stroke may be critical to the development of PSD. Subsequent findings confirmed this early hypothesis.7 and even indicated an association with other 5-HTT polymorphisms such as the variable number of tandem repeats in the second intron 2.8

In a recent issue of this journal, a meta-analysis of four studies reported a positive and significant association between the 5-HTTLPR short variant genotype and PSD. No effect was observed for other 5-HTTLPR polymorphisms such as the single-nucleotide polymorphism rs 25531 and variable number of tandem repeats in the second intron 2.9 Unfortunately the lack of consistent measures of environmental adversity in the pooled studies precluded the assessment of the interaction between stroke, stress and genotype. Another limitation acknowledged by the authors is the presence of potential confounding factors such as publication bias, gender, ethnicity and season of birth, which may undermine the generalisability of the results. Moreover, since preliminary findings indicated that other gene polymorphisms such as the BDNF val66met polymorphism may be involved in the pathogenesis of PSD,10 the relationship between 5-HTTLPR and other functional polymorphisms should be further explored.

Of particular interest is the recent report that s allele carriers may be more likely than l carriers to benefit from psychological interventions for PSD.11 This finding is in line with an earlier study, which documented that the s/s genotype in maltreated children was linked to increased benefit from social supports.12 It can thus be argued that the 5-HTT gene polymorphism may not determine stress susceptibility but instead may enhance sensitivity to environmental stimuli in general.13

It is worth noting that the 5-HTT gene functional polymorphism has been reported to modify the risk for depression in other medical conditions such as irritable bowel syndrome,14 chronic coronary disease15 and after hip fracture in the elderly.16 There is also evidence that 5-HTTLPR may influence the risk of stroke. Reduced central serotonergic responsivity has been linked to stroke risk factors such as metabolic syndrome,17 hypertension18 and preclinical carotid artery atherosclerosis.19 More recently, 5-HTTLPR has been shown to moderate cardiovascular reactivity to social stress20 and has been found to be independently associated with increased body mass index level and obesity in non-elderly stroke patients.21

In addition to the 5-HTT gene polymorphism, other possible causal pathways of PSD have been proposed. In a review of current hypotheses about the pathophysiology of PSD Santos et al22 contended that the cumulative burden of vascular brain pathology may give rise to depressive symptoms in stroke survivors.22 Furthermore, growing evidence that low-grade inflammation is associated with depression23 has led some authors to postulate an involvement of proinflammatory cytokines in PSD,24 even although conclusive data are still lacking. Robinson and Bloom25 suggested that interruption by ischaemic lesions of the catecholamine-containing pathways ascending from the brain stem to the cerebral cortex may be implicated in the genesis of apathy and depression after a stroke.25 With regard to lesion location theories, establishing an association between localisation of stroke and onset of depressive symptoms has so far proved elusive.26 ,27 As far as the role of psychosocial factors is concerned, the assumption that PSD may predominantly represent a psychological response to functional disability following stroke was called into question by an early report that when compared with orthopaedic patients with similar level of disability stroke survivors still exhibited a greater rate of depression.28 Nonetheless, psychosocial factors such as social isolation following stroke would appear to be a major determinant of late onset PSD.22

With regard to major depression, an inconsistent pattern of findings in replication studies has raised uncertainty over the moderating effect of 5HTTLPR on life stress. The debate over the role of the 5-HTT gene polymorphism has been made even more controversial by recent attempts to systematically review the accumulated evidence. Indeed, contrary to previous meta-analyses29 ,30 yielding evidence of no or small effect of 5-HTTLPR polymorphism on depression vulnerability, Karg et al31 conducted a more inclusive meta-analysis of 54 studies and found robust evidence that 5-HTTLPR moderates the relationship between stress and depression.31 The authors reported a particularly strong association between the s allele and increased susceptibility to depression in the context of childhood maltreatment and physical illness, thus suggesting that definition of specific stressors may help reduce the variability between studies.

In a review of candidate gene by environment interaction studies Duncan et al32 demonstrated that 96% of novel papers were statistically significant compared with only 27% of replication attempts.32 Furthermore, they found that positive replication studies were underpowered compared with negative ones which suggested a publication bias towards positive findings. The authors concluded that meta-analyses using broad inclusion criteria like Karg et al's may be skewed towards false positive results and may still be unable to detect publication bias in spite of appropriate statistical correction methods.

Instead of a ‘pure statistical’ approach of the meta-analytic studies based exclusively on human observational data, Wankerl et al33 contended that a ‘convergent evidence’ approach inclusive of data stemming from other research fields such as animal and neuroimaging research may be better suited to validate the stress sensitivity hypothesis of 5HTTLPR.33 Evidence from animal studies has so far supported the moderating role of 5-HTTLPR in stress regulation. Barr et al34 demonstrated that in 6 month-old macaques hypothalamic-pituitary-adrenal axis activity was modulated by the interaction between 5-HTT genotype and different rearing conditions.34 Consistent with these findings, 5-HTT knockout mice were documented to display a depressive-like phenotype and neuronal changes in the infralimbic cortex and basolateral amygdala following stress exposure.35 Using functional neuroimaging techniques in the attempt to identify the underlying neurobiological correlate of 5-HTTLPR, Hariri et al36 provided first evidence of greater amygdala activity in response to fearful stimuli among individuals carrying one or two copies of the s allele.36 However, a meta-analysis of 31 functional imaging studies and four unpublished data sets yielded a marginally statistically significant but small effect of 5-HTTLPR on left and right amygdala activity, with evidence of substantial between-study heterogeneity.37 Moreover, the effect size of the association between 5-HTTLPR and amygdala activation only accounted for around 1% of the variance in amygdala activation.

Based on the evidence that proximal SLEs do not play a key role in the 5-HTTLPR by stress interaction, Brown and Harris38 proposed that an early interplay of childhood maltreatment and 5-HTT gene polymorphism may mainly contribute to the chronicity of depression as opposed to triggering its onset.38 Their model is consistent with the hypothesis that the early life disruption of serotonergic brain networks’ maturation may confer liability to depression in adulthood.39

Other factors have been shown to modulate the 5-HTTLPR by stress interaction. While a positive association between the 5-HTTLPR s allele and depression has been reported consistently in young adults, contradictory results have been found in adolescents and older samples.13 Sjoberg et al40  found that while the s allele seems to predispose girls to depression in the face of adverse life circumstances, it may have a protective effect on boys.40 Uher and McGuffin13 outlined a number of methodological pitfalls which may account for the heterogeneity of research findings.13 Objective measures of SLEs appear to be less prone to recall bias or distorted reporting of past stressors due to concomitant depression and thus preferable to self-report questionnaires. Moreover, current life events questionnaires may not give adequate weight to life events of relevance to pubertal males such as those concerning peer prestige. The definition of the genotype poses some problems too and the contribution of trait neuroticism, dominance of alleles and epistasis with other gene polymorphisms and allelic variants of 5-HTTLPR such as the rs25531 remains an unresolved issue.

Even when the 5-HTTLPR polymorphisms have been investigated in association with antidepressant response, results have been conflicting. The most recent meta-analysis by Porcelli et al41 concluded that 5-HTTLPR may be a predictor of antidepressant response and remission in Caucasians but not in Asians.41 This result differed from an earlier meta-analysis which yielded no evidence of statistically significant effect of 5-HTTLPR on antidepressant response.42

Jasinska et al43 formulated a mechanistic model of how environmental adversity interacts with 5-HTT genotype to affect risk of depression. The authors proposed that genetically determined variability in serotonin reuptake may modulate the activity of recently characterised serotonergic interneurons in the dorsolateral part of dorsal raphe nuclei and alter the balance in the amygdala-ventromedial prefrontal cortex-dorsal raphe nucleus circuitry which subserves emotion regulation and stress reactivity.43

In conclusion, the aetiopathogenesis of PSD appears to be complex and multifactorial. Despite evidence that 5-HTT gene polymorphism may be involved in PSD, the effect of this common genetic variant is likely to be accounting for only a little proportion of the phenotypical variance. The new approach of whole genome-wide association studies has proved a major advance in the field of molecular genetics and hopefully will help us improve our understanding of the underlying neurobiological pathways of PSD through the identification of new genetic loci in association with PSD.