COMMENTARY

Stress and Resilience: Implications for Depression and Anxiety

Jerrold F. Rosenbaum, MD; Jennifer M. Covino, MPA

Disclosures

December 29, 2005

In This Article

Stress and Depression

Serotonin and the serotonin transporter (responsible for reuptake of serotonin within the brain's synapses) are pharmacologic targets for the treatment of depression. A study conducted by Caspi and colleagues[3] examined the impact of stressors on the risk for depression by examining a functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene. This study identified 2 alleles on the promoter region of the 5-HTT gene -- a short form (s) allele (associated with lower transcriptional activity) and a long form (l) allele. Findings from this study indicated that this genetic polymorphism in concert with stressful life events may leave individuals vulnerable to depression.

Subjects in the study were members of the Dunedin Multidisciplinary Health and Development study, a longitudinal study assessing participants at ages 3, 5, 7, 9, 11, 13, 15, 18, and 21. A previous study with this cohort[4] suggested that children with a genotype that conferred high levels of a functional polymorphism in the gene encoding monoamine oxidase A, a neurotransmitter-metabolizing enzyme, were at risk for developing antisocial behavior under conditions of maltreatment. Originally comprising 1037 children (52% male), this cohort retained 96% of their members to age 26. To determine the interaction of stressful life events that occurred between age 21and 26 years in relation to their 5-HTT gene-linked polymorphic region (HTTLPR) genotype, participants were separated into 3 groups: s/s homozygotes (n=147, 17%), s/l heterozygotes (n=435, 51%), and l/l homozygotes (n=265, 31%). A life history calendar was used to assess stressful events. Across the 3 genotypes, 30% indicated no stressful life event; 25% experienced 1 event; 20% experienced 2 events; 11% experienced 3 events; and 15% experienced 4 events, with significant difference across the 3 groups (P = .59), suggesting that the genotype did not play a role in risk of exposure to stressful life events. In addition, participants were given the Diagnostic Interview Schedule (at age 26) to measure depressive symptoms. In all, 17% met the criteria for a depressive episode in the past year (58% female vs 42% male; odds ratio 1.6; 95% confidence interval from 1.1 to 2.2) based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

Results of this study indicated that the interaction between the 5-HTTLPR and life events was significantly stronger (P = .02) in individuals who carried at least 1 copy of the "s" allele, in comparison with l/l homozygotes. In addition, the gene by environment (GXE) interaction predicted a diagnosis of depression among carriers of an "s" allele (P = .056) and also showed that the number of life events occurring after the 21st birthday predicted a diagnosis of depression at age 26 among those with an "s" allele who did not previously have a history of depression (P = .002 among s/s homozygotes and P = .67 among s/l heterozygotes), but not among l/l homozygotes in both cases. In addition, stressful life events predicted suicidal ideation or attempt in individuals with at least 1 copy of the "s" allele but not among the l/l homozygotes (P = .05). Also, those who carried an "s" 5-HTTLPR allele who experienced 4 or more life events comprised only 10% of the study cohort, but they accounted for 23% of all (n=133) cases of diagnosed depression; among all members who suffered 4 or more stressful events, 33% of individuals with at least 1 copy of the "s" allele became depressed, compared with only 17% of the l/l homozygotes.

Investigators then conducted an analysis predicting informant reports of depression at age 26 (P < .01) to rule out the possibility of self-report bias, and this analysis also revealed a significant (GXE) interaction. Taken together, these preliminary results indicate that a (GXE) interaction exists and, if replicated, these findings may be useful for predicting the onset of depressive symptoms, diagnosing depression (including new onset diagnosis), and predicting an informant's report of depressive behavior.

A subsequent study by Kaufman and others[5] examined this polymorphism in relationship to the risk for depression associated with a history of maltreatment, while simultaneously accounting for an individual's level of social support. This work verified the evidence described above by finding the effect of the 5-HTTLPR to be a risk factor for depression and further implicating a lack of social support as an additional risk and susceptibility factor for depression. Children who had been maltreated and who had no positive supports and an s/s genotype scored twice as high as the nonmaltreated children who had no positive supports and an s/s genotype. Maltreated children with an s/s genotype and positive supports had only minimally higher depression scores compared with nonmaltreated children with an s/s genotype and positive supports. This research supports the hypothesis of gene-environment interactions and that the risk associated with this genotype may be both positively and negatively influenced by both genetic and environmental factors. These preliminary studies are encouraging, and ongoing research will continue to elucidate these complex interactions.

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