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Genetic Polymorphism and Major Depression: New Theories

(PSYCHIATRIC TIMES) - Genetic studies are slowly leading to a better understanding of certain diseases as well as progress toward individualized drug therapy. Developments in DNA sequencing make it relatively simple to look for allelic (ie, alternative) versions of a gene by examining samples of a specific gene taken from different members of a population (or from a heterozygous individual). Genetic variants that appear in at least 1% of a population are called polymorphisms. With the cutoff at 1%, one does not get sidetracked by spontaneous mutations that may have occurred in—and spread by the descendants of—a single family.

5-HTT Polymorphism
Genetic investigations have targeted all the major behavioral health diseases. So far, however, the research effort has been marked by a paucity of replicable direct gene-disorder associations.1 A significant complication appears to be that most behavior-gene effects are indirect and depend on gene-environment interaction.

The best example is research on genetic polymorphisms of the serotonin transporter. A study by Caspi and colleagues2 first suggested that persons who pos-sess either 1 or 2 copies of the short (S) variant of the 5-HTTLPR (serotonin transporter–linked polymorphic region) gene were more likely to develop major depression than those with the long (L) variant. The promoter region of the serotonin transporter contains a 44–base pair insertion (L allele) or deletion (S allele). Compared with the L allele, the S allele is associated with a lower level of serotonin uptake and transcriptional efficiency of the serotonin transporter. This may result in increased vulnerability to develop major depression.

Although the results of the Caspi study have been replicated by other researchers,3 more than simple genetic variation is involved. A meta-analysis of the published investigations of S/L 5-HTT polymorphism and major depression, including 11 studies with 941 patients and 2110 controls, concluded that the association was not significant.4 However, another systematic review and meta-analysis that examined the association between 5-HTT polymorphism and “avoidance-related personality traits,” including neuroticism and related constructs (themselves strongly related to the risk of major depression), did find a modest relationship.5 According to Kendler and associates,6 the 5-HTT gene may be an example of a gene that influences vulnerability to major depression not by a direct effect but rather by indirectly increasing sensitivity to the environment’s pathogenic effects.

Aaron T. Beck,7 the originator of cognitive psychotherapy, recently published an influential article in which he suggests that negative cognitive processing is the mechanism by which S 5-HTTLPR variant carriers are linked to major depression. He cites recent work showing that hyperreactivity of the amygdala in S 5-HTTLPR variant carriers is associated with increased sensitivity to negative stimuli and leads to negative bias in the processing or interpretation of emotional stimuli.8 Beck also highlights the work of Hayden and colleagues,9 who found that nondepressed children homozygous for the S allele showed greater negative processing on a self-referential encoding task following a negative mood induction than children with L genotypes.

There are also other intriguing findings in persons with major depression who carry the S allele. For example, such persons show a poor response to SSRIs,10 increased risk of adverse effects with SSRIs,10 and increased risk of suicide attempts.11 So, is the S allele a marker for more severe illness or, alternatively, does it impair the serotonin system in a way that current SSRIs cannot remedy?

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