The Role of Serotonin Transporter Protein Gene in Antidepressant-Induced Mania in Bipolar Disorder

Background: The occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BP). The serotonin transporter (5-HTT) is the selective site of action of most proserotonergic compounds used to treat bipolar depression. The 5-HTT gene (SLC6A4) has 2 known polymorphisms. The aim of this study was to investigate the role of the SLC6A4 variants in the pathogenesis of antidepressant-induced mania in BP. Methods: Twenty-seven patients with a DSM-IV diagnosis of BP I or II, with at least 1 manic or hypomanic episode induced by treatment with proserotonergic antidepressants (IM+ group), were compared with 29 unrelated, matched patients with a diagnosis of BP I or II, who had been exposed to proserotonergic antidepressants without development of manic or hypomanic symptoms (IM˛ group). The 2 known polymorphisms of the SLC6A4 were genotyped, and allelic and genotypic association analyses were performed. Results: With respect to the polymorphism in the promoter region (5HTTLPR), IM+ patients had an excess of the short allele (n=34 [63%]) compared with IM˛ patients (n=17 [29%]) (x 2 1, 12.77; P , .001). The genotypic association analysis showed a higher rate of homozygosity for the short variant in the IM+ group (n=10 [37%]) than in the IM˛ group (n=2 [7%]) and a lower rate of homozygosity for the long variant in the IM+ group (n=3 [11%]) compared with the IM˛ group (n=14 [48%]) (x 2 2, 12.43; P=.002). No associations were found for the polymorphism involving a variable number of tandem repeats. Conclusion: If these results are replicated, the 5HTTLPR polymorphism may become an important predictor of abnormal response to medication in patients with BP.