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Preliminary Findings

Emanuela Mundo, MD; Melissa Walker, BSc; Tasha Cate, BA; Fabio Macciardi, MD, PhD; James L. Kennedy, MD

Arch Gen Psychiatry. 2001;58:539-544.

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%]) (²₁, 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%]) (²₂, 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.

From the Neurogenetics Section, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario.

Corresponding author: James L. Kennedy, MD, Neurogenetics Section, R-31, Centre for Addiction and Mental Health, Clarke Site, 250 College St, Toronto, Ontario, Canada M5T 1R8 (e-mail: James_Kennedy{at}CAMH.net).