The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings.
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%]) (chi(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%]) (chi(2)(2), 12.43; P =.002). No associations were found for the polymorphism involving a variable number of tandem repeats.


CONCLUSIONS
If these results are replicated, the 5HTTLPR polymorphism may become an important predictor of abnormal response to medication in patients with BP.
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Neurogenetics Section, R-31, Centre for Addiction and Mental Health, Clarke Site, 250 College St, Toronto, Ontario, Canada M5T 1R8. James_Kennedy@CAMH.net
Walker
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Macciardi
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Kennedy
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D000328:Adult; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000139:chemically induced* / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics*; D017714:Community-Acquired Infections; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics*; D026901:Membrane Transport Proteins; D001523:Mental Disorders / Q000453:epidemiology; D009419:Nerve Tissue Proteins; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D012701:Serotonin / Q000235:genetics*; D018490:Serotonin Agents / Q000009:adverse effects / Q000627:therapeutic use; D050486:Serotonin Plasma Membrane Transport Proteins; D020080:Tandem Repeat Sequences / Q000235:genetics
D000928:Antidepressive Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin