Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia

The human serotonin transporter gene (5-HTT) demonstrates two polymorphisms with possible functional impact: a 44-bp insertion/deletion polymorphism o f the promoter region and a 17-bp variable number of tandem repeat polymorp hism (VNTR) in intron 2 (STin2). Such genetic polymorphisms in the serotoni nergic system may increase the susceptibility to schizophrenia or may serve as predictors of therapeutic response. We therefore analyzed these polymor phisms as susceptibility factors for schizophrenia by comparison of 684 sch izophrenic inpatients with 587 healthy controls. We furthermore compared th e therapeutic outcome of schizophrenic patients differentiated by the 5-HTT genotypes. Schizo-affective patients were more frequently homozygous for t he 44-bp insertion allele (Odds ratio, OR: 1.6, 95% confidence interval, Cl : 1.1-2.3, P < 0.03) than were all other schizophrenic patients and control s. The 17-bp VNTR alleles found were: STin2.7, 9, 10, and 12. Sequence anal ysis revealed seven different sequence motifs with an invariable arrangemen t. Patients with schizo-paranoid schizophrenia were more frequently homozyg ous for the STin2.12 allele than were controls (OR: 1.4, Cl: 1.1-1.8, P < 0 .007) and all other schizophrenic patients (OR: 1.6, Cl: 1.2-2.3). The STin 2.9 allele represented a risk factor for the residual subtype of schizophre nia (OR: 6.4, Cl: 2.5-16.2, P < 0.001). On the basis of global clinical imp ressions, as well as measurements with the positive and negative syndrome s cale we found no association of the polymorphisms with therapeutic response . In conclusion, the 44-bp polymorphism may be associated with the schizo-a ffective and the 17-bp VNTR with the residual and schizoparanoid subtype of schizophrenia, findings which require further biochemical and epidemiologi cal confirmation.