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Serotonergic pathways are known to play an essential role in the effects generated by antidepressants. Polymorphisms in serotonin receptor and transporter genes have been identified as an important factor. To investigate which of these polymorphisms may be useful to predict clinical outcome, we assessed their effect in a naturalistic clinical study. We studied the influence of the 5-hydroxytryptamine transporter (5-HTT) variable number of tandem repeats (VNTR), 5-HTTLPR/rs25531 and a 5-HTR2A intron 2 SNP with regard to response and side effects in 273 psychiatric inpatients. Main clinical assessments included Clinical Global Impressions ratings, paranoid depression scale self-rating scale and Dosage Record, and Treatment Emergent Symptoms (DOTES) Scale. We found significant associations between 5-HTTLPR/rs25531 S/L(G) alleles and response and side effects in 100 patients with selective serotonin reuptake inhibitor (SSRI) treatment (p = 0.037, CGI-I ≤ 2: 0% vs. 19% and p = 0.0005, DOTES cluster c: 0.76 vs. 0.19). 5-HTT VNTR and 5-HTR2A intron 2 polymorphisms were associated significantly with adverse effects in patients with selective and nonselective SRI (5-HTT VNTR 12/12: n = 170, p = 0.0001, side effect rates: 51% vs. 19% and rs7997012 [A/A]: n = 50, p = 0.020, side effects rates: 43% vs. 11%). No impact of the polymorphisms on mirtazapine treatment was found. Our study confirms the influence of serotonergic polymorphisms at the receptor and transporter level on SSRI response and side effects, supporting previous reports based on various study designs. The effects were strong enough to be noticed clinically in this naturalistic setting. However, randomized controlled trials are warranted to provide unequivocal evidence of the clinical usefulness of pretherapeutic screening for these polymorphisms.

The cytochrome P450 2D6 (CYP2D6) isoenzyme metabolizes about 25% of clinically used drugs. The impact of CYP2D6 metabolizer status on therapeutic outcome was assessed in 365 psychiatric in-patients treated with neuroleptics or antidepressants. Length of hospitalization and response onset were prolonged for patients receiving CYP2D6 drugs. Intermediate metabolizers (IMs) receiving CYP2D6 doses above the population median had more side effects after 4 weeks than extensive metabolizers with abovemedian doses (9/13, 69% vs 4/23, 17%, P ¼ 0.003), than IMs with belowmedian doses (5/22, 23%, P ¼ 0.012) and IMs with other medication (24/84, 29%, P ¼ 0.009). The Clinical Global Impression scale response was lower for IMs treated with CYP2D6 drugs (3/42, 7%) than for IMs with other medication (21/84, 25%, P ¼ 0.017) probably due to increased side effects. Identification of IM status (38% of study population) may help to reduce side effects and length/cost of hospitalization. Thus, not only poor and ultrarapid metabolizer but also IMs may benefit from CYP2D6 genotyping. This is of paramount interest since it greatly improves cost/benefit estimations for pretreatment CYP2D6 screening.