The serotonin transporter gene promoter polymorphism (5-HTTLPR) has been repeatedly associated with antidepressant response in mood disorder patients, but findings are not consistent across studies. A meta-analysis was performed on 15 studies including data of 1435 subjects. We tested three phenotypes: remission rate, response rate and response rate within 4 weeks using the cochrane review manager. We observed a significant association of the s/s variant of 5-HTTLPR with remission rate (P < 0.0001) and both s/s and s/l variants with response rate (P = 0.0002). Response rate within 4 weeks was associated in both models (P = 0.003-P < 0.00001). This effect is quite robust to ethnic differences although a significant heterogeneity is present in Asian samples.

This systematic review summarizes pharmacogenetic studies on antidepressant response and side effects. Out of the 17 genes we reviewed, 8 genes were entered into the meta-analysis (SLC6A4, HTR1A, HTR2A, TPH1, gene encoding the beta-3 subunit, brain-derived neurotrophic factor (BDNF), HTR3A and HTR3B). TPH1 218C/C genotype (7 studies, 754 subjects) was significantly associated with a better response (odds ratio, OR=1.62; P=0.005) with no heterogeneity between ethnicities. A better response was also observed in subjects with the Met variant within the BDNF 66Val/Met polymorphism (4 studies, 490 subjects; OR=1.63, P=0.02). Variable number of tandem repeats polymorphism within intron 2 (STin2) 12/12 genotype showed a trend toward a better response in Asians (STin2: 5 studies, 686 subjects; OR=3.89, P=0.03). As for side effects, pooled ORs of serotonin transporter gene promoter polymorphism (5-HTTLPR) l (9 studies, 2642 subjects) and HTR2A -1438G/G (7 studies, 801 subjects) were associated with a significant risk modulation (OR=0.64, P=0.0005) and (OR=1.91, P=0.0006), respectively. Interestingly, this significance became more robust when analyzed with side effect induced by selective serotonin reuptake inhibitors only (5-HTTLPR: P=0.0001, HTR2A: P<0.0001). No significant result could be observed for the other variants. These results were not corrected for multiple testing in each variant, phenotype and subcategory. This would have required a Bonferroni significance level of P<0.0023. Although some heterogeneity was present across studies, our finding suggests that 5-HTTLPR, STin2, HTR1A, HTR2A, TPH1 and BDNF may modulate antidepressant response.

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Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015–0.042), more significantly to fluvoxamine. The –1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010–0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022–0.042), and more significantly in paroxetine-treated patients (p = 0.002–0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.

No abstract

The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders.

These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.