Genetic variants in combination with early partial improvement as a clinical utility predictor of treatment outcome in major depressive disorder: The result of two pooled RCTs

Pharmacogenetics may allow for a personalized treatment, but a combination with clinical variables may further enhance prediction. In particular, in the present paper, we investigated early partial improvement (EPI) defined as 20% or more improvement by rating scales 2weeks after treatment, in combination with selected gene variants as a predictor of treatment outcome in patients with major depressive disorder. Two randomized controlled trials with 168 Japanese depressed patients were used. A stepwise multiple linear regression model with HAM-D score change at week 6 as the dependent variable and genotypes, EPI, baseline HAM-D score, age and sex as independent variables was performed in paroxetine, fluvoxamine and milnacipran, respectively, to estimate the prediction of HAM-D change at week 6. In the paroxetine sample, only EPI (P<0.001) was significantly associated with HAM-D change (n=81, R 2 =0.25, P<0.001). In the fluvoxamine sample, 5-HTTLPR La/Lg, S (P=0.029), FGF2 rs1449683C/T (P=0.013) and EPI (P=0.003) were associated with HAM-D change (n=42, R 2 =0.43, P<0.001). In the milnacipran sample, HTR-1A-1019C/G (P=0.001), ADRA2A-1297C/G (P=0.028) and EPI (P<0.001) were associated with outcome (n=45, R 2 =0.71, P<0.001). EPI in combination with genetic variants could be a useful predictor of treatment outcome and could strengthen the practical use of pharmacogenetic data in clinical practice

5-HTTLPR rs25531A > G differentially influence paroxetine and fluvoxamine antidepressant efficacy: a randomized, controlled trial.

A functional polymorphism in the transcriptional control region upstream, the serotonin transporter (SLC6A) coding sequence (5-HTTLPR) has been consistently associated with antidepressant response. More recently, another functional single nucleotide polymorphism within l variant has been reported, and the l variant with an adenosine at single nucleotide polymorphism rs25531 (lA) has been reported to have higher activity compared with the long variant with a guanine (lG)1 and lG expression is nearly equal to the s allele. Therefore, in the present work, we aimed to compare the effects of paroxetine and fluvoxamine in our previously reported sample expanding the analysis to rs25531 variants in a larger sample. The subjects of this study were in part previously reported investigating 5-HTTLPR.2 The method and design of this clinical trial were described elsewhere.2 Briefly, a total of 100 Japanese patients affected by major depression were randomly assigned to either paroxetine or fluvoxamine in a 6-week study. Response was evaluated by the percentage of the Hamilton Rating Scale for Depression (HAM-D) score change and by the rate of \u201cresponse\u201d defined as an at least 50% decrease after medication. The study was approved by the ethical committee of the Kansai Medical University and Osaka University. Written informed consent was obtained from each subject. Plasma levels of selective serotonin reuptake inhibitors (SSRIs) were determined after at least 2 weeks of stable dosage to evaluate compliance. Genomic DNA was isolated, and we detected lA and lG alleles by real-time polymerase chain reaction method following a previous study.1 Repeated-measures analysis of variance or analysis of covariance (ANCOVA) with baseline HAM-D scores were included in the model as covariant was performed. The low-expression s and lG alleles were grouped together as S' compared with the high-expression lA allele as L' following evidence from previous studies.1 For response rate, a logistic regression analysis was performed using response rate as the dependent variable and age, sex, dose, with or without sleep-induced drugs, HAM-D baseline, and the type of SSRIs as independent variables. Results were considered significant with an [alpha] level lower than 0.05. Eighty-one patients completed the 6-week study, whereas 19 patients withdrew during the course of the study. Genotype frequencies were s/s = 60.4%, s/lA = 22.2%, s/lG = 9.9%, lA/lA = 3.7%, lA/lG = 3.7%, and lG/lG = 0%. All were in Hardy-Weinberg equilibrium. Sociodemographic and clinical characteristics of the samples are shown in Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/JCP/A159. No significant differences were found for all sociodemographic and clinical characteristic factors between 2 SSRIs in each genotype group. The triallelic polymorphism was marginally associated with HAM-D score change at week 6 in the total sample (P = 0.04). Subsequent comparison of paroxetine and fluvoxamine in each genotype group showed that fluvoxamine-treated subjects were significantly less improved compared with paroxetine in S'/S' carriers on the HAM-D change over time (P = 0.0002), at week 2 (P = 0.016), at week 4 (P = 0.0004), and at week 6 (P = 0.001); mean HAM-D change of paroxetine and fluvoxamine at week 6 was 76.6% and 55.5%, respectively, whereas in L' allele carriers, no significant difference was found, and mean HAM-D change of both SSRIs was approximately 75% (Fig. 1). Response rate of subjects prescribed with paroxetine (week 4, 80.0%; week 6, 88.0%) was significantly higher compared with fluvoxamine (week 4, 43.8%; week 6, 62.5%) in S' allele homozygotes (week 4, P = 0.008; week 6, P = 0.038), whereas in L' allele carriers, response rate of paroxetine and fluvoxamine were, respectively, 78.6% and 100% at week 4 and 92.9% and 100% at week 6 without significant difference between the 2 agents (Supplemental Table 1, Supplemental Digital Content 1, http://links.lww.com/JCP/A159). When the sample was stratified by l and s variants only, therefore repeating our previously published analysis in this expanded sample not considering rs25531, a similar but less pronounced difference between 2 SSRIs was observed in s homozygotes only (repeated-measures ANCOVA, P = 0.013). However, at week 6, a different HAM-D change of paroxetine and fluvoxamine was observed in both variants (s: 73.7% and 58.9%; ANCOVA, P = 0.026; l: 80.4% and 62.4%; ANCOVA, P = 0.028, respectively) Supplemetal Figure 1, Supplemental Digital Content 2, http://links.lww.com/JCP/A160. Figure 1 Back to Top DISCUSSION The association of 5-HTTLPR with SSRI response is not always consistent, especially in Asian populations. Among other explanations, this heterogeneity could be explained by different types of SSRIs. In fact, we previously reported a different effect on paroxetine and fluvoxamine. In the present article, we observed that, taking into consideration rs25531 variants, the difference was even larger. The rs25531 is putatively located in the sixth repeat of the 5-HTTLPR, and the lG allele reduces SLC6A4 messenger RNA expression to levels nearly equivalent to those of the short allele,1 whereas the lA allele confers higher SLC6A4 expression. We observed that S' homozygotes (s and lG) benefit less from SSRI treatments compared with L' (lA) carriers. Interestingly, even for the same class of antidepressants, response was differently influenced by these variants in each compound. L' carriers had a better response than S' homozygotes only for fluvoxamine, whereas most of the patients with paroxetine had a good response regardless of genotype. When these 2 SSRIs were compared, stratified by only long and short variants of 5-HTTLPR without consideration of rs25531, the result was similar to a certain degree but not the same. That is, s/s carriers influenced less fluvoxamine outcome compared with when rs25531 was also considered, whereas both agents had a beneficial effect over time on l allele carriers, although with some difference at week 6. Therefore, a potential confounding effect of rs25531 was demonstrated. A possible reason lies in the pharmacodynamic profile. Paroxetine [Ki = 0.83 (0.06), mean (SE)] is a more potent serotonin reuptake inhibitor than fluvoxamine [Ki = 14 (1), mean (SE)] in the human brain.3 In addition, paroxetine has also a higher degree of affinity for norepinephrine transporter [Ki = 85 (5), mean (SE)] compared with fluvoxamine [Ki = 2950 (103), mean (SE)]. Thus, paroxetine could preserve the effectiveness regardless of genetic impact of SLC6A4, even in S' homozygotes. This is, to our best knowledge, the first open-label randomized controlled trial to compare SSRIs stratified by genetic influence of rs25531A > G on 5-HTTLPR. Two previous randomized controlled trials have demonstrated no significant differences in clinical response to treatment of depression between paroxetine and fluvoxamine in white populations,4,5 and there are no direct comparisons of paroxetine versus fluvoxamine in Asians. A much higher frequency of lA allele in whites compared with Japanese population could explain the different findings. Some previous studies investigated the association of SSRIs response with lA, lG, and s variants in white depressed patients. Our results were consistent with a previous study that tested its impact on paroxetine treatment showing no association.6 However, our results are in part opposite to a study using fluvoxamine that showed favorable response of lG compared with lA.7 This inconsistency could be due to low lG allele frequency and to the inclusion of bipolar disorder. There are possible limitations of the present study linked to the sample. The sample was already used in our previous articles, and results must therefore be interpreted with caution. In S'/S' carrier, we had a power of 0.80 to detect a large effect size of d = 0.76, which corresponded to a difference of approximately 16.8% HAM-D change between 2 SSRIs. Although in L' allele carriers, small sample size with insufficient power could lead type II error; however, the significant difference observed between 2 SSRIs in L allele carriers stratified by simple 5-HTTLPR not considering rs25531 could suggest considerable effect of rs25531 polymorphism. In conclusion, we expanded our previous study in terms of sample size and adding a further variant. This allowed us to evidence that rs25531 has an effect, particularly in fluvoxamine-treated subjects

[5-HT1A gene polymorphisms contributed to antidepressant response in major depression].

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) genotype carriers, independently from clinical variables. Furthermore minor allele homozygous carriers in all these 3 SNPs were associated with treatment response by various assessments such as HAM-D score change over time (P = 0.001), week 2 (P < 0.0001), 4 (P = 0.007), and 6 (P = 0.048) as well as response rate (P = 0.0005) and remission rate (P = 0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four papers

Effect of 5-HT1A gene polymorphisms on antidepressant response in major depressive disorder

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P&lt;0.0001), rs6295G/G (P&lt;0.0001) and rs1364043T/T (P¼0.018) genotype carriers (minor allele homozygotes), independently from clinical variables. Furthermore minor allele homozygous carriers in all these three SNPs were associated with treatment response by various assessment such as HAM-D score change over time (P¼0.001), week 2 (P&lt;0.0001), 4 (P¼0.007), and 6 (P¼0.048) as well as response rate (P¼0.0005) and remission rate (P¼0.004). We also pointed out the genotyping mis-definition of rs6295C/G in the previous four articles. In conclusion, this is the first study that reports a significant association of antidepressant response with rs10042486C/T and rs1364043T/G variants of HTR1A and also with rs10042486–rs6295–rs1364043 combination. This finding adds an important information for the pathway of detecting the genetics of antidepressant response even if results must be verified on larger samples

Switching to antipsychotic monotherapy vs. staying on antipsychotic polypharmacy in schizophrenia: A systematic review and meta-analysis

© 2019 Elsevier B.V. Background: While recent meta-analyses have reported the superiority of antipsychotic polypharmacy (APP) over antipsychotic monotherapy (APM) in schizophrenia, switching to APM can be beneficial in terms of side effects. To determine whether patients receiving APP should switch to APM or stay on APP, we conducted a systematic review and meta-analysis. Methods: Randomized controlled trials (RCTs) examining a switch from APP to APM vs. staying on APP were systematically selected from a previous meta-analysis comparing APP with APM in patients with schizophrenia. In addition, we conducted an updated systematic literature search using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Data on study discontinuation, relapse, psychopathology, neurocognition, extrapyramidal symptoms, and body weight/body mass index (BMI) were extracted and synthesized. Results: A total of 6 RCTs involving 341 patients were included. All studies examined a switch from 2 antipsychotic agents to a single agent. Clozapine-treated patients were included in 3 studies. There was a significant difference in study discontinuation due to all causes in favor of staying on APP (N = 6, n = 341, RR = 2.28, 95% CI = 1.50–3.46, P \u3c 0.001). There were no significant differences in relapse, any psychopathology, neurocognition, extrapyramidal symptoms, or body weight/BMI between the 2 groups. The quality of evidence was low to very low. Conclusions: The findings suggest that clinicians should closely monitor patient condition when switching to APM after receiving 2 antipsychotics. Given the low to very low overall quality of the evidence, the findings should be considered preliminary and inconclusive