RESUMO
BACKGROUND: Glycogen synthase kinase-3ß (GSK-3ß) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3ß gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown. OBJECTIVES: In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3ß gene and antidepressant treatment effects in patients with MDD. METHODS: Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3ß gene (rs6438552 and rs12630592) that influence brain volume in the hippocampus were genotyped. For the primary outcome, the relationship between genetic variations in the SNPs and the percent change in the Hamilton Rating Scale for Depression (HAM-D) score at week 6 was examined. In addition, rs334558, which has been reported repeatedly, was also genotyped. RESULTS: There was a significant correlation between the two SNPs and the percent change in the HAM-D scores at week 6 (rs6438552 A/A vs. A/G + G/G: p = 0.016; rs12630592 G/G vs. G/T + T/T: p = 0.016). There was high linkage disequilibrium between the rs6438552 and rs12630592 SNPs. The correlation between high therapeutic response over time and the two SNPs were also confirmed (rs6438552 A/A vs. others: p = 0.031; rs12630592 G/G vs. others: p = 0.031). CONCLUSIONS: Our results suggest that two GSK-3ß variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Glicogênio Sintase Quinase 3 beta/genética , Hipocampo/patologia , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Fluvoxamina/uso terapêutico , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Paroxetina/uso terapêutico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Antidepressants have variable therapeutic effects, depending on genetic and environmental factors. Approximately 30% of major depressive disorder (MDD) patients do not respond significantly to antidepressants such as paroxetine, a selective serotonin reuptake inhibitor (SSRI). However, the biological mechanisms behind this phenomenon are mostly unknown. Here, we examined the role of patients' epigenetic background in SSRI efficacy. METHODS: Genome-wide DNA methylation analysis of the peripheral blood of Japanese MDD patients was performed by using the Infinium HumanMethylation450 BeadChip. RESULTS: We compared the results of the 10 patients who best responded to paroxetine (BR) with the 10 worst responders (WR), and found 623 CpG sites with a >10% difference in DNA methylation level. Among them, 218 sites were nominally significant between BR and WR (p < 0.05), and 2 sites (cg00594917 and cg07260927) were significantly different after false discovery rate (FDR) correction (q < 0.05). The methylation difference was greatest at cg00594917, located in the first exon of the PPFIA4 gene, which codes for liprin-α (p = 0.00012). Hierarchical cluster analysis of 23 CpG sites in the PPFIA4 gene distinguished BR and WR, except for 1 WR patient. The cg07260927 site was located in the 5'UTR of the heparin sulfate-glucosamine 3-sulfotransferase 1 (HS3ST1) gene (p = 0.00013). Hierarchical cluster analysis of 28 CpG sites in HS3ST1 distinguished BR and WR, except for 1 WR and 2 BR patients. CONCLUSION: Our results suggest that patients' DNA methylation profile at specific genes such as PPFIA4 and HS3ST1 is associated with individual variations in therapeutic responses to paroxetine.
Assuntos
Metilação de DNA/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Paroxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Análise por Conglomerados , Ilhas de CpG/efeitos dos fármacos , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Escalas de Graduação Psiquiátrica , Sulfotransferases/genéticaRESUMO
Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRI) are commonly used for treating major depression. Regretfully, significant heterogeneity exists regarding the benefits of SSRI/SNRI in individual cases. We previously reported that a polymorphism located in the serotonin transporter linked promoter region (5-HTT LPR) is associated with an interindividual difference in SSRI treatment efficacy. However, this explains only a small part of the variation of this complex phenotype. Other 5-HTT variants in the coding regions, 3' untranslated region (3' UTR), and introns adjacent to each exon could also contribute to treatment response. Therefore, we performed a sequencing analysis of the SLC6A4 gene (coding for 5-HTT) and investigated the association between variants detected in this study and the antidepressant response to SSRI/SNRI in 201 Japanese depressive patients. Seventeen novel mutations were identified by sequencing analysis. We found that the polymorphism G2563T (rs3813034) as a tag single-nucleotide polymorphism of IVS9 A-90G (rs140701), G2356T (rs1042173), and A3641C (rs7224199) is associated with interindividual variability of SSRI/SNRI efficacy at week 6, independent from clinical variables and effect of 5-HTT LPR (P < 0.001 by multiple regression analysis). This polymorphism could help determine individualized SSRI/SNRI treatments for depressive patients in combination with 5-HTT LPR.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Adulto , Transtorno Depressivo Maior/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Análise de Sequência/métodos , Resultado do TratamentoRESUMO
Individual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486-rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G-T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted.
Assuntos
Antipsicóticos/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Receptor 5-HT1A de Serotonina/genética , Esquizofrenia/genética , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Adulto , Aripiprazol/uso terapêutico , Feminino , Haplótipos/genética , Humanos , Isoindóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Individual differences in serotonin 7 receptor (5-HT7R) may result in variable response to antipsychotics with 5-HT7R antagonism. This study investigated the relationship between single nucleotide polymorphisms (SNPs) in the 5-HT7R gene (HTR7) and the efficacy of second-generation antipsychotic drugs with a high affinity for this receptor in Japanese schizophrenia. METHODS: Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. All patients were genotyped for three candidate SNPs (rs12412496, rs7916403, and rs1935349). Patient improvement on the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks was assessed as the primary outcome. PANSS 5-factor scores were investigated as the secondary outcome. RESULTS: Improvement on the PANSS total score and genetic polymorphisms showed no correlation. The rs12412496-rs7916403-rs1935349 A-T-A haplotype was correlated with worse improvement in the cognition score (haplotype frequency: 0.285, p = 0.046, permuted p = 0.043). CONCLUSION: Our results show that HTR7 variants are not related to the overall improvement in schizophrenia symptoms.
Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Isoindóis/uso terapêutico , Receptores de Serotonina/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Tiazóis/uso terapêutico , Adulto , Povo Asiático , Feminino , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
Few data are available on the efficacy and safety of antipsychotics with different dopamine D2 receptor (D2-R)-binding properties in drug-naïve and non-drug-naïve schizophrenia. Thus, we aimed to assess whether antipsychotic medication history influences efficacy and tolerability in schizophrenia, based on a randomized controlled study of antipsychotics with mechanisms involving either full antagonism or partial agonism of D2-R. Patients with schizophrenia were recruited and given perospirone or aripiprazole in a 12-week, flexible-dose, open-label, randomized controlled study. Data were analyzed after dividing the patients into antipsychotic-naïve and antipsychotic-treated group according to antipsychotic medication histories. Efficacy and safety were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Drug-Induced Extrapyramidal Symptoms Scale, and the Barnes Akathisia Rating Scale. In patients receiving perospirone, the antipsychotic-naïve group (n = 22) showed greater symptom improvement than that shown by the antipsychotic-treated group (n = 29), as assessed by efficacy evaluation scales such as the PANSS total, positive, and excited component score (p = .006, p < .001, p = .003, respectively). In patients receiving aripiprazole, however, there was no significant difference in efficacy between the antipsychotic-naïve (n = 18) and antipsychotic-treated (n = 31) groups. No significant intra-group or inter-group difference was noted with respect to any of the tolerability-related parameters assessed. The present study data support the hypothesis that antipsychotic medication history may influence efficacy in patients who receive a D2-R full antagonist but not a D2-R partial agonist.
Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Isoindóis/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Tiazóis/uso terapêutico , Adulto , Idoso , Acatisia Induzida por Medicamentos/etiologia , Doenças dos Gânglios da Base/induzido quimicamente , Agonismo Parcial de Drogas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Dopamina D2/agonistas , Resultado do Tratamento , Adulto JovemRESUMO
Major depressive disorder is a chronic condition that can recur and relapse. It would be clinically useful to know the patient background to predict the chronicity of depressive symptoms, and the change in diagnosis of bipolar disorder. This study included 197 patients enrolled in a six-week randomized controlled trial with a two-year follow-up. We conducted multiple logistic regression analyses to identify the clinical and sociodemographic characteristics associated with persistent depressive disorder (PDD), relapse, and changes in bipolar disorder diagnosis. The significantly correlated factors were residual symptoms, including insight, work and activity, and general somatic symptoms at week six. We could not identify any factors that contributed to relapse or change in the diagnosis of bipolar disorder. We found that the specific residual symptoms of acute treatment affected long-term treatment outcomes for depression. Attention should be paid to the residual symptoms of depression in the early stages of treatment, and measures should be considered to improve them. There are several limitations to this study, including the fact that PDD may exist among patients who discontinued treatment, treatment was not standardized during the study period, and adherence was confirmed verbally.
RESUMO
AIM: Perospirone is classified as a second-generation antipsychotic agent for the treatment of schizophrenia. Perospirone binds with high affinity to serotonin 5-HT2A receptors and dopamine D2 receptors. There are no reports of clinical comparisons of perospirone and risperidone in multicenter studies. To clarify the clinical traits of perospirone in the treatment of schizophrenia, the clinical efficacies and side-effects of perospirone and risperidone were compared in a randomized clinical multicenter trial. METHODS: Sixty-six schizophrenia patients were enrolled in the trial. The Positive and Negative Syndrome Scale (PANSS) total, positive, negative and general symptoms scores and Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) scores were investigated at 0, 4, 8 and 12 weeks. RESULTS: Significant reductions in the PANSS total and subscale scores were observed in both the perospirone and risperidone groups, with no significant between-group differences at 4 and 12 weeks. Risperidone improved the total scores and overall psychopathologic symptom total scores more effectively than perospirone at week 8. There were no significant differences in the DIEPSS scores at 0, 4, 8 and 12 weeks between the perospirone and risperidone groups. The numbers of patients who dropped out did not differ between the perospirone and risperidone groups. CONCLUSIONS: Perospirone was as effective as risperidone against positive and negative symptoms in patients with schizophrenia. Both antipsychotic agents were equally well-tolerated.
Assuntos
Antipsicóticos/uso terapêutico , Isoindóis/uso terapêutico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Tiazóis/uso terapêutico , Adolescente , Adulto , Idoso , Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Feminino , Humanos , Isoindóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Risperidona/efeitos adversos , Tiazóis/efeitos adversosRESUMO
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 < 0.0001), rs6295G/G (P < 0.0001) and rs1364043T/T (P = 0.018) 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 (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 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.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Polimorfismo de Nucleotídeo Único , Receptor 5-HT1A de Serotonina/genética , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Sequência de Bases , Primers do DNA , Humanos , Desequilíbrio de LigaçãoRESUMO
OBJECTIVE: The alpha 2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity. Recently, the functional defect of ADRA2A has been implicated as a cause of depression, attention deficit hyperactivity disorder, and Tourette syndrome. In this study, the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) was examined in depressed patients. METHOD: Ninety-three Japanese depressed patients were recruited in the present study, assigned randomly to paroxetine or milnacipran, and assessed by the Hamilton Rating Scale for Depression (HAM-D) scoring every 2 weeks before and after drug administration. The ADRA2A C-1297G polymorphism was considered in the association analysis with the efficacy of antidepressants. RESULTS: There were significant differences in the HAM-D percent score change over time (P = 0.019) among C/C, C/G, and G/G of the ADRA2A C-1297G polymorphism in the total subjects. The C allele carriers of the ADRA2A C-1297G polymorphism showed a significantly better improvement than G/G subjects at weeks 2, 4, and over time (P = 0.037) in the milnacipran group. DISCUSSION: Our findings suggest that ADRA2A plays an important role in depression therapy. The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs, especially milnacipran, although the functional change brought about by C-1297G polymorphism has not yet been fully identified in vivo and in vitro. CONCLUSIONS: The ADRA2A polymorphism could be a reasonable candidate to predict the response to milnacipran. Our results are still preliminary, and a large sample size will be required to confirm our findings. However, to the best of our knowledge, this study is the first to suggest a possible association of ADRA2A variants with the SNRI response.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Ciclopropanos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Receptores Adrenérgicos alfa 2/genética , Inibidores da Captação Adrenérgica/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Povo Asiático , Ciclopropanos/uso terapêutico , Transtorno Depressivo Maior/fisiopatologia , Feminino , Regulação da Expressão Gênica , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Milnaciprano , Paroxetina/farmacologia , Paroxetina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Escalas de Graduação Psiquiátrica , Fatores de TempoRESUMO
The G-protein beta3 subunit (GNB3) gene is a key modulator of signal transduction and is a major candidate for SSRIs response. The aim of the present study is to test a possible effect of the C825T polymorphism on the antidepressant response and intolerance to selective serotonin reuptake inhibitors (SSRIs) in 146 Japanese samples with major depression treated with paroxetine or fluvoxamine for 6 weeks. The severity of depression symptom was assessed using the 21-item Hamilton Rating Scale for Depression (HAM-D) and adverse drug reactions were evaluated bi-weekly. No association with SSRIs treatment response was observed in 107 completers also including HAM-D baseline scores, SSRI type or/and 5-HTTLPR variants in the model as covariates. Furthermore, no significant association could be observed with intolerance to SSRIs in the whole subjects. The result suggests that C825T variants of GNB3 cannot play a major role as a predictor of treatment response as well as intolerance to SSRIs in Japanese patients with major depression.
Assuntos
Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Proteínas Heterotriméricas de Ligação ao GTP/genética , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Antidepressivos/sangue , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Feminino , Fluvoxamina/efeitos adversos , Fluvoxamina/sangue , Fluvoxamina/uso terapêutico , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Paroxetina/efeitos adversos , Paroxetina/sangue , Paroxetina/uso terapêutico , Polimorfismo Genético/genética , Escalas de Graduação Psiquiátrica , Inibidores Seletivos de Recaptação de Serotonina/sangueRESUMO
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. Multidrug resistance 1 (ABCB1, MDR1) gene encodes a blood-brain barrier transporter P-glycoprotein that plays an important role in controlling the passage of substances between the blood and brain. In the present study, we therefore examined the possible association of 3 functional ABCB1 polymorphisms (C3435T: rs1045642, G2677T/A: rs2032582 and C1236T: rs1128503) with response to paroxetine in a Japanese major depression sample followed for 6 weeks. Analysis of covariance at week 6 with baseline scores included in the model as covariate showed significant association of the non-synonymous SNP G2677T/A with treatment response to paroxetine (p=0.011). Furthermore, the wild variants haplotype (3435C-2677G-1236T) resulted associated with poor response (p=0.006). To our best knowledge, this study is the first suggestion of a possible association of ABCB1 variants with SSRIs response.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Paroxetina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Povo Asiático/genética , Transtorno Depressivo Maior/psicologia , Resistência a Múltiplos Medicamentos/genética , Feminino , Genes MDR/genética , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/farmacologia , Farmacogenética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Fatores Sexuais , Resultado do TratamentoRESUMO
BACKGROUND: Variability in antidepressant response is due to genetic and environmental factors. Since SSRIs exert their activity enhancing the serotonin turnover, genes coding for proteins of the serotonin system are key candidates for a possible genetic influence with response to SSRIs. Therefore tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin in the raphe nuclei could be a candidate. In the present study, we examined the possible association of the TPH1 218A/C polymorphism with response to SSRIs in a sample of Japanese patients with major depression. METHODS: The 21-item Hamilton Rating Scale for Depression (HAM-D) was administered to evaluate depressive symptoms at baseline and bi-weekly over 6 weeks of treatment. All patients were genotyped for the TPH1 218A/C polymorphism. RESULTS: Repeated-measures analysis of variance of HAM-D score change over time with baseline scores and 5-HTTLPR variants included in the model as covariate showed no significant association of this SNP with treatment response to SSRIs. Furthermore, no significant association of this SNP could be observed with both responder rate at weeks 2, 4 and 6 and intolerance to SSRIs. CONCLUSION: The result suggests that 218A/C variants of TPH1 cannot play a major role as predictor of treatment response as well as intolerance in Japanese patients with major depression.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Triptofano Hidroxilase/genética , Adulto , Análise de Variância , Antidepressivos/sangue , Feminino , Seguimentos , Genótipo , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Inibidores Seletivos de Recaptação de Serotonina/sangue , Índice de Gravidade de DoençaRESUMO
The present study aimed to compare the effects of two currently used selective serotonin reuptake inhibitors (SSRIs) in Japan taking the individual background in 5-HTT gene-linked polymorphic region (5HTTLPR) genotype into account. Clinical responses to paroxetine and fluvoxamine were evaluated by total and cluster depressive symptoms for 81 Japanese patients who were diagnosed with major depression. Patients with the l allele had a greater percentage reduction on the total score (P=0.059) and somatic anxiety items (P=0.026) of the 21-item Hamilton Depression Rating Scale (HAM-D) score compared to s/s genotype carriers. Paroxetine was significantly more effective than fluvoxamine in the s/s carriers, as evaluated on the percentage reduction in total score (P=0.012) and core (P=0.049) HAM-D after 4 weeks of medication, but not in the l/s carriers. These findings suggest that the genetic test may be useful in investigating the efficacy of the two SSRIs, and that normalization by the 5HTTLPR genotypes may lead to improvement of the precision of comparative analysis.
Assuntos
Antidepressivos de Segunda Geração/uso terapêutico , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Fluvoxamina/uso terapêutico , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Paroxetina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto , Antidepressivos de Segunda Geração/efeitos adversos , Cromatografia Líquida de Alta Pressão , Feminino , Fluvoxamina/efeitos adversos , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Paroxetina/efeitos adversos , Pacientes Desistentes do Tratamento , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Escalas de Graduação Psiquiátrica , Proteínas da Membrana Plasmática de Transporte de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversosAssuntos
Antidepressivos de Segunda Geração/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Síndrome de Secreção Inadequada de HAD/induzido quimicamente , Paroxetina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Amoxapina/uso terapêutico , Antidepressivos de Segunda Geração/uso terapêutico , Humanos , Hiponatremia/induzido quimicamente , Síndrome de Secreção Inadequada de HAD/diagnóstico , Masculino , Pessoa de Meia-Idade , Sódio/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Alzheimer's disease (AD) is affected by apolipoprotein E (ApoE); however, its effects assessed by means of cognitive tests and by neuroimaging have not been sufficiently studied. METHODS: We administered the Alzheimer's Disease Assessment Scale (ADAS) and single-photon emission computed tomography imaging in patients with AD medicated with donepezil at baseline and after 1 year. Patients were classified as with or without ApoE4 and we evaluated the progress of AD. RESULTS: Analysis of covariance showed that cerebral blood flow after 1 year in subjects with ApoE4 is significantly reduced in some areas including the left lenticular nucleus, left thalamus, and right hippocampus compared with subjects without ApoE4. Paired t tests showed significantly reduced blood flow in several regions including the right hippocampus in subjects with ApoE4 and significant deterioration of ideational praxis in subjects without ApoE4. CONCLUSION: This study provides evidence that supports the notion of ApoE4 playing an important role in the progress of AD.
RESUMO
OBJECT: To evaluate the efficacy and safety of aripiprazole and perospirone in Japanese patients with schizophrenia. METHODS: In this 12-week, randomized, flexible-dose, open-label study, patients diagnosed with schizophrenia were randomized to receive aripiprazole (3-30 mg/day, n=49) or perospirone (8-48 mg/day, n=51). Efficacy and safety were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity Scale (CGI-S), the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) and the Barnes Akathisia Rating Scale (BAS) before treatment and every 4 weeks after the initiation of treatment. RESULTS: Fifty-eight patients completed this study (aripiprazole, n=31; perospirone, n=27). No significant differences in gender, episode, age, schizophrenia type, weight, previous treatment and PANSS score were observed between the two groups at baseline. Both groups showed significant improvements during the study, with reductions in the total PANSS scores (Repeated measure analysis of variance, both p<0.0001). There were no significant differences in the PANSS change scores, CGI-S change scores, DIEPSS total score, BAS total score or over time between groups. The most common adverse event was insomnia in both groups. CONCLUSIONS: In Japanese schizophrenia patients, aripiprazole and perospirone showed equal efficacy, tolerability and patient compliance. Both drugs showed good efficacy for treating schizophrenia. This paper is the first randomized study to evaluate the comparative efficacy and safety of aripiprazole and perospirone in the treatment of patients with schizophrenia.
Assuntos
Antipsicóticos/uso terapêutico , Isoindóis/uso terapêutico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêutico , Adolescente , Adulto , Idoso , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol , Feminino , Humanos , Isoindóis/administração & dosagem , Isoindóis/efeitos adversos , Japão , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do TratamentoRESUMO
Sexual dysfunction is a major side effect of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). We conducted a genome-wide association study to identify the genetic factors contributing to the risk of SSRI/SNRI-induced sexual dysfunction by testing 186 320 single nucleotide polymorphism (SNP) markers in a cohort of 201 Japanese major depression patients including 36 with sexual dysfunction induced by SSRI (paroxetine or fluvoxamine) or SNRI (milnacipran). The Cochran-Armitage trend test showed that 11 SNPs, tightly clustered in a distinct region on chromosome 14q21.3, were associated with SSRI/SNRI-induced sexual dysfunction at a genome-wide significance level after false discovery rate (FDR) correction, and the strongest SNP association was with rs1160351 (P=3.04 × 10(-7), risk ratio=2.92, 95% confidence interval (CI)=1.79-4.76). These SNPs mapped to the intronic region of the MDGA2 gene. A Manhattan plot showed that the strong association peak remained in MDGA2 after adjustment for sex and age in a multivariable logistic regression analysis although P values increased slightly and became non-significant. Replication studies with larger sample sizes are required to validate this exploratory study, but our findings may provide insights into the genetic basis of sexual dysfunction induced by SSRI/SNRI.
Assuntos
Ciclopropanos/efeitos adversos , Fluvoxamina/efeitos adversos , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Moléculas de Adesão de Célula Nervosa/genética , Paroxetina/efeitos adversos , Disfunções Sexuais Fisiológicas/induzido quimicamente , Disfunções Sexuais Psicogênicas/genética , Inibidores da Captação Adrenérgica/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Povo Asiático/psicologia , Estudos de Coortes , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Milnaciprano , Polimorfismo de Nucleotídeo Único/genética , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Disfunções Sexuais Psicogênicas/complicaçõesRESUMO
Antidepressant response usually appears in 2 to 4 weeks and 30-40% of patients do not show a significant response although biochemical changes of monoaminergic system occur within hours after administration. Genetic factors could play a role in this process and genes involved in synaptic plasticity and neurogenesis are possible candidates. In fact, antidepressants and electroconvulsive therapy increase basic fibroblast growth factor (FGF2) and the rs1449683C/T polymorphism within this gene has been found to be a predictor for both an elevated mRNA and protein level of FGF2. Therefore we examined the possible association of rs1449683C/T and a panel of tagging SNPs in SSRI efficacy and side effects in 144 Japanese major depressive subjects followed for 6 weeks. We observed a significant association of rs1449683T (p=0.010) and rs308393C (p=0.029) variant carriers toward a better response to SSRI and of rs1048201 with higher frequency of drop out due to side effects (p=0.010), independently from clinical variables. Furthermore the rs308447T-rs308393C-rs1449683T haplotype was associated with higher response rate (p=0.012) while the rs1048201T-rs3747676T haplotype was significantly associated with higher dropped out rate (p=0.015). In conclusion, this is the first study investigating the association of antidepressant response and intolerance with FGF2 variants. This finding adds an important piece of information for the pathway of detecting the genetics of antidepressant response.
Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Fator 2 de Crescimento de Fibroblastos/genética , Gastroenteropatias/induzido quimicamente , Polimorfismo de Nucleotídeo Único , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Estudos de Coortes , Transtorno Depressivo Maior/sangue , Haplótipos , Humanos , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Inibidores Seletivos de Recaptação de Serotonina/sangue , Resultado do TratamentoRESUMO
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.