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The response to antidepressants varies significantly among individuals and is difficult to predict before treatment. In this randomized control trial, we explored cytokines that correlate with the therapeutic effect of mirtazapine (MIR) and selective serotonin reuptake inhibitors (SSRIs) and whether they could be predictors of remission for each antidepressant. Plasma cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assayed in 95 participants before medication and assayed by the enzyme-linked immunosorbent assay. The Hamilton Rating Scale for Depression assessed depressive symptoms over 4 weeks. In the SSRI group, the baseline GM-CSF level was significantly higher in the remission group than in the non-remission group (p = 0.022). In the MIR group, the baseline level of TNF-α was significantly higher (p = 0.039) and IL-2 was lower (p = 0.032) in the remission group than in the non-remission group. In patients prescribed with MIR, the cut-off values of TNF-α (10.035 pg/ml) and IL-2 (1.170 pg/ml) calculated from the receiver operating characteristic curve suggested that the remission rate, which corresponds to a positive predictive value, could be increased from 31.3% to 60.0% and 50.0%, respectively. For those prescribed with SSRIs, the remission rate was 37.0% and using the cut-off value of GM-CSF (0.205 pg/ml), the remission rate could be almost doubled to 70%. Our study shows that pretreatment plasma concentrations of TNF-α, IL-2, and GM-CSF may suggest the predictability of remission by SSRIs or MIR.

令和元年度, Glycogen synthase kinase-3β (GSK-3β) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3β gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown., In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3β gene and antidepressant treatment effects in patients with MDD., Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3β 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., 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)., Our results suggest that two GSK-3β variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.

CONSORT 2010 checklist of information to include when reporting a randomised trial. (PDF 136 kb)

We aimed to compare the efficacy and tolerability of mirtazapine versus SSRIs and to assess whether “non-response at week 4” may be a clinical indicator for combining mirtazapine and SSRIs for subsequent treatment. One-hundred fifty-four outpatients with MDD were randomized to receive mirtazapine or SSRIs in step I (4 weeks). Non-responders in step I were randomly assigned to either mirtazapine or SSRIs monotherapy or their combination in step IIa while responders in step I continued the same monotherapy in step IIb for 4 weeks. In step I, mirtazapine showed significantly faster improvement as shown by higher remission rate at week 2 with NNT = 8 compared to SSRIs. Somnolence rate was higher in mirtazapine and nausea rate was higher in SSRIs. In step IIa, combination therapy showed a more favorable time course than SSRIs monotherapy. For subjects taking SSRIs in step I, combination therapy showed significant better improvement in the Hamilton Depression Rating (HAM-D) score both at week 6 (p = 0.006) and 8 (p = 0.013) than SSRIs monotherapy. About 80% of responders at week 4 could reach remission at week 8 and 64% of non-responders could not reach remission at week 8 for patients who continued monotherapy. When mirtazapine was added on for SSRIs non-responders at week 4, the remission rate increased by 5% and HAM-D score improved by 4 points. While for mirtazapine non-responders, SSRIs add-on was not equally effective. Mirtazapine may provide a faster improvement and “non-response at week 4” may be indicator to mirtazapine add-on for patients receiving SSRIs.

Purpose: The aim of this study was to compare the effects of risperidone long-acting injection (RLAI) and paliperidone palmitate (PP) on non-acute-phase social functioning in patients with schizophrenia. Patients and Methods: In this 6-month pilot, open-label, randomized controlled study, 30 patients with schizophrenia who had been treated with RLAI were randomly allocated to the RLAI continuation group or switched to the PP group. Patients were evaluated at baseline and 6 months with the Social Functioning Scale (SFS) as the primary outcome variable and University of California San Diego Performance-Based Skills Assessment Brief (UPSA-B), Social Emotional Cognition Task (SECT), Positive and Negative Syndrome Scale (PANSS), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores as secondary outcomes. Results: At baseline, the two groups did not significantly differ in demographic or clinical features. The two groups did not differ in total score changes for the UPSA-B, the SECT, the PANSS, and the DIEPSS. However, the total scores and the two subscales of the SFS, i.e. independence-competence and independence-performance, were more improved in the PP group compared to the RLAI group (total scores, p = 0.038; competence, p = 0.001, and performance, p = 0.007, respectively). Conclusion: These results suggest that PP may improve the total social functioning, independent life competence, and performance as compared to the RLAI group. However, these results are preliminary and need independent replication in larger samples before any definitive statement can be made.

Background Recently, long-acting injection (LAI) of second-generation antipsychotics has become a valuable strategy for the treatment of schizophrenia. However, few studies have compared the effects of different LAI antipsychotics on cognitive functions so far. The present study aimed to compare the influence of risperidone LAIs (RLAI) and paliperidone palmitate LAIs (PP) on cognitive function in outpatients with schizophrenia. Methods In this 6-month, open-label, randomized, and controlled study, 30 patients with schizophrenia who were treated with RLAIs were randomly allocated to the RLAI-continued group or the PP group. At baseline and 6 months, the patients were evaluated using the Brief Assessment of Cognition in Schizophrenia (BACS) that was the primary outcome of the study. The Subjective Well-being under Neuroleptic drug treatment-Short form (SWNS), the Positive and Negative Syndrome Scale (PANSS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were secondary outcome variables and they were tested at the same time points. Results The two groups did not differ in terms of PANSS, DIEPSS, or SWNS total score changes. However, the BACS score for the attention and processing speed item showed higher improvement in the PP group than the RLAI group (p = 0.039). Conclusions The results of this preliminary study suggest that PPs may improve attention and processing speed more than RLAIs. Anyway, a replication in a larger and double-blind study is needed. Trial registration UMIN000014470. Registered 10 July 2014 Electronic supplementary material The online version of this article (doi:10.1186/s12888-016-0883-9) contains supplementary material, which is available to authorized users.

Background: This meta-analysis was conducted to evaluate whether HTR1A gene polymorphisms impact the efficacy of antipsychotic drugs in patients with schizophrenia. Methods: Candidate gene studies that were published in English up to August 6, 2015 were identified by a literature search of PubMed, Web of Science, and Google scholar. Data were pooled from individual clinical trials considering overall symptoms, positive symptoms and negative symptoms, and standard mean differences were calculated by applying a random-effects model. Results: The present meta-analysis included a total of 1281 patients from 10 studies. Three polymorphisms of HTR1A (rs6295, rs878567, and rs1423691) were selected for the analysis. In the pooled data from all studies, none of these HTR1A polymorphisms correlated significantly with either overall symptoms or positive symptoms. However, C allele carriers of the rs6295 polymorphism showed a significantly greater negative symptoms improvement than G allele carriers ( P =.04, standardized mean difference =-0.14, 95％CI = 0.01 to 0.28). Conclusions: The results of our present analysis indicate that the HTR1A rs6295 polymorphism may impact negative symptoms improvement but not on either overall symptoms or positive symptoms improvement. However, this meta-analysis was based on a small number of studies and patients, and the effect size on negative symptoms was small. Given this limitation, the results should be confirmed by further investigations.

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.

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.

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