Pre-treatment plasma cytokine levels as potential predictors of short-term remission of depression.

OBJECTIVES: The response to antidepressants varies significantly among individuals and is difficult to predict before treatment. In this randomised 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. METHODS: Plasma cytokines, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, 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. RESULTS: In the SSRI group, the baseline GM-CSF level was significantly higher in the remission group than in the non-remission group (p = .022). In the MIR group, the baseline level of TNF-α was significantly higher (p = .039) and IL-2 was lower (p = .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%. CONCLUSIONS: Our study shows that pre-treatment plasma concentrations of TNF-α, IL-2, and GM-CSF may suggest the predictability of remission by SSRIs or MIR.

Effect of single caffeine intake on neuropsychological functions in healthy volunteers: A double-blind placebo-controlled study.

OBJECTIVE: We investigated the effects of a single instance of caffeine intake on neurocognitive functions and driving performance in healthy subjects using an established cognitive battery and a driving simulator system. METHODS: This study was conducted in a double-blind, randomized, placebo-controlled manner from February 19, 2016 to August 6, 2016. Caffeine intake was discontinued 3 days prior to the study. Participants were randomly assigned to receive 200-mg doses of caffeine or a placebo. Thirty minutes after administration, cognitive functions were evaluated via the Symbol Digit Coding Test (SDC), the Stroop Test (ST), the Shifting Attention Test (SAT) and the Four Part Continuous Performance Test (FPCPT). After the cognitive function tests were conducted, driving performance was evaluated using a driving simulator. We measured the brake reaction time (BRT) in the Harsh-braking test and the standard deviation of the lateral position (SDLP) in the Road-tracking test. RESULTS: Of 100 randomized subjects, 50 (50%) of 100 in the caffeine group and 50 (50%) of 100 in the placebo group completed the study. Participants in the caffeine group had more correct responses than participants in the placebo group on the SAT (P = 0.03) and made fewer errors (P = 0.02). Participants in the caffeine group exhibited shorter times in the Harsh-braking test than participants in the placebo group (P = 0.048). CONCLUSIONS: A single instance of caffeine intake changed some neurocognitive functions and driving performance in healthy volunteers. TRIAL REGISTRATION: UMIN000023576.

Attention-deficit/hyperactivity disorder symptoms and suicidal behavior in adult psychiatric outpatients.

AIM: We aimed to examine the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidal behavior in psychiatric outpatients and whether this association differs among patients with different psychiatric disorders. METHODS: Cross-sectional data came from the Japan Prevalence Study of Adult ADHD at Psychiatric Outpatient Care, which included psychiatric outpatients aged 18-65 years recruited from one university hospital and three general psychiatric outpatient clinics in Kitakyushu City, Fukuoka, Japan from April 2014 to January 2015 (N = 864). The Adult ADHD Self-Report Scale (ASRS) Screener was used to collect information on ADHD symptoms. Reports of current and lifetime suicidal behavior were also obtained. A multivariable Poisson regression analysis was used to examine the association between ADHD symptoms and suicidal behavior. RESULTS: After adjusting for covariates there was a strong association between possible ADHD (ASRS ≥14) and suicidal behavior with prevalence ratios ranging from 1.17 (lifetime suicidal ideation) to 1.59 (lifetime suicide attempt) and 2.36 (current suicidal ideation). When ASRS strata were used, there was a dose-response association between increasing ADHD symptoms and suicidal ideation and suicide attempts. Analyses of individual ICD-10 psychiatric disorders showed that associations varied across disorders and that for anxiety disorder, ADHD symptoms were significantly linked to all forms of suicidal behavior. CONCLUSION: ADHD symptom severity is associated with an increased risk for suicidal behavior in general psychiatric outpatients. As ADHD symptoms are common among adult psychiatric outpatients, detecting and treating ADHD in this population may be important for preventing suicidal behavior.

Influence of Single-Nucleotide Polymorphisms in PPAR-δ, PPAR-γ, and PRKAA2 on the Changes in Anthropometric Indices and Blood Measurements through Exercise-Centered Lifestyle Intervention in Japanese Middle-Aged Men.

The purpose of the current study was to examine the influence of single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-δ (PPAR-δ), PPAR-γ, and α2 isoforms of the catalytic subunit of AMP-activated protein kinase (PRKAA2) on the extent of changes in anthropometric indices and blood measurements through exercise-centered lifestyle intervention in middle-aged men. A total of 109 Japanese middle-aged male subjects (47.0 ± 0.4 years) participated in the baseline health checkup, 6-month exercise-centered lifestyle intervention, and second checkup conducted several months after the subject completed the intervention. The body mass index (BMI), waist circumference, and clinical measurements, including hemoglobin Alc (HbA1c), triglyceride (TG), alanine aminotransferase (ALT), and γ-glutamyl-transpeptidase (γ-GTP), were measured at the baseline and second checkup. The three SNPs of PPAR-δ A/G (rs2267668), PPAR-γ C/G (rs1801282), and PRKAA2 A/G (rs1418442) were determined. Blunted responses in the reduction in the BMI and waist circumference were observed in A/A carriers of PPAR-δ SNP compared with G allele carriers (all p < 0.05). The A/A carriers also displayed less-marked improvements in HbA1c, TG, ALT, and γ-GTP (all p < 0.05). The current results suggest that A/A carriers of PPAR-δ SNP (rs2267668) may enjoy fewer beneficial effects of exercise-centered lifestyle intervention on anthropometric indices and blood measurements.

Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.

MeCP2 knockdown reveals DNA methylation-independent gene repression of target genes in living cells and a bias in the cellular location of target gene products.

MeCP2, a methyl-CpG binding domain (MBD) protein, is known to bind to methylated CpG sites via a conserved MBD, leading to transcriptional repression. However, studies in cell-free system for gene repression and MeCP2 binding have suggested that DNA methylation-independent repression also occurs in living cells. It has been difficult to characterize the target genes of MeCP2 because a limited number have been identified to date. In this context, we screened for MeCP2 target genes using knockdown (KD) experiments combined with microarray gene expression analyses. Of the 49 genes that showed a more than three-fold increase in expression in two independent KD experiments conducted with different siRNA sets, unexpectedly, half (24 genes) did not contain promoter CpG islands (CGIs). Of seven selected genes that did contain CGIs, only two were methylated at the CGI, bound MeCP2 before KD, and reduced MeCP2 after KD. For three, MeCP2 was observed to bind to the unmethylated CGI before KD, and for one MeCP2 was reduced after KD. Another two genes neither had DNA methylation nor bound MeCP2 before KD. Gene ontology analysis suggested that MeCP2 represses a certain group of genes. These results suggest that in addition to the canonical gene repression function, MeCP2 can repress gene expression by binding to unmethylated DNA in particular genes in living cells.