Wakako Umene-Nakano

Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression

In the present study, we compared plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha(TNFalpha), and brain-derived neurotrophic factor (BDNF) among selective serotonin reuptake inhibitor (SSRI)- or serotonin noradrenaline reuptake inhibitor (SNRI)-responsive depressed patients (n=31), SSRI- or SNRI-refractory depressed patients (n=20), and healthy controls (n=30). The plasma levels of IL-6 and TNF-alpha were significantly higher in depressed patients than in healthy controls. Treatment with antidepressants significantly reduced plasma levels of IL-6 and TNF-alpha. In addition, the plasma IL-6 level, but not the plasma TNF-alpha level, was higher in SSRI-refractory than SSRI-responsive depressed patients, and higher in SNRI-refractory than SNRI-responsive depressed patients. On the other hand, the plasma BDNF level was significantly lower in depressed patients than in healthy controls, whereas no difference was found in plasma BDNF levels between SSRI-responsive and -refractory depressed patients or between SNRI-responsive and -refractory depressed patients. These results suggest that higher plasma IL-6 activity is associated with the refractoriness of depression, and plasma IL-6 levels might be a predictor for response to SSRIs or SNRI.

Efficacy of electroconvulsive therapy is associated with changing blood levels of homovanillic acid and brain-derived neurotrophic factor (BDNF) in refractory depressed patients: a pilot study.

Electroconvulsive therapy (ECT) is effective for patients with antidepressant medication-resistant depression. However, the mechanisms of ECTs effectiveness for treating depression are not fully understood. We therefore investigated ECTs effects on blood levels of brain-derived neurotrophic factor (BDNF), catecholamine metabolites, and nitric oxide (NO) in 18 treatment-refractory depressed patients. Serum BDNF levels increased significantly following ECT in responders to ECT (before ECT: 8.0+/-9.7 ng/mL; five weeks after start of ECT: 15.1+/-11.1 ng/mL), whereas BDNF levels in non-responders were unchanged (before ECT: 11.5+/-11.0 ng/mL; five weeks after start of ECT: 9.4+/-7.5 ng/mL). Furthermore, the plasma HVA levels, but not MHPG levels, were significantly reduced after ECT (before ECT: 8.5+/-1.9 ng/mL; five weeks after start of ECT: 5.8+/-2.2 ng/mL). This latter finding occurred in parallel with the improvement of depressive symptoms in all patients. These results suggest that the mechanisms underlying ECTs effect on refractory depression may be related to dopaminergic neurons and BDNF.

Reduction of brain γ-aminobutyric acid (GABA) concentrations in early-stage schizophrenia patients: 3T Proton MRS study

It has been reported that γ-aminobutyric acid (GABA) neurotransmission appears to be altered in schizophrenia patients. Presynaptic markers of both GABA synthesis and reuptake are decreased in the cerebral cortex of schizophrenic subjects (Impagnatiello et al., 1998), while the density of postsynaptic GABAA receptors is upregulated in the prefrontal cortex (Hanada et al., 1992; Benes et al., 1992). Based on these findings, we hypothesized that patients with early-stage schizophrenia would have lower GABA levels in the brain compared to matched healthy subjects. In the present study, we measured brain concentrations of GABA. To our knowledge, this is the first report to examine the functions of GABAergic neurons in early-stage schizophrenia patients. A total of 18 patients (9 males, 9 females; age 29± 11 years) who fulfilled the DSM-IV-TR criteria for schizophrenia were enrolled in the study and underwent all MRS evaluations. All patients were screened by the Structured Clinical Interview for DSM-IV Disorders (First et al., 1995). The patients psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). The patients total cumulative exposure to a chlorpromazineequivalent dose of antipsychotic drugs was 9381±1382 mg (mean±SD). Eighteen healthy volunteers (9 males, 9 females; age range 30±11 years) with no current or past psychiatric history also participated in the study as sexand age-matched controls. All subjects were examined with H MRS by a 3T MR system (Signa EXCITE 3T; GE Medical Systems) with a standard quadrature head coil (GE Medical Systems). Standard PRESS spectra were acquired at TE=26 ms and 68 ms for quantification. GABA concentrations were measured using a MEGA-PRESS sequence (Mescher et al., 1998). The regions of interest (ROIs) for H MRS were set for the frontal lobe, the left basal ganglia, and the parieto-occipital lobe (ROI size=3.0 cm× 3.0 cm×3.0 cm) using two oriented images (axial and sagittal) for each region. The nonpaired t-test was used to compare the brain levels of GABA. This studywas approved by

Does the ‘hikikomori’ syndrome of social withdrawal exist outside Japan? A preliminary international investigation

PurposeTo explore whether the ‘hikikomori’ syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated.MethodsTwo hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome’s prevalence in their country, etiology, diagnosis, suicide risk, and treatment.ResultsOut of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents’ felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization.ConclusionsPatients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings.

The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder

The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (Pallele modelxa0=xa00.007 and Precessive modelxa0=xa00.01). When divided by diagnostic subgroup (MDDxa0=xa03,119 patients and 4,380 controls or BPxa0=xa01,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: Pallele modelxa0=xa00.006, Precessive modelxa0=xa00.01; BP: Pdominant modelxa0=xa00.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (Pallele modelxa0=xa00.0002, Pdominant modelxa0=xa00.0008, and Precessive modelxa0=xa00.01). When divided by diagnostic subgroup (MDDxa0=xa01,013 patients and 1,728 controls or BPxa0=xa01,051 patients and 2,099 controls), rs878567 was associated with MDD (Pallele modelxa0=xa00.0007 and Pdominant modelxa0=xa00.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs.

SIRT1 gene is associated with major depressive disorder in the Japanese population.

BACKGROUNDnMany studies including our previous ones as to PROKR2 and CLOCK have suggested that circadian genes may be involved in the mechanisms of mood disorders and their treatment responses. Also several recent investigations have reported that SIRT1 plays an important role in the circadian system as conventional circadian clock genes, and also have some relation to dopaminergic metabolism. So we considered the SIRT1 gene to be a good candidate gene for the pathophysiology for MDD and SSRI responses in MDD, and conducted a case-control study using four tagging SNPs (450 MDD patients, including 261 patients treated by SSRIs and 766 controls).nnnMETHODnThe MDD patients in this study had scores of 12 or higher on the 17 items of the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D). We defined a clinical response as a decrease of more than 50% in baseline SIGH-D within 8 weeks, and clinical remission as an SIGH-D score of less than 7 at 8 weeks. Marker-trait association analysis was used to evaluate allele and genotype association with the chi-square test, and haplotype association analysis was evaluated with a likelihood ratio test.nnnRESULTnWe found an association between rs10997875 in SIRT1 gene and MDD in the allele/genotype analysis. In addition, this significance of these associations survived Bonferroni correction. However, we did not find any association between SIRT1 gene and SSRI therapeutic response in MDD in the allele/genotype analysis or haplotype analysis.nnnLIMITATIONSnA replication study using larger samples may be required for conclusive results, since our sample size was small.nnnCONCLUSIONSnOur results suggest that rs10997875 in SIRT1 gene may play a role in the pathophysiology of MDD in the Japanese population.

The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients

BACKGROUNDnWe investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response.nnnMETHODSnA total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20-74years; mean±S.D., 51±15). The patients clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders.nnnRESULTSnNo correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at T0. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at T0.nnnCONCLUSIONSnThese results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression.

Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression.

Only two-thirds of depressive patients respond to antidepressant treatment. Recently, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we examined the effects of various atypical antipsychotic drugs as adjuvant to antidepressants, including selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors, tricyclic antidepressants and mood stabilizers, on plasma BDNF levels in refractory depressed patients. Forty-five patients who met the DSM-IV criteria for major depressive disorder (n=31) or bipolar disorder (10 with bipolar I, 4 with bipolar II) were enrolled in the study. Twenty-one were male and 24 were female, and their ages ranged from 28 to 71 (mean+/-SD=49+/-12) years. Plasma BDNF levels were measured using a sandwich ELISA. The plasma BDNF levels in responders (those showing a decline in HAM-D scores of 50% or more) were significantly increased 4weeks after the administration of each atypical antipsychotic drug, while the levels in non-responders were not changed. Furthermore, there was a significant correlation between the changes in HAM-D scores and the changes in plasma BDNF levels. These results suggest that adding an atypical antipsychotic drug to ongoing treatment with an antidepressant or mood stabilizer is useful and well-tolerated for refractory depressed patients, and the efficacy of atypical antipsychotics as an adjuvant might involve an increase of plasma BDNF levels.

Different patterns of longitudinal changes in plasma levels of catecholamine metabolites and brain-derived neurotrophic factor after administration of atypical antipsychotics in first episode untreated schizophrenic patients.

In the present study, we longitudinally investigated the effects of risperidone, olanzapine, and aripiprazole on plasma levels of catecholamine metabolites and brain-derived neurotrophic factor (BDNF) in first-episode unmedicated schizophrenic patients. The subjects were 59 Japanese schizophrenic patients (35 males and 24 females; age range: 18–46 years; mean±SD: 25±16 years). The patients were treated with risperidone (n=32) in a dose range of 2–6 mg/day (mean±SD=3.4±1.9), olanzapine (n=18) in a dose range of 5–20 mg/day (mean±SD=12.1±5.8), or aripiprazole (n=9) in a dose range of 12–30 mg/day (mean±SD=22.8±10.1). All three drugs significantly decreased plasma homovanillic acid (HVA) levels within 8 weeks, although aripiprazole transiently raised this level before 8 weeks. All three drugs also significantly increased plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels within 8 weeks. On the other hand, none of them altered plasma BDNF levels. These results indicate that risperidone, olanzapine, and aripiprazole affect catecholaminergic systems in the brain, that the effects of aripiprazole on the dopaminergic systems seem to slightly different than those of risperidone and olanzapine, and that these atypical antipsychotic drugs might not alter BDNF levels, at least within 8 weeks of treatment.

six-month treatment with atypical antipsychotic drugs decreased frontal-lobe levels of glutamate plus glutamine in early-stage first-episode schizophrenia

Objective To study the effects of treatment with atypical antipsychotic drugs on brain levels of glutamate plus glutamine in early-stage first-episode schizophrenia. Participants Sixteen patients (eight males, eight females; aged 30 ± 11 years) completed the study. Methods We used administered 6 months of atypical antipsychotic drugs and used proton magnetic resonance spectroscopy to evaluate the results. Results We found that the administration of atypical antipsychotic drugs for 6 months decreased the glutamate plus glutamine/creatine ratio in the frontal lobe. These results suggest that the administration of atypical antipsychotic drugs for at least 6 months decreased glutamatergic neurotransmissions in the frontal lobe in early-stage first-episode schizophrenia, but there was no difference in frontal-lobe levels between patients and control subjects before administration. Conclusion Taking these findings into account, the glutamatergic and GABAergic neurons are implicated in early-stage first-episode schizophrenia, but in complex ways.