Lower plasma tumor necrosis factor-α is associated with symptomatic remission in patients with schizophrenia.

We investigated the plasma tumor necrosis factor (TNF)-α levels between patients with schizophrenia remission and healthy controls, and the association between the plasma TNF-α levels and cognitive function and social function. This cross-sectional study included 48 patients with schizophrenia who fulfilled the remission criteria and 20 healthy controls. Plasma TNF-α levels were measured using the enzyme-linked immunosorbent assay, and cognitive function was assessed using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J). We measured social function using the Social Functioning Scale (SFS-J). The plasma TNF-α levels were significantly lower in the remission schizophrenia group (31.7 ± 27.4 ng/mL) compared to the heathy control group (55.1 ± 38.5 ng/mL) (P = 0.01). In contrast, no correlation was observed between the plasma levels of TNF-α and all BACS-J scores and all SFS-J scores in either group. This result suggests that plasma TNF-α levels may serve as a clinical biomarker of remission of schizophrenia and that the plasma TNF-α levels bore no association with cognitive function. Thus, TNF-α may have potential as a useful indicator of the therapeutic response in patients with schizophrenia.

Effects of Exercise on Functional Recovery in Patients with Bipolar Depression: A Study Protocol for a Randomized Controlled Trial.

Treatment of bipolar disorder is prone to prolongation despite various treatments, including medication. The efficacy of exercise treatment (i.e., interventions involving physical exercise and sports intervention) for major depressive disorders has been reported for depressive symptoms, cognitive function, and sleep disturbances. However, its efficacy for bipolar disorder has yet to be established. We designed a randomized, controlled, double-blind clinical trial that includes 100 patients with bipolar disorder aged 20-65 years. This will be a cluster-randomized, two-group trial that will be conducted in ten psychiatric hospitals. The hospitals will be randomly assigned to an exercise intervention + treatment as usual (exercise) group or a placebo exercise intervention (stretching) + treatment as usual (control) group. Patients will be assessed using an extensive battery of clinical tests, physical parameters, sleep status, biological parameters (cytokines, neurotrophic factors), and genetic parameters (DNA and RNA) at baseline after a 6-week intervention period, at 10-week follow-up, and at 6-month follow-up. This innovative study may provide important evidence for the effectiveness of exercise in the treatment of bipolar depression based on clinical, biological, genetic, and physiological markers.

Effects of treatment contents on changes in resilience among workers with mood or anxiety disorders: A 3-month longitudinal study.

Aim: The aim of this study was to identify factors that influence changes in resilience among workers with mental health disorders, leading to effective treatment and support. Methods: Among the new patients at an institution, 81 who were working and had the ICD-10 diagnoses F3 and F4 were included. Resilience was measured at the initial visit and 3 months later using the S-H resilience test. Univariate and multiple regression analyses were conducted using the change in resilience between the two measurements as the objective variable, and treatment and attendance at work as explanatory variables. Results: There were no significant differences in resilience abilities between pre- and postmeasurement for the subjects as a whole. However, tests for the subgroups of diagnostic category, attendance at work, and treatment showed that resilience improved significantly in the mood disorder group, the leaving employment group, and the group receiving additional treatment. The results of the multiple regression analysis showed that treatment type (with or without additional treatment) had an effect on the degree of change in resilience, and among these "inpatient treatment" and "re-work program" were suggested to have an effect. Conclusion: The resilience of workers with mental health disorders was found to improve even after only 3 months of treatment, depending on the content of the treatment. We believe the significance of this study is the quantitative indication of the transition of resilience, which has not been made concrete until now.

Lysophosphatidic acid levels in cerebrospinal fluid and plasma samples in patients with major depressive disorder.

Major depressive disorder (MDD) is the most common psychiatric disorders. However, a biochemical marker has yet to be established for clinical purposes. It is proposed that lysophosphatidic acid (LPA, 1-acyl-2-sn-glycerol-3-phosphoate) plays some important roles in emotional regulation of experimental animals. Therefore, in this study, we measured LPA levels using enzyme-linked immunosorbent assays of cerebrospinal fluid (CSF) and plasma samples from patients with MDD. The participants were 52 patients and 49 normal healthy controls for CSF study, and 47 patients and 44 controls for plasma study. We used the Japanese version of the GRID Hamilton Depression Rating Scale (17-item version) for the assessment of depressive symptoms. We found no associations between LPA levels (CSF or plasma) and either diagnosis or severity of MDD, or with psychotropic medication. In conclusion, our data suggest that LPA levels likely would not serve as a practical biomarker of MDD.

Levels of lysophosphatidic acid in cerebrospinal fluid and plasma of patients with schizophrenia.

It is suggested that lysophosphatidic acid (LPA) plays a key role in the pathophysiology of schizophrenia. In this study, we measured LPA levels by enzyme-linked immunosorbent assay in cerebrospinal fluid (CSF) and plasma samples. The participants were 49 patients with schizophrenia and 49 normal healthy controls for CSF study, and 42 patients and 44 controls for plasma study. We found that LPA levels in the patients were not significantly different from those of controls in CSF (controls: 0.189 ±â€¯0.077 µM, patients: 0.175 ±â€¯0.067 µM; P = 0.318) and plasma samples (controls: 0.131 ±â€¯0.067 µM, patients: 0.120 ±â€¯0.075 µM; P = 0.465). On the other hand, CSF levels in medicated patients (0.162 ±â€¯0.061 µM) were significantly lower than those observed in unmedicated patients (0.224 ±â€¯0.067 µM, P = 0.038), suggesting that our findings could be masked by the influence of medication with antipsychotics. Interestingly, we detected significant negative correlation between PANSS scores and plasma LPA levels, especially in males and in unmedicated patients. Our result suggests that LPA levels in CSF and plasma samples would not serve as a diagnostic biomarker, but plasma levels could be used for symptomatic assessment of schizophrenia.

Systemic administration of a delta opioid receptor agonist, KNT-127, facilitates extinction learning of fear memory in rats.

Strategies to facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of a delta opioid receptor agonist, KNT-127, has clear anxiolytic-like effects in rats, without impairing memory. These observations led us to hypothesize that KNT-127 might be an appropriate therapeutic agent for anxiety disorders when combined with exposure therapy. In the present study, we demonstrate that KNT-127 (3 mg/kg) facilitates extinction learning of fear memory using the contextual fear conditioning test. As expected, a partial agonist at the glycine-binding site on the glutamatergic N-methyl-d-aspartate receptor, d-cycloserine (15 mg/kg), facilitated extinction learning of contextual fear in rats. In contrast, a benzodiazepine anxiolytic, diazepam (1 mg/kg), impaired the fear extinction learning. Interestingly, the facilitatory effect of KNT-127 on extinction learning was observed not only after a 10-min re-exposure, but also after a much shorter (2-min) re-exposure to the context, while d-cycloserine was ineffective at facilitating extinction when a short-duration exposure was given. Our findings may suggest that administration of a delta opioid receptor agonist might have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders.

A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients.

BACKGROUND: Clinical and pharmacological studies of obsessive-compulsive disorder (OCD) have suggested that the serotonergic systems are involved in the pathogenesis, while structural imaging studies have found some neuroanatomical abnormalities in OCD patients. In the etiopathogenesis of OCD, few studies have performed concurrent assessment of genetic and neuroanatomical variables. METHODS: We carried out a two-way ANOVA between a variable number of tandem repeat polymorphisms (5-HTTLPR) in the serotonin transporter gene and gray matter (GM) volumes in 40 OCD patients and 40 healthy controls (HCs). RESULTS: We found that relative to the HCs, the OCD patients showed significant decreased GM volume in the right hippocampus, and increased GM volume in the left precentral gyrus. 5-HTTLPR polymorphism in OCD patients had a statistical tendency of stronger effects on the right frontal pole than those in HCs. CONCLUSIONS: Our results showed that the neuroanatomical changes of specific GM regions could be endophenotypes of 5-HTTLPR polymorphism in OCD.

Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats.

We previously demonstrated that a single treatment of a non-peptidic delta opioid receptor agonist, KNT-127, has an antidepressant-like effect in rodents in the forced swim test. Here we evaluated the effect of repeated administration of the potential antidepressant KNT-127 in an olfactory-bulbectomized (OBX) rat model. Male Wistar rats (8-12 weeks old) underwent olfactory bulbectomy. From 14days after surgery each was weighed and administered either KNT-127 (3mgkg-1/day), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mgkg-1/day), or vehicle, daily for 14 days. Hyperemotionality was measured on days 3, 5, 7, 10, and 14. Repeated administration of KNT-127 significantly decreased total and individual hyperemotionality scores (attack, startle, struggle and fight) over the entire period. Conversely, fluoxetine did not show any significant effect on days 3, 5, 7, or 14 but significantly reduced the total score on day 10. The inhibitory effects of KNT-127 were greater than those of fluoxetine. The KNT-127 and control groups both gained weight, while the fluoxetine group lost weight. Our results suggest that KNT-127 is a potential lead compound for antidepressant therapy, with high efficacy, a relatively rapid onset of therapeutic effect, and without the possible adverse effects of weight loss caused by SSRIs.

The voltage-gated sodium channel activator veratrine induces anxiogenic-like behaviors in rats.

In this study, we investigated the anxiogenic-like effects of systemically administered veratrine in rat models of anxiety. In the light/dark test, veratrine (0.6 mg/kg, s.c.) significantly and dose-dependently decreased the time rats spent in and the number of entries into a light box 30 min after administration, suggesting that veratrine increases anxiety-like behaviors. These findings were also supported by results from the elevated-plus maze test and the tail-swing behavior test. In addition, veratrine (0.6 mg/kg, s.c.) significantly increased the plasma concentration of corticosterone, an endogenous biomarker for anxiety, compared to vehicle. On the basis of these results, we conclude that veratrine induces anxiogenic-like behaviors in rats. The anxiogenic-like behaviors induced by veratrine (0.6 mg/kg, s.c.) were completely abolished by co-treatment with the typical benzodiazepine anxiolytic diazepam (1 mg/kg, s.c.), when assessed in the elevated-plus maze test. Similar results were obtained with co-treatment with riluzole (10 mg/kg, p.o.), which directly affects the glutamatergic system and has recently been suggested to have anxiolytic-like effects. In conclusion, this study provides evidence that systemically administered veratrine induces anxiogenic-like behaviors in rats. We propose the veratrine model as a novel pathological animal model to explore possible candidate drugs for anxiolytics.

Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies.

To determine the epidemiological, clinical, and genetic characteristics of congenital hypomyelinating leukodystrophies, including Pelizaeus-Merzbacher disease (PMD), we conducted a nationwide epidemiological survey in Japan. A two-step survey targeting all medical institutions specializing in pediatric neurology and childhood disability (919 institutes) in Japan was performed. Detailed information was collected for 101 patients (86 males and 15 females) with congenital hypomyelinating leukodystrophies. The prevalence of congenital hypomyelinating disorders was 0.78 per 100,000 people (0-19 years old), and the incidence was 1.40 per 100,000 live births. Molecular testing was performed in 75 % of patients, and PLP1 gene abnormalities were observed in 62 %. The incidence of PMD with PLP1 mutations was estimated to be 1.45 per 100,000 male live births and that for congenital hypomyelinating disorders with unknown cause to be 0.41 per 100,000 live births. Patients with PLP1 mutations showed a higher proportion of nystagmus and hypotonia, both of which tend to disappear over time. Our results constitute the first nationwide survey of congenital hypomyelinating disorders, and provide the epidemiological, clinical, and genetic landscapes of these disorders.

Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine.

Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating disorder caused by the duplication and missense mutations of the proteolipid protein 1 (PLP1) gene. PLP1 missense proteins accumulate in the endoplasmic reticulum (ER) of premature oligodendrocytes and induce severe ER stress followed by apoptosis of the cells. Here, we demonstrate that an anti-malaria drug, chloroquine, decreases the amount of an ER-resident mutant PLP1 containing an alanine-243 to valine (A243V) substitution, which induces severe PMD in human. By preventing mutant PLP1 translation through enhancing the phosphorylation of eukaryotic initiation factor 2 alpha, chloroquine ameliorated the ER stress induced by the mutant protein in HeLa cells. Chroloquine also attenuated ER stress in the primary oligodendrocytes obtained from myelin synthesis deficit (msd) mice, which carry the same PLP1 mutation. In the spinal cords of msd mice, chloroquine inhibited ER stress and upregulated the expression of marker genes of mature oligodendrocytes. Chloroquine-mediated attenuation of ER stress was observed in HeLa cells treated with tunicamycin, an N-glycosylation inhibitor, but not with thapsigargin, a sarco/ER Ca(2+)ATPase inhibitor, which confirms its efficacy against ER stress caused by nascent proteins. These findings indicate that chloroquine is an ER stress attenuator with potential use in treating PMD and possibly other ER stress-related diseases.

GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.

OBJECTIVE: Pelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167A>G) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variant. METHODS: We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays. RESULTS: A novel GJC2 mutation (c.-170A>G) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167A>G mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10. INTERPRETATION: These findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies.

Partial PLP1 deletion causing X-linked dominant spastic paraplegia type 2.

BACKGROUND: Proteolipid protein 1 gene (PLP1) mutations result in a continuum of neurological findings characterized by X-linked hypomyelinating leukodystrophies of the central nervous system, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease. PATIENTS: We report spastic paraplegia type 2 in three individuals in one family. A 29-year-old man developed progressive spastic quadriplegia from early childhood with dysarthria, ataxia, dysphagia, and intellectual delay, but he displayed no nystagmus. His mother developed adult-onset mild spastic diplegia with dementia developing in later life, whereas his sister exhibited spastic diplegia from childhood, complicated by motor developmental delay and dysphagia. All three individuals had initially mild but progressive neurological phenotypes, no nystagmus, normal brainstem auditory-evoked potentials, and demyelinating peripheral neuropathy, but with varying clinical severity. RESULTS: A 33-kb deletion encompassing exon 2 to 7 of PLP1 was identified in all three patients. Cloning of the junction fragment of the genomic recombination revealed a short palindromic sequence at the distal breakpoint, potentially facilitating a double-strand deoxyribonucleic acid break, followed by nonhomologous end joining. X-inactivation study and sequencing of the undeleted PLP1 alleles failed to explain the differences in severity between the two female patients. CONCLUSIONS: PLP1 partial deletion is a rare cause of spastic paraplegia type 2 and exhibits X-linked dominant inheritance with variable expressivity.

Nominal association between a polymorphism in DGKH and bipolar disorder detected in a meta-analysis of East Asian case-control samples.

AIM: Recent genome-wide association studies (GWAS) of bipolar disorder (BD) have detected new candidate genes, including DGKH, DFNB31 and SORCS2. However, the results of these GWAS were not necessarily consistent, indicating the importance of replication studies. In this study, we tested the genetic association of DGKH, DFNB31 and SORCS2 with BD. METHODS: We genotyped 18 single-nucleotide polymorphisms (SNP) in DGKH, DFNB31 and SORCS2 using Japanese samples (366 cases and 370 controls). We also performed a meta-analysis of four SNP in DGKH, using the previously published allele frequency data of Han-Chinese case-control samples (1139 cases and 1138 controls). RESULTS: IN the association analysis using Japanese samples, a SNP in SORCS2 (rs10937823) showed nominal genotypic association. However, we could not find any association in an additional analysis of tag SNP around rs10937823. In the meta-analysis of SNP in DGKH, rs9315897, which was not significantly associated with BD in the previous Chinese study, showed nominal association. CONCLUSION: Although the association was not strong, the result of this study would support the association between DGKH and BD.

Inhibitory effects of SSRIs on IFN-γ induced microglial activation through the regulation of intracellular calcium.

Microglia, which are a major glial component of the central nervous system (CNS), have recently been suggested to mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia are also known to play a critical role as resident immunocompetent and phagocytic cells in the CNS. Immunological dysfunction has recently been demonstrated to be associated with the pathophysiology of depression. However, to date there have only been a few studies on the relationship between microglia and depression. We therefore investigated if antidepressants can inhibit microglial activation in vitro. Our results showed that the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline significantly inhibited the generation of NO and tumor necrosis factor (TNF)-α from interferon (IFN)-γ-activated 6-3 microglia. We further investigated the intracellular signaling mechanism underlying NO and TNF-α release from IFN-γ-activated 6-3 microglia. Our results suggest that paroxetine and sertraline may inhibit microglial activation through inhibition of IFN-γ-induced elevation of intracellular Ca(2+). Our results suggest that the inhibitory effect of paroxetine and sertraline on microglial activation may not be a prerequisite for antidepressant function, but an additional beneficial effect.

Brain-derived neurotrophic factor induces sustained elevation of intracellular Ca2+ in rodent microglia.

Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca(2+) concentration ([Ca(2+)]i) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca(2+)]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca(2+)]i elevation. Pretreatment with BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IFN-gamma-induced increase in [Ca(2+)]i, along with a rise in basal levels of [Ca(2+)]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders.

Association analysis of adenosine A1 receptor gene (ADORA1) polymorphisms with schizophrenia in a Japanese population.

OBJECTIVE: The human adenosine A1 receptor gene (ADORA1) localizes to chromosome 1q32 is 76.8 kbp in length and contains six exons. ADORA1 is ubiquitously expressed in the central nervous system and clinical and pharmacological evidence suggest the involvement of adenosine neurotransmission in the pathogenesis of schizophrenia. Therefore, we investigated the contribution of genetic variations of ADORA1 to the pathophysiological mechanisms of Japanese schizophrenia patients. METHODS: We performed genetic analysis of 29 polymorphic markers in 200 schizophrenic patients and 210 healthy controls from the Kyushu region of Japan. In statistical analysis, we performed the univariate analysis with genotypes and allele frequencies, linkage disequilibrium (LD) analyses, multivariate analysis, haplotype analysis, and sliding window haplotype analysis. RESULTS: In univariate analysis, no statistical difference was shown, after Bonferroni correction. By LD analysis, however, we could not find any LD blocks. In haplotype analysis, a total of 359 haplotypes were estimated. In multivariate analysis, we found three statistically different markers. In sliding window haplotype analysis, there were four statistically different haplotypes. CONCLUSION: This is the first study describing the involvement of ADORA1 polymorphisms in the pathophysiological mechanisms of schizophrenia in a Japanese population. These results corroborate our previous pharmacological and neurochemical studies in the rat that have suggested an association between ADORA1 neurotransmission and the schizophrenic effects of the N-methyl-D-aspartate receptor antagonist phencyclidine. Thus, ADORA1 polymorphisms may represent good candidate markers for schizophrenia research and ADORA1 may be involved in the pathophysiological mechanisms of schizophrenia in Japanese populations.

Effects of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine on phencyclidine-induced behavior and expression of the immediate-early genes in the discrete brain regions of rats.

Because of the possible interaction between adenosine receptors and dopaminergic functions, the compound acting on the specific adenosine receptor subtype may be a candidate for novel antipsychotic drugs. To elucidate the antipsychotic potential of the selective adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA), we examined herein the effects of CPA on phencyclidine (PCP)-induced behavior and expression of the immediate-early genes (IEGs), arc, c-fos and jun B, in the discrete brain regions of rats. PCP (7.5 mg/kg, s.c.) increased locomotor activity and head weaving in rats and this effect was significantly attenuated by pretreatment with CPA (0.5 mg/kg, s.c.). PCP increased the mRNA levels of c-fos and jun B in the medial prefrontal cortex, nucleus accumbens and posterior cingulate cortex, while leaving the striatum and hippocampus unaffected. CPA pretreatment significantly attenuated the PCP-induced increase in c-fos mRNA levels in the medial prefrontal cortex and nucleus accumbens. CPA also significantly attenuated the PCP-induced arc expression in the medial prefrontal cortex and posterior cingulate cortex. When administered alone, CPA decreased the mRNA levels of all IEGs examined in the nucleus accumbens, but not in other brain regions. Based on the ability of CPA to inhibit PCP-induced hyperlocomotion and its interaction with neural systems in the medial prefrontal cortex, posterior cingulate cortex and nucleus accumbens, the present results provide further evidence for a significant antipsychotic effect of the adenosine A(1) receptor agonist.