Tomihisa Niitsu

Decreased Serum Levels of Mature Brain-Derived Neurotrophic Factor (BDNF), but Not Its Precursor proBDNF, in Patients with Major Depressive Disorder

Background Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD. Methodology/Principal Findings Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients. Conclusions/Significance These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.

A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia

BackgroundCognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia.MethodsA randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured.ResultsIn all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial.ConclusionsThis first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.

Sigma-1 Receptor Agonists as Therapeutic Drugs for Cognitive Impairment in Neuropsychiatric Diseases

Cognitive impairment is a core feature of patients with neuropsychiatric diseases such as schizophrenia and psychotic depression. The drugs currently used to treat cognitive impairment have significant limitations, ensuring that the search for more effective therapies remains active. Endoplasmic reticulum protein sigma-1 receptors are unique binding sites in the brain that exert a potent effect on multiple neurotransmitter systems. Accumulating evidence suggests that sigma-1 receptors play a role in both the pathophysiology of neuropsychiatric diseases, and the mechanistic action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil and neurosteroids. Among SSRIs, fluvoxamine, a potent sigma-1 receptor agonist, has the highest affinity at sigma-1 receptors. Sigma-1 receptor agonists greatly potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells, an effect that is antagonized by treatment with the selective sigma-1 receptor antagonist NE-100. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia is significantly improved by sub-chronic administration of sigma-1 receptor agonists such as fluvoxamine, SA4503 (cutamesine) and donepezil. This effect is antagonized by co-administration of NE-100. A positron emission tomography (PET) study using the specific sigma-1 receptor ligand [11C]SA4503 demonstrates that fluvoxamine and donepezil bind to sigma-1 receptors in the healthy human brain. In clinical studies, some sigma-1 receptor agonists, including fluvoxamine, donepezil and neurosteroids, improve cognitive impairment and clinical symptoms in neuropsychiatric diseases. In this article, we review the recent findings on sigma-1 receptor agonists as potential therapeutic drugs for the treatment of cognitive impairment in schizophrenia and psychotic depression.

Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia

Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.

Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis.

AbstractSeveral studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density.

A positive correlation between serum levels of mature brain-derived neurotrophic factor and negative symptoms in schizophrenia

A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed.

A randomized, double-blind, placebo-controlled trial of fluvoxamine in patients with schizophrenia: a preliminary study.

Abstract Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.

Decreased levels of serum oxytocin in pediatric patients with Attention Deficit/Hyperactivity Disorder

Attention Deficit/Hyperactivity Disorder (ADHD) and autism spectrum disorder (ASD) are highly comorbid, and both disorders share executive function deficits. Accumulating evidence suggests that ASD patients have significantly lower peripheral oxytocin (OXT) levels compared with their normal counterparts, and that the repetitive behavior seen in ASD is related to abnormalities in the OXT system. In this study, we investigated whether serum levels of OXT are altered in pediatric patients with ADHD. We measured serum OXT levels: drug naive ADHD (n=23), medicated ADHD (n=13), and age- and sex- matched, neurotypical controls (n=22). Patients were evaluated using the ADHD-RS. Serum levels of OXT in total subjects with ADHD were significantly decreased compared with those of neurotypical controls, and serum levels of OXT in drug naive ADHD patients were significantly lower than those in medicated ADHD patients. Interestingly, there was a significant negative correlation between serum OXT levels and ADHD-RS total scores, as well as ADHD-RS inattentive scores in all ADHD patients. In conclusion, this study suggests that decreased levels of OXT may play a role in the pathophysiology of patients with ADHD and its inherent inattentiveness.

Increased serum levels of serine enantiomers in patients with depression

Objective Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). Results Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001). Conclusion This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Association between serum levels of glial cell-line derived neurotrophic factor and attention deficits in schizophrenia.

Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the brief psychiatry rating scale, the scale for the assessment of negative symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia.