Gohei Yagi

Elevated plasma nitrate levels in depressive states

BACKGROUND Previous studies have shown that nitric oxide (NO) synthase inhibitors show preclinical antidepressant-like properties, suggesting that NO is involved in the pathogenesis of depression. The purpose of this study is to examine whether or not NO production increases in depressed patients. METHODS Plasma nitrate concentrations, an index of NO production, were measured by high-performance liquid chromatography in depressed patients (n=17) and compared with patients suffering anxiety (n=6) and with healthy controls (n=12). RESULTS Plasma nitrate concentrations were significantly higher in depressed patients than in patients with an anxiety disorder (P<0.05) or in controls (P<0.01). LIMITATIONS The study group was small. The source of the surplus production of NO in patients with major depressive episode remains unclear. CONCLUSIONS These results suggest that NO production is increased in depression.

Association between dopamine D4 receptor (D4DR) Exon III polymorphism and novelty seeking in Japanese subjects

This study was designed to assess the association between novelty seeking and D4DR gene polymorphism in the Japanese population. The 48 bp repeat polymorphism in the third exon of the dopamine D4 receptor gene of 153 normal female students was correlated with personality feature results from the Japanese version of Cloningers Temperament and Character Inventory. The Novelty Seeking subscale of Exploratory Excitability had a significant association with long alleles of the polymorphic exon III repeat sequence of D4DR. Our results suggest that there is an association between long alleles of the polymorphic exon III repeat sequence of D4DR and the personality traits of the Novelty Seeking subscale of Exploratory Excitability, regardless of racial differences in the frequencies of D4DR exon III repeat polymorphism.

Serum interleukin-6 in schizophrenic patients

We examined serum interleukin-6 (IL-6) in 90 schizophrenic patients in remission and 90 normal controls using enzyme-linked immuno-sorbent assay (ELISA). We found a significant difference in variation between the schizophrenic and the control groups (F = 10.9, P less than .002). The difference in distribution was also statistically significant by Kolmogorov-Smirnov (chi-square = 45.0, P less than .001). Eight patients had aberrantly high serum levels of interleukin-6. Since the higher levels of IL-6 are characteristically found in several autoimmune disorders, our finding suggests a link between schizophrenia and immune response, which could be either autoimmune or a process induced by reactivation of viruses.

Dopamine D2, D3 and D4 receptor and transporter gene polymorphisms and mood disorders

Disturbances in dopaminergic systems have been implicated in the etiology of mood disorders. Although genetic factors also play an important role, no major gene has been identified. We conducted an association study using the dopamine D2, D3 and D4 receptor, and transporter gene polymorphisms, comparing 101 mood-disorder patients (52 bipolar and 49 unipolar) and 100 controls. Our results suggest that there is a significant association between the dopamine D4 receptor gene and mood disorders, especially major depression, but no association between the other polymorphisms and mood disorders. Further investigations are needed to clarify the clinical significance of this association in the pathophysiology of mood disorders.

Serum interleukin-18 levels are elevated in schizophrenia

Interleukin-18 (IL-18) is a recently discovered proinflammatory cytokine which plays a pivotal role in T helper 1 (Th1) responses. IL-18 is produced by macrophage-like cells, and inappropriate IL-18 production has been known to be involved in immunological disturbances. Schizophrenia is a common disease whose pathogenesis is still unclear; however, an activation of the inflammatory response system, including the Th1 cytokine response, may be related to the pathophysiology of schizophrenia. We measured the serum IL-18 levels of 66 schizophrenics and age- and sex-matched control subjects by using an ELISA assay. We found significantly increased serum IL-18 levels in the schizophrenic patients (P=0.0002). This finding supports the hypothesis that immune activation is involved in the pathophysiology of schizophrenia.

Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia

Antipsychotic polypharmacy has been empirically used and a recent trend in favour of that mode of therapy has been suggested for the treatment of schizophrenia. The clinical efficacy, however, still remains to be clarified. In order to critically evaluate the usefulness of such kind of psychopharmacotherapy, antipsychotic combination regimen (polypharmacy) was switched to a treatment with the single main antipsychotic (monotherapy) in cross-tapered fashion, while approximately maintaining the total amount, for patients with chronic schizophrenia. Patients had been treated with an average of three antipsychotics and maintained with the same antipsychotic polypharmacy regimen for more than 6 months before the entry. They were followed up with an antipsychotic monopharmacy and evaluated at 24 wk after completion of switching. Forty-seven patients were recruited for this study. Of 44 patients for whom evaluation was possible, 24 (54.5%) remained stable, while 10 (22.7%) showed improvement and the same number of patients ended in a deleterious status. Twenty-two patients were converted to antipsychotic monotherapy, while another 12 needed minimal dosing of low-potency agents. Overall, social functioning, evaluated by the Global Assessment of Functioning and the Clinical Global Impression, remained unchanged. Eighteen of 34 successful patients showed adverse effects of the main antipsychotic medication, which necessitated a significant dose reduction. Nine out of 10 deteriorating patients had been treated with a combination of low- and high-potency antipsychotics. It is suggested that many instances of antipsychotic polypharmacy is avoidable. The result is compatible with the current treatment recommendations, which dictate the use of a single antipsychotic agent.

Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol

Previous clinical trials have clearly shown the superiority of olanzapine to haloperidol in the improvement of extrapyramidal symptoms (EPS) in schizophrenic patients. The primary purpose of this study was to compare EPS profiles in Japanese schizophrenic patients treated with an atypical antipsychotic, olanzapine, or a typical antipsychotic, haloperidol, as measured by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The DIEPSS, which consists of eight individual parameters and one global assessment (overall severity), was used to evaluate 182 patients enrolled in this 8-week study. The primary safety analysis was maximum change (that could be either a decrease or increase) from baseline in DIEPSS total score. Secondary analyses included change from baseline to maximum in DIEPSS total score, change from baseline to endpoint (LOCF) in DIEPSS total score, and the rank sum of the maximum change (that could be either a decrease or increase) from baseline in the DIEPSS individual items. Incidence of treatment-emergent EPS adverse events using the DIEPSS scale was also analyzed. The olanzapine group showed statistically significant superiority to the haloperidol group on the primary analysis (p<0.001). Secondary analyses also demonstrated olanzapines superiority in DIEPSS total, parkinsonism, akathisia and overall severity scores (all p< or =0.014). Categorical analysis of treatment-emergent akathisia and parkinsonism syndromes at endpoint showed improvement in the olanzapine group but worsening in the haloperidol group. The results from this study suggest that olanzapine, as in Caucasian populations, is a safe treatment in Japanese patients chronically ill with schizophrenia.

Effectiveness of antipsychotic polypharmacy for patients with treatment refractory schizophrenia: an open-label trial of olanzapine plus risperidone for those who failed to respond to a sequential treatment with olanzapine, quetiapine and risperidone.

To evaluate the effectiveness of antipsychotic polypharmacy in a methodologically sound manner.

Dopamine Transporter Gene Polymorphism and Psychiatric Symptoms Seen in Schizophrenic Patients at Their First Episode

To investigate the possible role of the dopamine transporter (DAT) gene in determining the phenotype in human subjects, allele frequencies for the 40-bp variable number of tandem repeats (VNTR) polymorphism at this site were compared between 117 Japanese normal controls and 118 schizophrenic patients, including six subgroups: early-onset, those with a family history, and those suffering from one of the following psychiatric symptoms at their first episode: delusion and hallucination; disorganization; bizarre behavior; and negative symptoms. No significant differences were observed between the group as a whole or any subgroup of schizophrenic patients and controls. The results indicate that VNTR polymorphism in the DAT gene is unlikely to be a major contributor to any of the psychiatric parameters examined in the present population of schizophrenic subjects.

Augmentation of atypical antipsychotics with valproic acid. An open-label study for most difficult patients with schizophrenia

Most difficult inpatients with schizophrenia are in serious needs but obviously underrepresented in clinical trials.