A survey on the drug therapy for delirium.

Delirium, which is experienced by 10-30% of inpatients, is commonly seen in daily practice. A survey was conducted of the delirium medications, and results were obtained from 28 psychiatric departments and related facilities. Haloperidol was used in 67% cases for the treatment of delirium. Ninety-seven per cent of facilities considered haloperidol as the drug of first choice, while 57% thought this drug had few side-effects and was easy to use. However, because the use of this drug is not covered by health insurance in Japan, its use is limited. We expect that this study on medication for the treatment of delirium will be a first step in increasing the approved indications for drugs used for the treatment of delirium, and to reduce off-label use.

Combination of inflammatory cytokines increases nitrite and nitrate levels in the paraventricular nucleus of conscious rats.

Inflammatory cytokines stimulate glial cells in vitro to produce nitric oxide (NO) from inducible NO synthase (iNOS). Whether the stimulation with cytokines produces NO derived from iNOS has not hitherto been demonstrated in the vivo brain. Nitrite and nitrate (NOx(-)) levels in the rat paraventricular nucleus (PVN) were measured before and after intraparenchymal microinjection of cytokines with a microdialysis technique. The cytokines, tumor necrosis factor (TNF)-alpha (10 ng), interleukin (IL)-1 beta (2 ng), and interferon (IFN)-gamma (2 ng) were microinjected. None of the cytokines alone had any effect on the NOx(-) levels for 8 h. But a combination of TNF-alpha and IFN-gamma gradually increased NOx(-) levels beginning at 140 min after the microinjection, and NOx(-) levels reached 1.8 times the basal level at 380 min. A combination of TNF-alpha and IL-1 beta increased NOx(-) beginning at 340 min, reaching 1.7 times the basal level at 440 min, whereas a combination of IL-1 beta and IFN-gamma had no effect. Microinjection of a mixture of all three cytokines increased NOx(-) levels beginning at 120 min, reaching 3.3 times the basal level at 400 min. Aminoguanidine, which is a selective inhibitor of iNOS, reduced NOx(-) levels induced by the mixed cytokine treatment. Semi-quantitative RT-PCR for iNOS mRNA was done. The intensity of the iNOS mRNA band for the cytokine-treated PVN was stronger than that for the vehicle-treated PVN. These results suggest that the increased NOx(-) after the treatment with mixed cytokines were dependent on iNOS activity. This is the first report to indicate that only cytokines induce NOS in vivo in the brain.

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.

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.

Outcome of schizophrenia in a non-industrialized society: comparative study between Bali and Tokyo.

OBJECTIVE: The aim of the present study was to contrast the outcome of schizophrenic patients between Bali and Tokyo, the former being a non-industrialized society and the latter an industrialized society in Asia. METHOD: A total of 51 Balinese schizophrenics and 40 schizophrenics in Tokyo were evaluated by five outcome measures at a 5-year follow-up. RESULTS: No significant difference was found in the mean scores of the Positive and Negative Syndrome Scale, Eguma's Social Adjustment Scale and the re-admission rates between the subjects in the two sites. The cumulative length of stay in hospital during the 5-year period was significantly shorter in Bali. The percentage of subjects on psychiatric medication at the follow-up was significantly lower in Bali than that in Tokyo. CONCLUSION: Although the clinical outcome of schizophrenics in Bali was not superior to that in Tokyo, the subjects in Bali tended to be able to live in society without neuroleptic medication.

A contribution to genome-wide association studies: search for susceptibility loci for schizophrenia using DNA microsatellite markers on chromosomes 19, 20, 21 and 22.

As an initial step for genome-wide association studies, we sought an association between schizophrenia and 34 microsatellite markers on chromosomes 19, 20, 21 and 22 by a case-control design. The samples examined for an association were 168 schizophrenic patients and 146 control subjects in the Japanese population. The allele distribution of the 34 loci differed significantly between Japanese and French populations. Significant deviation from the Hardy-Weinberg equilibrium was observed at D19S209 and D21S1256 in the control subjects. Case-control comparisons of the initial screening revealed a significant difference in allele frequency at D20S95 and a trend of difference at D20S118. To confirm these possible associations, additional samples consisting of 110 schizophrenic patients and 116 control subjects were examined, and an association between D20S95 and schizophrenia was confirmed (corrected P value after Bonferroni correction, 0.00035). D20S95 is located close to the gene (CHGB) encoding chromogranin B. These findings suggest that CHGB could be an important candidate gene involved in the development of schizophrenia.

[Early phase II study of quetiapine fumarate on schizophrenia].

The efficacy and safety of quetiapine fumurate in the treatment of patients with schizophrenia were evaluated in an 8-week, multicenter, open-label study. The results of this study which included a total of 54 patients showed good efficacy and safety profile for quetiapine fumarate as seen by the improvement rate (moderate or above in the final global improvement rating) of 49.1% and safety rate (no problem in overall safety rating) of 66.0%. The mean BPRS total score decreased significantly from 55.5 +/- 10.9 points at baseline to 45.4 +/- 13.0 points at the completion of administration. The PANSS scores also showed significant improvement on all scales; the mean scores decreased from 20.7 +/- 6.3 points at baseline to 17.7 +/- 6.9 points at withdrawal or completion of administration on the positive scale, from 27.8 +/- 5.8 points to 24.0 +/- 7.3 points on the negative scale, and from 51.4 +/- 10.1 points to 44.7 +/- 12.4 points on the general psychopathology scale. Although the most frequent adverse reactions were somnolence (18.9%), insomnia (17.0%), nervousness (13.2%), dizziness (13.2%), malaise (13.2%), postural hypotension (11.3%), tachycardia (9.4%), and constipation (9.4%), the incidence of extrapyramidal symptoms was low (11.3%). From these results, quetiapine fumarate was suggested to be highly effective and safe for the treatment of schizophrenia.

Environmental and possible genetic contributions to character dimensions of personality.

The relationship between dimensions of personality characteristics and the perceived rearing attitude of parents in the Japanese population were investigated. The scores on a measure of perceived parental attitude of 153 normal female students, measured on the Parker Parental Bonding Instrument, were correlated with personality features from the Japanese version of the Cloninger Temperament and Character Inventory. Self-directedness, especially the subclasses of Responsibility vs Blaming and Congruent Second Nature vs Incongruent Habits, was significantly related to high scores on Maternal Care and low scores on Maternal Overprotection. The subscale of Self-acceptance vs Self-striving correlated only with low scores on Maternal Overprotection. Paternal Care was only related to the total scale scores on Self-directedness. Results suggest that some personality traits may be related to the perceived attitudes of parents, especially of the mother, during childhood.

Aberrant interleukin-2 receptor-mediated blastoformation of peripheral blood lymphocytes in a severe major depressive episode.

BACKGROUND: We examined interleukin-2 (IL-2) related immune pathways in depression to elucidate mechanisms underlying various immunological disturbances associated with depression. METHODS: Subjects comprised 35 unmedicated patients with a major depressive episode without psychotic features and 36 age- and sex-matched healthy volunteers. The immune parameters examined included the numbers of B and T cells, IL-2 receptor-mediated blastoformation (IL-2R-mediated blastoformation), IL-2 production and expression of the IL-2 receptor alpha-subunit. RESULTS: The patients with a severe episode showed significantly lower IL-2R-mediated blastoformation than the controls. There was a statistically significant negative correlation between IL-2R-mediated blastoformation and the severity of depression at the time of entry. CONCLUSION: The reduced IL-2R-mediated blastoformation may partly explain several previously reported abnormal immune functions associated with depression.

A transcultural study of psychopharmacotherapy for schizophrenia of neuroleptic treatment between Tokyo and Bali.

We made a comparison of drug treatment for the patients with schizophrenia between two psychiatric hospitals in Tokyo, Japan, and Bali, Indonesia. An initial preliminary, cross-sectional study revealed that the mean daily dose of neuroleptics was significantly higher in Tokyo than it was in Bali. A second, longitudinal, study showed that the mean neuroleptic dose for newly admitted patients in the acute phase was higher, and the number of patients receiving maintenance treatment after discharge larger in Tokyo, while the mean duration of hospitalization was shorter, and the re-admission rate 1 year after discharge lower in Bali. These findings suggest that the course of schizophrenia is more favorable in Bali. As a result of lower dose of neuroleptics, the prevalence of tardic dyskinesia was much lower in Bali than it was in Tokyo.

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 Cloninger's 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.

Low superoxide dismutase activity in schizophrenic patients with tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a therapy-resistant adverse effect of neuroleptics. Although the exact pathophysiology of TD is unknown, oxygen radicals have been speculated to play a role in TD based on several lines of evidence. Superoxide dismutase (SOD) is a key enzyme which scavenges oxygen radicals. The authors investigated the association between erythrocyte SOD activity and TD. METHODS: Erythrocyte SOD activities were measured, blinded as to the presence or absence of TD. In 30 patients with schizophrenia who had been on typical neuroleptics for more than 10 years. TD severity was independently assessed, using the abnormal involuntary movement scale (AIMS), by two raters. RESULTS: There was a significant decrease in erythrocyte SOD activity in the definite TD group (N = 10) as compared with the no TD (N = 8) and questionable TD (N = 12) groups. Erythrocyte Cu,Zn-SOD activities correlated with AIMS scores. CONCLUSIONS: Patients with TD had low SOD activities as compared to those without TD. As a causal link between SOD activity and TD was not established in this study, larger prospective studies are warranted to determine whether patients with low SOD activity are susceptible to neuroleptic-induced TD.

Endothelium-dependent and -independent vasoactive actions of a Japanese kampo medicine, Saiko-ka-ryukotsu-borei-to.

Saiko-ka-ryukotsu-borei-to (TJ-12) is a Japanese kampo medicine used clinically for the treatment of hypertension and atherosclerosis. We investigated the effects of TJ-12 on the contraction of rat thoracic aorta induced by norepinephrine, 5-hydroxytryptamine and high potassium. TJ-12 relaxed endothelium-denuded rings, which had been precontracted with 1 microM norepinephrine, in a dose-dependent manner with an IC50 of 50 micrograms/mL. However, in the presence of TJ-12, endothelium-intact rings initially showed enhanced norepinephrine-induced contraction, followed by relaxation. Interestingly, TJ-12 dose-dependently reversed nitric oxide (2 microM)-induced relaxation of norepinephrine-induced precontraction ofendothelium-denuded rings, with an IC50 of 20 micrograms/mL. In serotonin-contracted rings, TJ-12 caused slight, though statistically significant, relaxation only at high doses (> 200 micrograms/mL). In constrat to these receptor-mediated contractions, TJ-12 failed to affect the tension produced by high potassium 40 mM). These results suggest that the antihypertensive effects of TJ-12 could be related to inhibition of norepinephrine-induced vasoconstriction. In addition, our in vitro experiments revealed an inhibitory effect on nitric oxide-induced relaxation.

Nilvadipine is effective for chronic schizophrenia in a double-blind placebo-controlled study. off.

We investigated the efficacy of nilvadipine, a calcium channel inhibitor, for psychiatric symptoms and tardive dyskinesia in 30 patients with chronic schizophrenia in a placebo-controlled double-blind crossover study. The total scores of the Brief Psychiatric Rating Scale decreased significantly when the patients were on nilvadipine compared with placebo. Improvement was particularly significant in emotional withdrawal and uncooperativeness. Nilvadipine was not effective, however, for tardive dyskinesia. No adverse effects, such as hypotension, occurred.

Effectiveness of shakuyaku-kanzo-to in neuroleptic-induced hyperprolactinemia: a preliminary report.

We investigated the efficacy of Shakuyaku-kanzo-to (TJ-68) in neuroleptic-induced hyperprolactinemia in 11 treated schizophrenic patients. The mean plasma prolactin level decreased significantly from 28.9 +/- 14.5 ng/mL at baseline to 22.0 +/- 15.2 ng/mL at 4 weeks. Potassium levels did not change significantly. Neither the exacerbation of psychosis nor other adverse effects occurred.