Cross-cultural equivalence in depression assessment: Japan-Europe-North American study.

OBJECTIVE: Worldwide use of the Hamilton Rating Scale for Depression (HRSD) presupposes that depression symptomatology can be measured the same way across countries but no empirical study has yet examined this issue. We therefore examined cross-cultural consistency of factor structure of HRSD. METHOD: A 17-item HRSD data were sought for 5,185 individuals diagnosed with major depression in Japan, Europe and North America. Candidate factor structures were obtained with simultaneous component analysis (SCA) across the three cultures. They were then submitted to multiple-group confirmatory factor analysis (CFA). RESULTS: According to SCA, 3-, 4- or 5-factor solutions were found to optimally and adequately summarize the variables for all the three populations. When submitted to CFA, the 5-factor solution was the best fitting and the most parsimonious: they were 'anhedonia/retardation,''guilt/agitation,''bodily symptoms,''insomnia' and 'appetite.' CONCLUSION: Common underlying factors exist for HRSD among Japanese, European and American patients with major depression.

Plasma orexin-A is lower in patients with narcolepsy.

Recently identified hypothalamic peptides called orexins (or hypocretins) have been implicated in the sleep-wake cycle and in sleep disorder narcolepsy. Neuropathological studies have shown that in patients with narcolepsy, global reduction in the expression of orexins occurs due to the loss of orexin neurons in the hypothalamus. Cerebrospinal fluid analysis has confirmed a reduced or undetectable level of orexin-A in most narcolepsy patients. In this study, measurement of plasma orexin showed significantly lower concentrations in patients with narcolepsy than in age- and gender-matched normal controls. These data suggest that low levels of orexin-A in plasma could serve as a biological marker for narcolepsy.

Efficacy and safety of olanzapine, an atypical antipsychotic, in patients with schizophrenia: results of an open-label multicenter study in Japan.

This first clinical study of olanzapine in Japanese patients with schizophrenia was conducted to investigate the efficacy and safety of olanzapine. Eighty-one patients were included in the analysis set. Mean modal dose for those patients were 9.4 +/- 3.6 mg/day. For the primary efficacy measure (Final Global Improvement Rating score), 14.8% of patients had remarkable improvement, 59.3% of patients had moderate improvement or better, and 86.4% of patients had slight improvement or better. Results from the Brief Psychiatric Rating Scale showed improvement from baseline in all clusters including positive psychotic symptoms (thought disturbance) but also against negative symptoms (anergia). The most commonly reported treatment-emergent signs and symptoms with > or =10% incidence, were insomnia, weight increase, excitement, sleepiness, and anxiety. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms, and events reported were tremor (6.2%), muscle rigidity (3.7%), and akathisia (2.5%). The most commonly reported treatment-emergent laboratory changes, with > or = 20% of incidence, were prolactin elevations (24.3%) followed by increases in triglycerides (20.4%). However, mean prolactin values tended to be normalized during the study. This study result suggests that olanzapine is an "atypical" antipsychotic.

The effect of zolpidem and zopiclone on memory.

The effect of 10 mg of zolpidem (ZLP) on memory function was evaluated in healthy male adults using word recall test, passage recall test, and Sternberg's memory scanning task. This study was carried out as a double-blind cross-over study with 7.5 mg of zopiclone (ZPC) and a placebo. No difference was noted between the active drugs and placebo in the number of words recalled from the word list presented before administration. No evidence of retrograde amnesia was suggested. However, encoding ability was slightly affected as indicated by a decrease in the number of words recalled from the list presented after administration. Slight impairment of a delayed recall was noted for both of the active drugs, but the effect disappeared the next morning. In the memory scanning task, ZLP prolonged a non-specific component of reaction time 1.5 h after administration, but the effect disappeared after 12.5 h. ZPC did not prolong the reaction time. The two active drugs showed no specific effects on either memory scanning or response-selection stage in short-term memory at any time. The findings suggest that residual effects did not reach clinical significance at the standard dosage, although the active drugs slightly affected encoding ability and retention soon after administration.

Olanzapine optimal dose: results of an open-label multicenter study in schizophrenic patients. Olanzapine Late-Phase II Study Group.

This open-label clinical study was conducted for patients with schizophrenia in order to investigate the efficacy, safety and optimal dose of olanzapine. One hundred and fifty-six of the 159 enrolled patients were included in the analysis set. For the primary efficacy measure, the Final Global Improvement Rating (FGIR) score, 15.4% of patients had remarkable improvement, 58.3% of patients had moderate improvement or more, 79.5% of patients had slight improvement or more, and 10.3% of patients had increase in disease symptomatology (worsening). Results from the Brief Psychiatric Rating Scale (BPRS) in all individual items were improved from baseline. Olanzapine was effective not only against positive psychotic symptoms but also against negative symptoms. This was consistent with results from the Positive and Negative Syndrome Scale (PANSS). For the majority of patients, a dose range of 7.5-10.0mg/day, as a lower bound on the minimally effective dose, was suggested by the results of the dose to first response based on improvement in Global Improvement Rating (GIR) analyses. The ratio of olanzapine dose to equivalent haloperidol dose was estimated at 1.2 :1. The most commonly reported treatment-emergent signs and symptoms (TESS) occurring at a frequency of 10% or more were insomnia, weight increase, excitement, sleepiness, anxiety, malaise and dull headaches. There was a low incidence of extrapyramidal treatment-emergent signs and symptoms; the most commonly reported were akathisia (6.4%), tremor (5.8%) and muscle rigidity (2.6%).

The effects of zolpidem and zopiclone on daytime sleepiness and psychomotor performance.

Zolpidem (ZLP), which has selective affinity to the BZ1 (omega 1) receptor and a short half-life, is a novel hypnotic. The objective of this study is to compare the residual effects of standard clinical doses of ZLP and zopiclone (ZPC), a short-acting hypnotic marginally selective for the BZ1 (omega 1) receptor, given in a single dose on daytime sleepiness and psychomotor function. This study was carried out as a double-blind cross-over study with 10 mg ZLP, 7.5 mg ZPC and a placebo in 12 healthy male adults. In the multiple sleep latency test, sleep latency was not reduced but increased by ZLP and ZPC as well as the placebo when drug plasma levels had nearly reached the peak. Subjects administered ZLP were significantly more feeble, lethargic and antagonistic in mood rating scales than those administered ZPC. The incidence of severe behavioral side effects was higher in the case of ZLP than in the case of ZPC over the same period. Sleep latency the next morning was significantly shorter in the case of ZPC than in the case of ZLP or the placebo. The tapping test performed at the same time demonstrated that the number of taps was significantly less in the case of ZPC than in the case of ZLP or the placebo. The results of the present study suggest that ZLP acts more rapidly than ZPC. On the other hand, ZLP has less residual effect on sleepiness and psychomotor function the next morning.

Pharmacokinetic and pharmacodynamic interactions among haloperidol, carteolol hydrochloride and biperiden hydrochloride.

A beta-adrenoceptor blocker and an anticholinergic agent are often prescribed concomitantly for the treatment of neuroleptic-induced akathisia. The aim of this study was to investigate possible pharmacokinetic interactions of neuroleptic haloperidol with the beta-blocker carteolol and the anticholinergic biperiden. In a 5-step, open-labeled, oral single-dose study, eight healthy male volunteers received 2 mg haloperidol, 10 mg carteolol hydrochloride, and 2 mg biperiden hydrochloride: first each drug alone, then a combination of haloperidol and carteolol, and then all three drugs concurrently. Serum concentrations of haloperidol, carteolol, and biperiden were determined up to 24 hr postdosing, and a safety evaluation was conducted throughout the study. Carteolol increased the area under the haloperidol serum concentration-time curve (AUC0-t) 1.4-fold (P = 0.0014) and decreased the serum clearance of haloperidol up to 67% (P = 0.0127). Biperiden reduced the serum haloperidol concentrations increased by the administration of carteolol. No significant changes of the serum pharmacokinetics of carteolol and biperiden were found as a result of any drug combinations. Adverse events of the central nervous system such as sleepiness and changes in pupil size were observed, but all were mild with clinical insignificance.

Epidemiological study on sleep habits and insomnia of new outpatients visiting general hospitals in Japan.

A large scale epidemiological survey of sleep habits, specifically for insomnia, was conducted using 6277 new outpatients from 11 general hospitals in Japan. They were requested to answer a questionnaire newly designed for this study, which consisted of 34 questions concerning sociodemographic characteristics, current medical conditions, sleep habits, current or past sleep complaints, symptoms of parasomnia, use of hypnotics/anxiolytics and other aspects of daily life. Insomnia was the focus of analysis using chi2 statistics and, additionally, logistic regression to explore the predictors of insomnia. Bedtime was 23:30 and wake-up time was 6:35 on average, with a mean sleep time of 6.77 h on weekdays. The number of subjects with current sleep complaints was 1276, of which 735 (11.7% of the total sample) had insomnia lasting for 1 month or more. Only 37.6% of those were taking hypnotics and/or anxiolytics. Old age, female sex, neurology, psychiatry, early bedtime, late wake-up time, living alone and dissatisfaction with the bedroom environment for sleep were found to be associated with long-term insomnia. This study helps to provide a framework for further studies using the general population.

Comparison of pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly and young subjects.

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.

[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.

Demographic features of patients seeking cosmetic surgery.

The demographic features of 415 patients seeking cosmetic surgery were investigated from a psychiatric point of view. Of the 415 patients, 198 (47.7%) were found to have mental disorders according to ICD-10 including: 17 with schizophrenia, 20 with other persistent delusional disorders, 33 with depressive episode, 47 with neurotic disorders, 42 with hypochondriacal disorder, five with paranoid personality disorder and 14 with histrionic personality disorder. The rate of subjects with poor social adjustment was 56.0%. It was noteworthy that such a considerable number of patients with mental disorders or with poor social adjustment had sought cosmetic surgery. Distinct gender differences were found: male subjects were characterized to have a greater number of mental disorders, especially dysmorphophobia (other persistent delusional disorders plus hypochondriacal disorder) and showed the narrow age range between teenage and young adult age when they were preoccupied with their 'deformity', and poor social function. A history of frequent operations was not considered to be an indicator for mental abnormality. The diagnostic issue in dysmorphophobia is briefly described.

Effects of washing procedure on platelets pretreated with serotonin uptake inhibitors in vitro: low Ki values predict long-lasting inhibition of serotonin uptake in vivo.

The effect of a washing procedure on serotonin (5-HT) uptake in vitro was investigated using human platelets pretreated with nine 5-HT uptake inhibitors and various Ki values to confirm the assumption that a drug with high affinity for the 5-HT uptake site would be hardly removed and have a long-lasting effect in vivo. Among the drugs tested, those with low Ki values, such as clomipramine, duloxetine and paroxetine, inhibited 5-HT uptake even after removal from the medium, while those with high Ki values such as amitriptyline, desipramine, imipramine, mianserin, trazodone, and zimelidine were easily removed by washing. The results indicated that low Ki values might be proportionally related to the long-lasting binding of drugs to the 5-HT uptake site. The results also suggested that the threshold Ki value which could separate 5-HT uptake inhibitors with a probable long-lasting effect in vivo from those without the effect would be between 5 nM and 42 nM.

Survival analytic approach to long-term prescription of benzodiazepine hypnotics.

Eight hundred and sixty-two patients who visited the department of neuropsychiatry and who were prescribed benzodiazepine (BZ) hypnotics were investigated to evaluate the actual state of their use, in terms of age, gender, diagnostic categories according to ICD-9, duration of prescription and dose equivalent to diazepam prescribed. The frequency of prescriptions in subjects were surveyed using Kaplan-Meier survival analysis at every 3 months. Mean survival time to discontinuation was 8.5 months. A total of 60% of the subjects did not receive BZ hypnotics at the end of the third month, but 20% remained to be prescribed after 1 year. Moreover, 7.9% of the subjects were prescribed BZ hypnotics even after 3 years. The results indicated that 20% of patients who had started prescriptions for BZ hypnotics had the potential to induce dependence. The following variables were found in the long-term prescription: male patients; aged patients over 60; and affective psychoses (which mainly consisted of depression) including neurotic depression, in the present study. A low dose was considered to be associated with an ability to be free from BZ hypnotics in an early period.

[Neuroleptic malignant syndrome, syndrome malin].

Neuroleptic malignant syndrome (NMS) is an uncommon but serious complication of treatment with neurolepticus, made up of hyperthermia, muscular rigidity, disturbance of level of consciousness, autonomic instability and elevated serum creatine phosphokinase. Onset of NMS is often related to commencement of treatment, change of drug, or increase dose, but may occur in the absence of such an event. Physical stress has been suggested as a precipitating factor. NMS is thought to occur from central dopamine depletion in the hypothalamus and basal ganglia. In addition, it is thought that several neurotransmitters, serotonin, noradrenaline and GABA, are related in the mechanism of NMS.

Long-lasting inhibition of 5-HT uptake of platelets in subjects treated by duloxetine, a potential antidepressant.

Duloxetine is an inhibitor of serotonin and norepinephrine uptake, and is being developed as a new antidepressant. In the present study, using healthy volunteers who took 20 mg of duloxetine for 7 days, the plasma concentrations of duloxetine and the ex vivo serotonin uptake rate in the platelets were simultaneously monitored during and after administration. Furthermore, a comparison was made by measuring parameters for serotonin uptake in vitro and [3H]paroxetine binding before and after administration. Actual values of the uptake inhibition rate ex vivo were stronger than those expected in spite of the dilution of plasma in the experiment, and the inhibitory effect was seen even after the drug was no longer detected in plasma. No significant changes were observed in Vmax, Km, Bmax or Kd. Thereafter, the effect of the washing procedure was examined in platelets treated with different antidepressants in vitro. The minimum effect was seen in platelets treated by duloxetine or paroxetine, while desipramine-treated platelets showed susceptibility to the procedure. These results suggest that duloxetine was hardly dissociated from the serotonin uptake site, which was responsible for the strong and long-lasting effect of plasma.