Kotaro Hatta

Preventive Effects of Ramelteon on Delirium: A Randomized Placebo-Controlled Trial

IMPORTANCE No highly effective interventions to prevent delirium have been identified. OBJECTIVE To examine whether ramelteon, a melatonin agonist, is effective for the prevention of delirium. DESIGN, SETTING, AND PARTICIPANTS A multicenter, rater-blinded, randomized placebo-controlled trial was performed in intensive care units and regular acute wards of 4 university hospitals and 1 general hospital. Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were excluded from the study if they had an expected stay or life expectancy of less than 48 hours. INTERVENTIONS Sixty-seven patients were randomly assigned using the sealed envelope method to receive ramelteon (8 mg/d; 33 patients) or placebo (34 patients) every night for 7 days. MAIN OUTCOMES AND MEASURES Incidence of delirium, as defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS Ramelteon was associated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). Even after risk factors were controlled for, ramelteon was still associated with a lower incidence of delirium (P = .01; odds ratio, 0.07 [95% CI, 0.008-0.54]). The Kaplan-Meier estimates of time to development of delirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo. Comparison by log-rank test showed that the frequency of delirium was significantly lower in patients taking ramelteon than in those taking placebo (χ(2) = 9.83; P = .002). CONCLUSIONS AND RELEVANCE Ramelteon administered nightly to elderly patients admitted for acute care may provide protection against delirium. This finding supports a possible pathogenic role of melatonin neurotransmission in delirium. TRIAL REGISTRATION University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000005591.

The association between intravenous haloperidol and prolonged QT interval.

Although intravenous haloperidol (HAL) is an effective medication that is often prescribed to treat agitation, several instances of torsade de pointes or prolonged QT interval have been reported. To investigate the association between intravenous HAL and QT prolongation and between intravenous HAL and ventricular tachyarrhythmia, a cross-sectional cohort study was performed that included measuring corrected QT intervals (QTc) on an emergency basis before intravenous HAL and continuously monitoring electrocardiographic (ECG) findings after intravenous HAL. During a 2-month period, 47 patients received intravenous injections to control psychotic disruptive behavior. According to clinical practice, patients were divided as follows. The FZ-alone group was treated with intravenous flunitrazepam (FZ), and the FZ-plus-HAL group received intravenous FZ followed by intravenous HAL. Although the difference in the mean QTc immediately after intravenous FZ between the two groups was not significant, the mean QTc after 8 hours in the FZ-plus-HAL group was longer than that in the FZ-alone group (p < 0.001). Four patients in the FZ-plus-HAL group had a QTc of more than 500 msec after 8 hours. The change in QTc during 8 hours significantly differed between the two groups (t = 2.64, p > 0.05). Furthermore, the change in QTc was moderately correlated with the dose of intravenous HAL, as evidenced by a coefficient of correlation of 0.48 (p < 0.001). However, ventricular tachyarrhythmia was not detected among 307 patients within a 1-year period, although the ECG was continuously monitored for at least 8 hours after intravenous HAL. The modest nature of QTc prolongation and the apparent absence of ventricular tachyarrhythmia under continuous ECG monitoring indicate that QTc prolongation associated with intravenous HAL is not necessarily dangerous. However, in an emergency situation, clinicians cannot exclude patients predisposed to torsade de pointes, such as those with inherited ion channel disorders. Therefore, clinicians should be aware of the association between intravenous HAL and QT prolongation.

Nonthermal effects of mobile-phone frequency microwaves on uteroplacental functions in pregnant rats

Exposure to high-density microwaves can cause detrimental effects on the testis, eye, and other tissues, and induce significant biologic changes through thermal actions. To examine nonthermal effect of continuous wave (CW) 915MHz microwaves used in cellular phones, we compared the effects of microwaves with those of heat. Thirty-six pregnant rats were assigned to six groups: rats exposed to microwaves at 0.6 or 3mW/cm(2) incident power density at 915MHz for 90min, rats immersed in water at 38 or 40 degrees C, which induces about the same increase in colonic temperature of 1.0 or 3.5 degrees C as 0.6 or 3mW/cm(2) microwaves, respectively; rats immersed in water at 34 degrees C, which is considered to be thermoneutral; and control rats. We identified significant differences in the uteroplacental circulation, and in placental endocrine and immune functions between pregnant rats immersed in water at 34 and 38 degrees C, but not between rats immersed at 38 degrees C and those exposed to microwaves at 0.6mW/cm(2). By contrast, we observed significant decreases in uteroplacental blood flow and estradiol in rats exposed to microwaves at 3mW/cm(2) as compared with those immersed in water at 40 degrees C. These results suggest microwaves at 0.6mW/cm(2) at 915MHz, equal to a specific absorption rate (SAR) of 0.4W/kg, which is the maximum permissible exposure level recommended by the American National Standards Institute (ANSI), do not exert nonthermal effects on blood estradiol and progesterone, on splenic natural killer cell activity, on the uteroplacental circulation.

Electroconvulsive therapy improves severe pain associated with fibromyalgia

Abstract The pathophysiology of fibromyalgia remains unknown. Several reports have recently suggested the novel concept that fibromyalgia is due to the central nervous system becoming hyper‐responsive to a peripheral stimulus. The effect of electroconvulsive therapy (ECT) as pain remedication in cases of fibromyalgia without major depressive disorder was studied in a prospective trial lasting three months. All of the patients taking part in the study fulfilled the American College of Rheumatology diagnostic criteria for fibromyalgia. Technetium‐99m ethyl cysteinate dimer single photon emission computed tomography was used to assess regional cerebral blood flow (rCBF) before and after a course of ECT. Pain assessment in the patients was undertaken by use of the visual analog scale (VAS) and by evaluation of tender points (TPs). Beck’s depression inventory (BDI) was further used to assess depressive mood change in the patients. Our study clearly demonstrated that pain was significantly less severe after ECT, as indicated by the VAS scale for pain and the evaluation of TPs. A further notable observation was that thalamic blood flow was also improved. We conclude that a course of ECT produced notable improvements in both intractable severe pain associated with fibromyalgia and also in terms of thalamic blood flow.

Prolonged QT interval in acute psychotic patients

Some recent clinical studies indicate that hypokalemia is characteristic for acute psychotic patients at the time of emergency admission. As hypokalemia is one of the major causes for prolonged QT interval, it was hypothesized that acute psychotic patients could show prolonged QT interval. Sixty-seven drug-free, acute psychotic patients were evaluated for corrected QT (QTc) interval, as well as demographic and clinical characteristics at the time of emergency admission. The mean QTc interval of psychiatric emergency patients was prolonged, and the mean QTc interval of psychiatric emergency patients was longer than that of psychiatric outpatients (t=5.20, P<0.0001). Age- or gender-related difference, circadian fluctuation of QT interval, medication, concomitant disease, obesity, and serum electrolytes except potassium were not major causes. There was a significant negative correlation as evidenced by a coefficient of correlation of -0.28 (P<0.05). As psychiatric emergency patients often receive parenteral antipsychotics, which may have adverse effects on prolonged QT interval, paying attention to QT interval might have some clinical significance on emergency admission.

Effectiveness of second-generation antipsychotics with acute-phase schizophrenia

PURPOSE Although olanzapine may have advantages over other second-generation antipsychotics (SGAs) regarding longer time to treatment discontinuation among chronically ill patients, little evidence has been provided for the comparative effectiveness of SGAs in the acute phase. We aimed to determine if any of four SGAs were more effective in treating newly admitted acute schizophrenic patients. We performed a rater-blinded, randomized controlled trial of four SGAs in 15 psychiatric emergency sites. Eligible patients were 18-64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A final total of 78 patients were randomly assigned by means of sealed envelopes to receive risperidone (3-12 mg/day; n=20), olanzapine (10-20 mg/day; n=17), quetiapine (300-750 mg/day; n=20), or aripiprazole (12-30 mg/day; n=21), with follow-up at 8 weeks. The primary outcome measure was all-cause treatment discontinuation. RESULTS Overall, 37% (29/78) of patients discontinued the study medication before 8 weeks: 25% for risperidone; 12% for olanzapine; 55% for quetiapine; and 52% for aripiprazole. Time to treatment discontinuation for any cause was significantly longer in the olanzapine group than in the quetiapine (p=0.006) or aripiprazole (p=0.008) groups, but not compared to the risperidone group (p=0.32). Time to treatment discontinuation was significantly longer in the risperidone group than in the quetiapine group (p=0.048), but not compared to the aripiprazole group (p=0.062). However, the rate of p.r.n. intramuscular haloperidol use was significantly higher in the aripiprazole group than in other groups (p=0.029). CONCLUSION Olanzapine and risperidone are superior to quetiapine and aripiprazole for the acute treatment of psychosis in hospitalized patients.

Abnormal physiological conditions in acute schizophrenic patients on emergency admission: dehydration, hypokalemia, leukocytosis and elevated serum muscle enzymes.

Abstract This study investigated varieties and incidence of abnormal physiological conditions in acute schizophrenic patients on emergency. Laboratory data obtained prior to treatment from patients, admitted on an emergency basis during an 18-month period, were evaluated retrospectively, as well as demographics and clinical characteristics. Of 259 male acute schizophrenic patients (ICD-10: F2), 6.9% revealed dehydration, a third had hypokalemia and leukocytosis, and two thirds showed elevated serum muscle enzymes. These percentages were statistically significant compared with those of outpatients. In addition, the former three of these conditions in the F2 group were as frequent as those in alcohol and/or psychoactive substance abusers (ICD-10: F1) on emergency admission, although elevated serum muscle enzymes in the F2 group was less frequent than that in the F1 group. In order to prevent these abnormal physiological conditions from worsening and becoming life-threatening, one fourth of the F2 group [dehydration, 6.9%, severe hypokalemia (< 3.0 mEq/l), 2.3%, and markedly elevated serum muscle enzymes (creatine phosphokinase > 1000 IU/l), 16.5%] required medical management such as fluid therapy and various types of monitoring. In cases of a behavioral emergency, laboratory screening and monitoring of urinary output were essential. Due to their lack of cooperation, case history, physical examination, and initial vital signs did not contribute to detection of their medical condition.

Antipsychotics for delirium in the general hospital setting in consecutive 2453 inpatients: a prospective observational study.

Attention to risk of antipsychotics for older patients with delirium has been paid. A clinical question was whether risk of antipsychotics for older patients with delirium would exceed efficacy of those even in the general hospital setting.

Hypokalemia and agitation in acute psychotic patients

Hypokalemia is caused partly by intensive exercise. Some evidence suggests that psychological distress may cause hypokalemia. The relationship between the decline of serum potassium concentration and the level of symptoms of acute agitation, which was defined as a total score on a subset of six categories on the 18-item Brief Psychiatric Rating Scale (anxiety, tension, mannerism and posturing, hostility, uncooperativeness, psychomotor excitement), was examined in 313 schizophrenic men, admitted on an emergency basis during a 24-month period. In addition, change in serum potassium concentration after sedation was investigated. Serum potassium concentration in the severely agitated group was lower than that in the mild group. There was a significant correlation between serum potassium concentration and the level of symptoms of acute agitation (r = -0.30, P < 0.0001). Although the decline of serum potassium concentration in the patients who were sufficiently sedated improved within 8 h, that in the patients showing high scores on the acute agitation subset even 8 h after emergency admission was prolonged. Results indicate that sedation improves acute agitation-induced hypokalemia. rights

The Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and the Fibromyalgia Symptom Scale: reliability and validity

The aim of this study was to investigate the reliability and the validity of the Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010-J), and its quantification scale, the Fibromyalgia Symptom Scale (FS-J). In this study, we divided patients with chronic pain without psychiatric disorders other than depression into two groups according to the 1990 ACR Diagnostic Criteria for Fibromyalgia, a fibromyalgia group and a non-fibromyalgia group (rheumatoid arthritis, osteoarthritis, and gout). Patients in both groups were assessed using the ACR 2010-J and FS-J. Seventy-seven of 94 (82%) patients in the fibromyalgia group met the ACR 2010-J, whereas 9% (4/43) of the non-fibromyalgia group did so, with a sensitivity of 82%, specificity of 91%, positive predictive value of 95%, negative predictive value of 70%, and positive likelihood ratio of 8.8. Mean total scores on the FS-J significantly differentiated the fibromyalgia from the non-fibromyalgia group. The scale had high inter-rater reliability and high internal consistency. With a cutoff score of 10, the positive likelihood ratio was 10.1. Our findings indicate that the ACR 2010-J and FS-J have high reliability and validity, and are useful for assessing fibromyalgia in Japanese populations with chronic pain. As regards the positive likelihood ratio, that of the FS-J might be suitable as a positive test.