Real-world effectiveness of antipsychotic monotherapy and polytherapy in 1543 patients with acute-phase schizophrenia.

PURPOSE: The effectiveness of antipsychotic treatments in the acute phase of schizophrenia in actual clinical practice remains somewhat unclear. Therefore, the purpose of the present naturalistic, multi-center study conducted from 1 year starting in September 2017 was to examine the response rate to an initial or second antipsychotic in newly admitted patients with acute-phase schizophrenia, as well as the response rate and quality of augmentation with two antipsychotics in patients who failed to respond to both the initial and second antipsychotics. RESULTS: In total, there were 660 (42.8%) and 243 (15.7%) responders to an initial and a second antipsychotic, respectively; thus, 58.5% of all patients were responders to an initial or second antipsychotic. Among 581 nonresponders (37.7%), the initial antipsychotic or a third antipsychotic was added to the second antipsychotic. Among these patients, 89.8% showed a Clinical Global Impression-Improvement score ≤3 (from 'minimally improved' to 'very much improved'). The rates of adverse events such as hyperglycemia, hyper-low-density lipoprotein cholesterolemia, hypertriglyceridemia, hyperprolactinemia, QTc prolongation, and extrapyramidal symptoms were not high in patients receiving augmentation with two antipsychotics compared with all patients, and no serious adverse events were reported. CONCLUSION: Antipsychotic augmentation may be an option in acute-phase treatment for patients who do not respond to either an initial or a second antipsychotic.

[Psychiatric Experts' Opinion on the Diagnosis and Treatment for Behavioral and Psychological Symptoms of Dementia].

Besides data cited from several articles about behavioral and psychological symptoms of dementia (BPSD), including diagnosis and treatment guidelines of dementia published by Japanese Society of Neurology in 2017, how BPSD are elucidated in three dimensions, bio-psycho-social, in the clinical practice are defined by four specialists at dementia centers. In fact, understanding the following two aspects is highly emphasized. The first aspect relates to the symptoms directly elicited by the pathological process of the cause disease of dementia; another aspect is how a person with dementia recognizes the outside world and attempts to adapt to the surroundings inapproately.

Discrimination between patients with mild Alzheimer's disease and healthy subjects based on cerebral blood flow images of the lateral views in xenon-enhanced computed tomography.

BACKGROUND: Quantitative cerebral blood flow (CBF) measurement is expected to help early detection of functional abnormalities caused by Alzheimer's disease (AD) and enable AD treatment to begin in its early stages. Recently, a technique of layer analysis was reported that allowed CBF to be analyzed from the outer to inner layers of the brain. The aim of this work was to develop methods for discriminating between patients with mild AD and healthy subjects based on CBF images of the lateral views created with the layer analysis technique in xenon-enhanced computed tomography. METHODS: Xenon-enhanced computed tomography using a wide-volume CT was performed on 17 patients with mild AD aged 75 or older and on 15 healthy age-matched volunteers. For each subject, we created CBF images of the right and left lateral views with a depth of 10-15 mm from the surface of the brain. Ten circular regions of interest (ROI) were placed on each image, and CBF was calculated for each ROI. We determined discriminant ROI that had CBF that could be used to differentiate between the AD and volunteer groups. AD patients' CBF range (mean - SD to mean + SD) and healthy volunteers' CBF range (mean - SD to mean + SD) were obtained for each ROI. Receiver-operator curves were created to identify patients with AD for each of the discriminant ROI and for the AD patients' and healthy volunteers' CBF ranges. RESULTS: We selected an ROI on both the right and left temporal lobes as the discriminant ROI. Areas under the receiver-operator curve were 93.3% using the ROI on the right temporal lobe, 95.3% using the ROI on the left temporal lobe, and 92.4% using the AD patients' and healthy volunteers' CBF ranges. CONCLUSIONS: We could effectively discriminate between patients with mild AD and healthy subjects using ROI placed on CBF images of the lateral views in xenon-enhanced computed tomography.

Discrimination Between Patients With Alzheimer Disease and Healthy Subjects Using Layer Analysis of Cerebral Blood Flow and Xenon Solubility Coefficient in Xenon-Enhanced Computed Tomography.

OBJECTIVE: The aim of this study was to develop a method for discriminating between patients with Alzheimer disease (AD) and healthy subjects using layer analysis of cerebral blood flow (CBF) and xenon solubility coefficient (λ) in xenon-enhanced computed tomography (CT). METHODS: Xenon-enhanced CT was performed on 27 patients with AD (81.7 [3.3] years old) and 15 healthy volunteers (78.6 [4.0] years old) using a wide volume CT. For each subject, we created the first- (surface) to sixth-layer images of CBF and λ for the 6 viewing directions (layer thickness, 5 mm). For the discriminant views, receiver operating characteristic curves for the ratio of CBF to λ were created to identify patients with AD. RESULTS: For the third- and fourth-layer left lateral views, which were designated as the discriminant views, areas under the receiver operating characteristic curve were 96.8% and 97.4%, respectively. CONCLUSIONS: With the use of the discriminant views obtained by xenon-enhanced CT, we could effectively discriminate between patients with AD and healthy subjects using both CBF and λ.

Antipsychotic switching versus augmentation among early non-responders to risperidone or olanzapine in acute-phase schizophrenia.

PURPOSE: We examined whether augmentation with olanzapine would be superior to switching to olanzapine among early non-responders (ENRs) to risperidone, and whether augmentation with risperidone would be superior to switching to risperidone among ENRs to olanzapine. We performed a rater-blinded, randomized clinical trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. ENRs to the initial antipsychotic (Clinical Global Impressions-Improvement Scale: ≥ 4 at 2 weeks) were allocated to receive either augmentation with or switching to the other antipsychotic (RIS+OLZ vs. RIS-OLZ; OLZ+RIS vs. OLZ-RIS) RESULTS: Sixty patients who completed 2 weeks of risperidone treatment were divided into 33 early responders (RIS-ER) and 27 ENRs (RIS+OLZ, n=14; RIS-OLZ, n=13). Although time to treatment discontinuation for any cause was significantly shorter in RIS+OLZ group (54.1 days [95% confidence interval, 41.3-67.0]) than in RIS-ER group (68.7 [61.2-76.2]; P=0.050), it was not significantly shorter in RIS-OLZ group (58.5 [43.1-73.9]) than in RIS-ER group (P=0.19). Sixty patients who completed 2 weeks of olanzapine treatment were divided into 36 early responders (OLZ-ER) and 24 ENRs (OLZ+RIS, n=11; OLZ-RIS, n=13). Although time to treatment discontinuation for any cause was significantly shorter in OLZ-RIS group (56.1days [40.7-71.5]) than in OLZ-ER group (74.9 [68.5-81.3]; P=0.008), it was not significantly shorter in OLZ+RIS group (64.6 [49.6-79.6]) than in OLZ-ER group (P=0.20). CONCLUSION: Despite the lack of pharmacokinetic investigation of dose adequacy in this study, it is possible that switching to olanzapine among ENRs to risperidone might have a small advantage over augmentation with olanzapine, while augmentation with risperidone might have a small advantage over switching to risperidone among ENRs to olanzapine. Further research is required before it would be appropriate to modify routine practice in the direction of these findings.

The possibility that requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.

We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 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 total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3-12 mg/day; n=20) and olanzapine (10-40 mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30 ng/mL after 11-16 h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20-50 ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.

[Rate and characteristics of dementia patients who visit psychiatric emergency hospitals for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Japan].

BACKGROUND: Neuropsychiatric symptoms and behavioral changes, known as behavioral and psychological symptoms of dementia (BPSD), are often observed in patients with dementia. BPSD impairs a patient's quality of life, increases the burden on the caregivers, and can be a predictor of the need for institutionalization. BPSD can aggravate on holidays or at night, when general psychiatric clinics are closed. When psychiatric symptoms aggravate on holidays or at night in patients with psychiatric disorders other than dementia, such as schizophrenia and manic psychosis, the patients visit psychiatric emergency hospitals. However, it has not been assessed whether patients with dementia visit psychiatric emergency hospitals for the treatment of BPSD on holidays or at night, although dementia patients are increasing and account for 10.5% of psychiatric outpatients in Japan. AIMS: To determine the percentage of dementia patients with BPSD in all psychiatric patients who visit psychiatric emergency hospitals, and the characteristics of patients with BPSD in Japan. METHOD: We developed two questionnaires. One was for psychiatric emergency hospitals and assessed the numbers of all patients, patients over 65 years old, and patients over 65 years and with BPSD or BPSD-like symptoms, who visited the psychiatric emergency hospitals on holidays or at night. The other questionnaire was for each patient over 65 years and with BPSD, and assessed the patients' characteristics, including their diagnosis, sex, what kinds of BPSD or BPSD-like symptoms brought them to the hospital, and whether they had visited a psychiatric clinic or hospital during the preceding 12 months. The questionnaires were sent to 360 hospitals that belong to the Japan Psychiatric Hospitals Association and treat patients with acute psychotic symptoms or dementia. This prospective survey was conducted from October 1 to November 30, 2009. RESULTS: One hundred and forty-three hospitals returned the questionnaires (response rate: 39.7%). In the survey period, 3,527 patients visited the psychiatric emergency hospitals on holidays or at night, but only 67 patients over 65 years old (1.9%) visited the hospitals for BPSD or BPSD-like symptoms. Thirty-four of the 67 patients were men, and their average age was 79.4 +/- 6.4 years old. Thirty-five patients had visited but 25 patients had never visited psychiatric clinics or hospitals during the preceding 12 months. Eight patients had physical complications that required examination for several days, while 57 patients did not require such treatment. Forty-seven patients were diagnosed with dementia. Patients with Alzheimer's disease (AD) (29 patients) were the most common, followed by those with vascular dementia (VaD) (8 patients) and those with dementia with Lewy bodies (DLB) (4 patients). Among the 47 patients with dementia, agitation/aggression was the most frequent BPSD symptom (30 patients), followed by irritability (18 patients) and aberrant motor behaviors (17 patients). The BPSD symptoms observed at the psychiatric emergency hospitals differed due to the causative dementia. Agitation/aggression, aberrant motor behaviors, and irritability were the most frequent causative symptoms in AD, agitation/aggression and irritability were the most frequent causative symptoms in VaD, and hallucinations and illusions were the most frequent causative symptoms in DLB. CONCLUSIONS: Our survey revealed that few patients over 65 years old visited psychiatric emergency hospitals for BPSD on holidays or at night in Japan, and that many of them had not regularly visit psychiatric clinics or dementia hospitals in the preceding 12 months. These results indicate that dementia patients need to visit their doctors regularly to avoid visiting psychiatric emergency hospitals on holidays or at night, and caregivers should be aware that they can visit psychiatric emergency hospitals for the treatment of BPSD on holidays or at night.

A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone.

We examined whether augmentation with olanzapine would be superior to increased risperidone dose among acute schizophrenia patients showing early non-response to risperidone. We performed a rater-blinded, randomized controlled trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as Clinical Global Impressions-Improvement Scale score ≤3 following 2 weeks of treatment. Early non-responders were allocated to receive either augmentation with olanzapine (RIS+OLZ group) or increased risperidone dose (RIS+RIS group). The 78 patients who completed 2 weeks of treatment were divided into 52 early responders to risperidone and 26 early non-responders to risperidone (RIS+OLZ group, n=13; RIS+RIS group, n=13). No difference in the achievement of ≥50% improvement in Positive and Negative Syndrome Scale total score was observed between RIS+OLZ and RIS+RIS groups. Although time to treatment discontinuation for any cause was significantly shorter in the RIS+RIS group (6.8 weeks [95% confidence interval, 5.2-8.4]) than in early responders to risperidone (8.6 weeks [7.9-9.3]; P=0.018), there was no significant difference between the RIS+OLZ group (7.9 weeks [6.3-9.5]) and early responders to risperidone. Secondary outcomes justify the inclusion of augmentation arms in additional, larger studies comparing strategies for early non-responders.

Difference in early prediction of antipsychotic non-response between risperidone and olanzapine in the treatment of acute-phase schizophrenia.

PURPOSE: We examined whether early response/non-response to risperidone according to the Clinical Global Impressions-improvement scale (CGI-I) at 2 weeks could predict subsequent response. This prediction was also applied to olanzapine. We then investigated whether early non-responders (ENRs) to risperidone or olanzapine who switched to the other showed significantly greater improvement, compared with those staying on the initial antipsychotic. We performed a rater-blinded, randomized controlled trial in 18 psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as CGI-I ≤ 3 following 2 weeks of treatment. The primary outcome measure was achievement of remission and ≥ 50% improvement in the Positive and Negative Syndrome Scale at 4 weeks. RESULTS: At 4 weeks, 53% of risperidone early responders (ERs) went into remission, whereas only 9% of ENRs staying on risperidone (n=11) did (P=0.016). Similarly, at 4 weeks, 81% of risperidone ERs achieved ≥ 50% response, whereas only 9% of ENRs staying on risperidone achieved ≥ 50% response (P < 0.0001). In contrast, 58% of olanzapine ERs (n=33) went into remission, whereas 38% of ENRs staying on olanzapine (n=8) did at 4 weeks (P=0.44). Similarly, 61% of olanzapine ERs achieved ≥ 50% response, whereas 25% of ENRs staying on olanzapine achieved ≥ 50% response (P=0.12). The negative likelihood ratio for the prediction of ≥ 50% response at 4 weeks by early response status to risperidone at 2 weeks was 0.057. CONCLUSION: In newly admitted patients with acute schizophrenia, non-response to risperidone using CGI-I at 2 weeks can predict subsequent response. It looks like there is significant response to olanzapine that doesn't occur until 4 weeks. Thus, clinicians may want to switch to another drug earlier when risperidone is the first drug, and later when olanzapine is the first drug.

A prospective naturalistic multicentre study of intravenous medications in behavioural emergencies: haloperidol versus flunitrazepam.

A prospective naturalistic multicentre study for deep sedation was conducted in intensive care with continuous electrocardiogram (ECG) monitoring. Clinical purpose was enough sedation, which made uncooperative and disrupted patients receive brain computed tomography (CT), magnetic resonance imaging (MRI), or fluid therapy, with minimum drug doses. A first infusion was either haloperidol (HAL group) or flunitrazepam (FNP group). If enough sedation was not achieved, a second infusion, which was the opposite drug to the first infusion, was given. The proportion requiring a second infusion was higher in the HAL group than in the FNP group (82% vs. 36%, P<0.0001). The mean reduction of the Excited Component for Positive and Negative syndrome scale at 15 min was greater for the FNP first group (FNP+HAL group) than the HAL first group (HAL+FNP group) (68% [S.D. 17] vs. 54% [S.D. 31], P=0.02). The mean dose of flunitrazepam in the HAL+FNP group was significantly lower than that in the FNP+HAL-group (1.3 mg vs. 3.5 mg, P=0.0003). Thus, in terms of monotherapy and speed of action, flunitrazepam has advantages over haloperidol as a first infusion for deep sedation. Regarding drug dosages, haloperidol has an advantage over flunitrazepam as a first infusion in safety.

Prevalence of i.v. thiopental use in psychiatric emergency settings in Japan.

AIM: Because i.v. barbiturates such as thiopental carry the risk of apnea and laryngeal spasm in asthmatic patients, reducing the use of barbiturate in emergency situations is important. The purpose of the present study was therefore to investigate the prevalence of i.v. thiopental as a choice of sedation in behavioral emergency settings, we conducted a cross-sectional multicenter study. METHODS: Psychiatric emergency departments of seven hospitals were studied during a 4-month period. Patients with a score >15 on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) who received i.v. medication were included in the study. Drugs were chosen according to the Japanese guidelines, in which the first injection was either haloperidol or benzodiazepine in accordance with clinical requirements. A second injection, which was the opposite drug to the first injection was administered as needed. Only when excitement obviously increased following the first injection, which was considered uncontrollable without thiopental according to expert experience, was thiopental given as a second injection. A total of 137 patients were included. The mean age was 40.4 years (SD 13.1), and the rate of male gender, drug-naïve, and F2 (schizophrenia, schizotypal and delusional disorders) on the ICD-10 were 48.9%, 29.9%, and 65.7%, respectively. RESULTS: The rate of patients treated with thiopental as a second injection was 8.0% (n = 11). All of the first injections in patients treated with thiopental were not haloperidol but benzodiazepines (P = 0.0072). CONCLUSION: Because this multicenter study has an epidemiological character, the prevalence of i.v. thiopental use in psychiatric emergency settings in Japan is considered to be 8.0%.

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.

Olanzapine orally disintegrating tablet vs. risperidone oral solution in the treatment of acutely agitated psychotic patients.

OBJECTIVE: Efficacy and tolerability of risperidone oral solution (RIS-OS) and olanzapine orally disintegrating tablet (OLZ-ODT) were compared for the treatment of acute psychotic agitation. METHOD: During a 2-month period, patients scoring > or =15 on the Excited Component for Positive and Negative Syndrome Scale (PANSS-EC) were assigned to treatment with OLZ-ODT (n=34) or RIS-OS (n=53) on psychiatric emergency situations, and assessed every 15 min. RESULTS: Two (OLZ-ODT and RIS-OS) by five (0-, 15-, 30-, 45- and 60-min time points) repeated-measures analysis of variance revealed only a significant main effect of time course on PANSS-EC (F=82.2, P<.0001). No differences in the number of patients receiving additional injection due to worsening were found (OLZ-ODT, 11.8%; RIS-OS, 9.4%). No differences in rate of extrapyramidal symptoms and patient satisfaction with assigned treatment were found. However, patients in the OLZ-ODT group recovered significantly more from tachycardia than those in the RIS-OS group (t=2.17, P=.03). CONCLUSION: OLZ-ODT and RIS-OS treatments yielded similar improvements in acutely agitated patients who accepted oral medication. However, on one physiological parameter (i.e., tachycardia) OLZ-ODT might be superior to RIS-OS. Physiological indicators may also be useful for measuring levels of agitation.

[Integration of psychiatric treatment and rehabilitation].

Residual symptoms exist in psychiatric disorders, especially in schizophrenia. These become more serious according to the length of stay in hospital. Therefore, rehabilitation programs are necessary throughout the hospitalization. In the acute state also, psycho-social therapy and education are important. The most important is to give them the motivation toward their post-hospital life. Short stay in their residence before discharge gives us the information about the problems of patients' community lives. And to the patients and their families, it gives the confidence of community-living. 'Home-visit' by nursing staffs during this short stay further shows us how to support them and their families. These rehabilitation and support programs being prepared since 1986, the hospital-beds decreased from 603 to 505, admitted patients increased from 444 to 1586, and average length of stay shortened from 473 to 108 days. Whereas being treated outpatients increased from 2010 to 3439 for 10 years after 1990.

[The review of seclusion and restraint in psychiatric practice].

In order to create the least restrictive setting in psychiatric practice, we investigated the effects of an assessment by a committee on seclusion and restraint. Using consistent procedures, the committees, which were established in 9 hospitals, reviewed seclusion and restraint maintained for periods of over 2 weeks during a 4-month period. Frequency and duration of seclusion and restraint, staff perceptions of and attitudes to the review system, and patient satisfaction were evaluated before and after the study period. As a result of this review process, the frequency of seclusion decreased slightly in 7 hospitals and 1 of the remaining 2 hospitals showed an increased frequency of seclusion days that were partially interrupted. Frequency of restraint decreased slightly in 5 hospitals, and of the remaining 3, 1 interrupted all periods of restraint, while the other 2 institutions showed an increase in interruption of restraint periods. As there were no common patients in 2 specialist psychiatric emergency hospitals between before and after the study periods, statistical analyses were performed. Only minor variables such as duration of partially interrupted periods of restraint, and duration of periods of restraint that were partially released showed a statistically significant increase. Although patient satisfaction showed a significant increase, staff attitudes to and perceptions of the review system became appreciably more negative. These findings suggest that although the review system had the potential to slightly reduce the use of seclusion and restraint, and to increase patient satisfaction, staff burnout was risked because staff effort was perceived to be disproportionately high in relation to the effect achieved. Furthermore, the possibility remains that the slight decrease of seclusion and restraint demonstrated did not necessarily reflect the appropriate use of these strategies, and were not necessarily lasting effects. However, as differences in opinion existed between the review system committee and treating clinicians regarding continuation of long term seclusion and restraint, the review system could have a role in monitoring the long term use of seclusion and restraint. Further investigation is needed into the long term effectiveness of procedures reviewing the use of seclusion and restraint in the psychiatric setting, taking into account both positive and negative outcomes.