Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

AIMS: Benzodiazepine receptor agonists (BZ-RAs) are frequently prescribed to treat insomnia; however, their long-term use is not recommended. To introduce an appropriate pharmaco-therapy, the current state and background factors of BZ-RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ-J) and conducted a study of BZ-RAs' use disorder. METHODS: The Bendep-SRQ-J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ-RAs between 2012 and 2013. Clinical data collected were Bendep-SRQ-J scores, sleep disorders for which BZ-RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. RESULTS: Of the 707 patients prescribed BZ-RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. CONCLUSION: Using the Bendep-SRQ-J, we elucidated the current state of BZ-RA dependence. Nearly half of the patients were non-compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics.

Simulating Clinical Psychiatry for Medical Students: a Comprehensive Clinic Simulator with Virtual Patients and an Electronic Medical Record System.

OBJECTIVE: A number of programs representing virtual patients for use in teaching settings have been developed in the field of psychiatry; however, they simulate only the interview process, not the entire scope of treatment. The authors have developed software through which students can experience the practice of psychiatry (in particular, with dementia patients) in its entirety. This study compares this software with conventional learning methods. METHOD: The control group was 43 fifth-year medical students in 2014 who studied using a conventional learning method (taking lectures and being in contact with actual patients). The experimental group was 36 fifth-year medical students in 2015 that used computer software (taking lectures and with reduced time in contact with actual patients). The authors compared the two groups. Each group was tested before and after clinical training on their acquisition of knowledge of dementia. The control group was tested in 2014, and the experimental group was tested in 2015. RESULTS: The difference in average test scores between the two groups was statistically significant (p = 0.01), with the experimental group scoring higher. CONCLUSIONS: The results indicate that students who were taught using a computer-based software method were better able to answer a standard series of questions designed to evaluate their understanding of dementia than those who were taught in a conventional manner. This study demonstrated that there is a possibility to improve education in the field of psychiatry using a comprehensive clinic simulator.

The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease.

OBJECTIVE: Behavioural and psychological symptoms of dementia (BPSD) are commonly present in patients with Alzheimer's disease (AD). Disturbed sleep quality is also observed in AD patients. However, the effects of memantine on sleep architecture have not been investigated. The purpose of this study was to investigate the effects of memantine on polysomnography (PSG) variables and BPSD. METHODS: In total, 12 patients with AD (mean age: 79.0±4.1 years old) were enrolled in this study. The following tests were performed: the Neuropsychiatric Inventory for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, and PSG for evaluation of sleep architecture. After baseline examinations, patients were treated with memantine according to a standard prescription protocol. After being treated with 20 mg/day of memantine for 4 weeks, examinations were carried out again. RESULTS: All subjects completed the trial. The mean MMSE and NPI scores were 22.6±3.4 and 13.8±12.9, respectively. Treatment with memantine significantly decreased the NPI score (5.8±4.3, p<0.01). There were significant decreases in the scores of subscales for anxiety (p=0.04) and irritability/lability (p=0.04). PSG demonstrated a longer total sleep time (TST) (p<0.01), increases in sleep efficiency (p<0.01) and time spent in stage II (% TST, p=0.02), and decreases in nocturnal awakening (p<0.01), the periodic limb movement index (p<0.01), and time spent in stage I (% TST, p=0.02). CONCLUSION: Memantine was effective for reducing fragmented sleep and improving BPSD, and was well tolerated.

A patient with type II citrullinemia who developed refractory complex seizure.

A 31-year-old Japanese male was admitted to our hospital for refractory complex seizures. He had no history on medical or psychiatric illness. He began to exhibit aberrant behavior accompanied by cloudiness of consciousness. Thereafter, he exhibited partial seizures followed by a twilight state or abnormal behavior. Previous treatment with valproate and carbamazepine failed to improve his seizures. Because an increase in plasma ammonia was noted, anticonvulsant was discontinued within a week. He was then transferred to our department. Blood examination revealed an increase in ammonia. Amino acid analysis demonstrated a marked increase in citrulline and decrease in arginine. He was diagnosed with type II citrullinemia. After being treated with arginine hydrochloride, the seizures and disturbed consciousness improved. He was then discharged, and remains in remission. Accumulations of citrulline and ammonia and a reduction of arginine are noted in argininosuccinate synthetase deficiency, which results in the sudden emergence of consciousness disturbance and abnormal behavior. It is essential to examine amino acid levels as well as ammonia levels in patients with unexplained neuropsychiatric symptoms, especially those with altered consciousness levels and seizures.

Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia.

OBJECTIVE: This study aims to examine the effect of levothyroxine, a thyroid hormone, on a prolonged nocturnal sleep and excessive daytime somnolence (EDS) in patients with idiopathic hypersomnia. METHODS: In a prospective, open-label study, nine patients were enrolled. All subjects met criteria for idiopathic hypersomnia with long sleep time defined by the International Classification of Sleep Disorders, 2nd edition (ICSD-2). Subjects with sleep apnea syndrome, obesity or hypothyroidism were excluded. Sleep architecture and subjective daytime somnolence were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. After baseline examinations, levothyroxine (25µg/day) was orally administered every day. Mean total sleep time, ESS score at baseline were compared with those after treatment (2, 4 and 8 weeks). RESULTS: Mean age of participants was 23.8±13.7 years old. At baseline, mean total sleep time (hours) and ESS score were 12.9±0.3 and 17.8±1.4, respectively. Mean total sleep times after treatment were 9.1±0.7 and 8.5±1.0h at 4 and 8 treatment weeks, respectively. Mean ESS scores were 8.8±2.3 and 7.4±2.8 at 4 and 8 treatment weeks, respectively. One patient dropped out at the 2nd week due to poor effect. No adverse effects were noted. CONCLUSIONS: After treatment with levothyroxine for over 4 weeks, prolonged sleep time and EDS were improved. Levothyroxine was effective for hypersomnia and well tolerated.

[Sleep disturbances in the elderly: pathology, symptoms and treatment].

Although sleep disturbance is common among the elderly, such elderly patients have been considered difficult to treat because the underlying mechanisms are complicated. However, these patients often exhibit adverse effects such as daytime somnolence, poor motor coordination, and an increased risk of falls. This article reviews the pathology, symptoms, and management of sleep disturbances in elderly patients. As a consequence of aging, elderly people exhibit alterations in the sleep architecture and sleep-wake rhythm. Many studies employing polysomnography have demonstrated a shortened total sleep time; decreases in sleep efficiency, and time spent in slow wave sleep and rapid eye movement (REM) sleep; and increases in nocturnal arousal and in the proportion of stage I sleep. Furthermore, these patients usually exhibit a multiple sleep-wake rhythm, and an advanced sleep phase. For the treatment of sleep disturbances in the elderly, it is necessary to perform appropriate multidimensional assessment of the patient, such as the assessment of psychosocial factors, as well as medications and diseases that may cause sleep disturbances. Benzodiazepine (BZP) hypnotics have been the primary treatments for sleep disturbances, and are effective and safe when prescribed within the recommended guidelines. Hypnotic drugs should be used carefully to avoid causing delirium, amnesia, and falls. There have also been reports demonstrateing the effectiveness and tolerability of non-BZP hypnotics, antidepressants with fewer anticholinergic effects, atypical neuroleptics, and herbal prescriptions. In addition to alterations in the sleep architecture and sleep-wake rhythm, several sleep disorders become more prevalent in the elderly. These late-life sleep disorders include periodic limb movement disorder (PLMD), restless legs syndrome (RLS), and parasomnias such as REM sleep behavior disorder. As these disorders become more severe, it becomes more difficult to fall asleep and/or maintain sleep continuity, which results in a poorer subjective sleep quality. These disorders have a pathology distinct from those of primary insomnia, and require a different treatment strategy. Furthermore, these disorders are usually refractory to BZP hypnotics. Adequate evaluations and diagnoses are, therefore, essential for successful management.

Three patients with cancer who developed rapid-eye-movement sleep behavior disorder.

This article discusses the clinical significance of differentiating parasomnia, such as rapid-eye-movement (REM) sleep behavior disorder (RBD), from delirium in patients with advanced cancer. We describe three patients with advanced cancer who presented with aberrant behavior at night. All three patients developed violent behaviors when they were administered opioids and/or chemotherapy. Polysomnography (PSG) showed REM sleep with tonic electromyography. Previous treatment with neuroleptics had failed to improve their problematic behaviors. Diagnosis was made using criteria for REM behavior disorder of the International Classification of Sleep Disorders, 2nd edition, and PSG. Clonazepam (0.5 mg/day) was administered orally once at night. After treatment with clonazepam, aberrant and violent behaviors were improved. It should be noted that it is not rare for patients with advanced cancer to present with parasomnia, such as RBD, although organic brain syndrome, such as delirium, is more prevalent. Therefore, it is necessary to provide adequate assessment and treatment of aberrant behaviors in cancer patients.

Proposed dose equivalence between clonazepam and pramipexole in patients with restless legs syndrome.

BACKGROUND: Dopamine agonists are accepted as the first-line medications for restless legs syndrome (RLS). In some Asian countries, clonazepam is one of the prevalent medications for RLS because of its effect on sleep disturbances. To date, there have not been any studies that examined equivalent doses of pramipexole and clonazepam. To evaluate equivalent doses of pramipexole and clonazepam in RLS, we investigated the efficacy and tolerability after conversion from clonazepam to pramipexole, and examined dose equivalence between the two prescriptions. METHODS: In a prospective, open-label, multicenter study, 26 RLS patients treated with clonazepam (mean age: 69.2+/-11.0years old) were enrolled and then rapidly switched to pramipexole using a conversion calculation of 4:1 for daily doses. Then the daily dose of pramipexole was up titrated or tapered by 0.125mg/day at each subsequent examination. RLS symptoms and daytime somnolence were evaluated using the International RLS Study Group rating scale (IRLS), Clinical Global Impressions - Severity of illness (CGI-S) and the Epworth Sleepiness Scale (ESS), respectively. RESULTS: Conversion from clonazepam to pramipexole resulted in significant reductions of IRLS (16.3+/-8.7 to 9.1+/-6.3) and ESS (6.5+/-4.2 to 4.4+/-3.2). CGI scores demonstrated improvement after conversion. In 4 patients (15%), adverse events such as somnolence, sensation of oppression in the lower limbs, diarrhea, or nausea were present. Correlation analysis demonstrated a significant relationship between these daily doses. Spearman's correlation coefficient was 0.662. Our study, however, has some limitations since it is an open-label trial and includes only 26 patients. Further studies using a double-blind design or a crossover design are recommended. CONCLUSIONS: Statistical analysis demonstrated a 4:1 conversion for clonazepam to pramipexole. When switchover from clonazepam to pramipexole is done, this conversion ratio may be helpful to determine the initial dose of pramipexole for treating RLS.

[Restless legs syndrome].

Restless legs syndrome has been recognized to be a common disorder as one of the sleep disturbances. The main symptom is an unpleasant and uncomfortable sensation frequently localized in the leg between the knee and the ankle. Patients find the nature of the discomfort difficult to describe and use words like creeping, pulling, stretching, restless sensations, aching and even pain. The authors report signs, symptoms, epidemiology, pathogenesis, treatment of the syndrome in this paper.

Pathogenesis and symptomatology of hallucinations (delusions) of organic brain disorder and schizophrenia.

In this review article, in order to explore the mechanisms underlying the hallucinations/delusions of schizophrenia, we discuss the contribution of the following four questions: (i) can an understanding of dreams contribute to our understanding of the genesis of halluciations and/or delusions; (ii) are the mechanisms underlying psychotropic drug-induced psychoses the same as those underlying the hallucinations and/or delusions in schizophrenia; (iii) does disturbed consciousness contribute to the manifestation of psychotic features; and (iv) are the psychoses caused by organic brain disorders any different to the hallucinations and/or delusions seen in schizophrenia? We conclude that there is a strong association between drug-induced hallucinations or hallucinations associated with organic brain disorders and simple hallucinosis or fluctuations in arousal level. Because intermediate configurations and/or cross-staining phenomena exist for hallucinations and delusions, especially in schizophrenic disorders, it is difficult to isolate the hallucinations and to recognize them as being abnormal experiences.

Successful treatment with levothyroxine for idiopathic hypersomnia patients with subclinical hypothyroidism.

OBJECTIVE: Our objective was to discuss the effect of levothyroxine on excessive daytime sleepiness (EDS) and a prolonged nocturnal sleep at patients with idiopathic hypersomnia who presented with subclinical hypothyroidism. METHODS: We present two patients with hypersomnia who complained of EDS and a prolonged nocturnal sleep time. Sleep architecture and subjective daytime sleepiness were estimated by polysomnography (PSG) and Epworth Sleepiness Scale (ESS), respectively. Diagnoses were made using the International Classification of Sleep Disorders, 2nd Edition criteria for idiopathic hypersomnia with long sleep time. RESULTS: PSG demonstrated a short sleep latency, a prolonged total sleep time and normal proportions of all non-rapid eye movement (REM) and REM sleep stages. Nocturnal PSG excluded other causes of EDS. No medical, neurological and mental disorders were present. Their laboratory data indicated mildly elevated thyrotropin, despite free thyroxine (T4) and triiodothyronine (T3) estimates within their reference ranges, which is a characteristic of latent hypothyroidism. Levothyroxine (25 microg/day) was administrated orally. After treatment with levothyroxine for 8 weeks, the mean daily sleep times decreased. EDS was also improved, and a significant decrease in the ESS score was observed. Levothyroxine was effective for their hypersomnia and well tolerated. CONCLUSIONS: It should be noted that hypersomnia may be associated with subclinical hypothyroidism, although few abnormalities in physical and neurological examinations are present.

Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptoms of dementia.

OBJECTIVE: Recently, traditional herbal medicines have been reported to be effective for behavioral and psychological symptoms of dementia (BPSD). This study aims to examine the efficacy of Yi-Gan San (YGS) in the improvement of BPSD and sleep disorders in patients with dementia. METHODS: Five patients (1 male and 4 female) with dementia in accordance with DSM-IV criteria were investigated. Participants were treated with YGS for 4 weeks. The Nursing Home version of Neuropsychiatric Inventory (NPI-NH) for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, polysomnography for evaluation of sleep structure, and the Pittsburgh Sleep Quality Index for subjective sleep quality were carried out at baseline and at the end of treatment. RESULTS: All patients completed the trial. Significant improvements in the total NPI-NH score (34.0+/-6.5 to 12.8+/-6.6) as well as delusions, hallucinations, agitation/aggression, anxiety, and irritability/lability, whereas MMSE scores were unchanged. PSG revealed increases in total sleep time, sleep efficiency, stage 2 sleep, and decreases in the number of arousals and periodic limb movements. Subjective sleep quality was also improved. No adverse effects were observed. CONCLUSION: YGS was effective for BPSD and sleep disturbances, and well tolerated in patients with dementia. Further examinations using a double-blind placebo-controlled design are necessary.

A decrease in N-acetylaspartate and an increase in myoinositol in the anterior cingulate gyrus are associated with behavioral and psychological symptoms in Alzheimer's disease.

BACKGROUND AND PURPOSE: The cognitive decline in Alzheimer's disease (AD) patients has been reported to involve alterations in the medial temporal lobe and the posterior cingulate gyrus. On the other hand, the neurochemical pathologies of the behavioral and psychological symptoms of dementia (BPSD) have not been sufficiently discussed. The aim of this study was to clarify the pathologies of BPSD in AD patients. METHODS: Thirty patients with probable AD were included and underwent the following assessments: Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Story Recall Test (SRT), Behavioral pathology in Alzheimer's disease (BEHAVE-AD) and proton MRS ((1)H-MRS). None of them had been medicated for BPSD. RESULTS: The MRS study revealed that MMSE, CDT, and SRT scores were positively related to N-acetyl-aspartate (NAA)/creatine(Cr) and negatively related to myoinositol (mI)/Cr in the posterior cingulate gyrus, but not in the anterior cingulate gyrus. On the other hand, the scores obtained in two categories of BEHAVE-AD (delusional thought/ activity disturbances) were negatively related with NAA/Cr and positively related with mI/Cr in the anterior cingulate gyrus, but not in the posterior cingulate gyrus. CONCLUSION: We conclude that BPSD and the decline in cognitive function in AD might have separate pathologies.

Three patients with hemophagocytic syndrome who developed acute organic brain syndrome.

INTRODUCTION: We describe three patients with hemophagocytic syndrome (HPS) who developed acute organic brain syndrome. All three presented with high-grade fever and twilight state, and were admitted to our hospital. After admission, delirium developed in all three. As delirium improved, various other psychiatric symptoms, including hallucinations, agitation, hypoactivity, affective lability and insomnia, were noted. DISCUSSION: When treated with steroid hormones, immunoglobulin and neuroleptics, all patients demonstrated improvement in their psychiatric symptoms, as well as in their general condition and laboratory findings. Ultimately, they all recovered and were discharged. CONCLUSION: It needs to be noted that organic brain syndrome might be observed at the onset of HPS. Consequently, early diagnosis and treatment for psychiatric symptoms, as well as for HPS, are crucial.