Yuki Omori

Clozapine-induced seizures, electroencephalography abnormalities, and clinical responses in Japanese patients with schizophrenia.

Purpose We describe electroencephalography (EEG) abnormalities and seizures associated with clozapine treatment in Japanese patients with schizophrenia and retrospectively compare EEG results and total Positive and Negative Syndrome Scale (PANSS [T]) scores before and after treatment. Methods Twenty-six patients with treatment-resistant schizophrenia were enrolled in this study. EEG measurements were obtained prior to clozapine treatment and every 4 weeks thereafter. EEG measurements were also obtained at the time of seizure. After seizures or EEG abnormalities were noted, additional EEGs were performed every 2 weeks. PANSS (T) scores were used to determine clozapine treatment outcome. Results All 26 patients had normal baseline EEG measurements, and ten patients (38.5%) later manifested EEG abnormalities. The mean age was significantly lower than in the abnormal EEG group. Six patients (23.1%) experienced seizures. The mean dose of clozapine at the first occurrence of seizure was 383.3 mg/day. Five of six patients who experienced seizures in this study were successfully treated with valproate or lamotrigine without discontinuation of clozapine. The one patient who continued to experience seizures was successfully treated without antiepileptic drugs. The mean baseline PANSS (T) scores were not significantly different between the normal and abnormal EEG groups, but the mean score in the abnormal EEG group was significantly lower than that in the normal EEG group at the final follow-up (P=0.02). Conclusion EEG abnormalities may appear in younger patients, and our findings indicate that there is no need to discontinue clozapine when seizures occur. EEG abnormalities that appeared after clozapine treatment were associated with a good clinical response.

Clozapine-induced cardiomyopathy: A first case in Japan

Clozapine, with proven efficacy for treatment-resistant schizophrenia, was first introduced in Japan in 2009. However, clozapine has serious adverse effects, including agranulocytosis and cardiovascular events. There is a need to determine the predictive factors of adverse effects for Japanese patients and establish safe treatment. Herein, we report the first case of clozapine-induced cardiomyopathy in Japan. Four years ago, a 20-year-old man was diagnosed with schizophrenia and started risperidone at 7 mg/day in our hospital. Risperidone was changed to olanzapine at 20 mg/day because of ineffectiveness. Olanzapine was also inefficacious. The patient was diagnosed as treatment-resistant schizophrenia and admitted to our hospital for clozapine therapy. His Brief Psychiatric Rating Scale score was 45 points. Electrocardiogram (ECG) and general laboratory test results indicated no abnormal findings. His only medical history was cerebral palsy. After admission, he was gradually switched from olanzapine to 100 mg/day of clozapine for 9 days. He developed a fever with a body temperature of 37.5 °C 8 days after clozapine initiation. Physical and laboratory examinations indicated no abnormalities. Acetaminophen improved the fever, so the clozapine dose was gradually increased to 150 mg/day 13 days after the initiation of clozapine; however, hyperthermia continued (maximum body temperature, 39.6 °C). The clozapine dose was decreased to 50 mg/day, improving the fever. We diagnosed the fever as clozapine-induced benign fever. Eighteen days after clozapine was started, the patient complained of dyspnea, accompaniedwith sinus tachycardia (heart rate, 100 beats/min) and hypotension (blood pressure, 72/52 mmHg). A chest radiograph indicated cardiac outline enlargement and bilateral lung hyperlucency. An ultrasound cardiogram (UCG) showed diffuse global left ventricular hypokinesia with an ejection fraction (EF) of 25% and a 20-mm inferior vena cava dimension. No pericardial effusions were noted. There was mild tricuspid regurgitation as valvular abnormalities. The C-reactive protein level (23 mg/L) was elevated. White blood cell count, cardiac enzymes, and other laboratory test results were within normal limits. Consulted cardiovascular specialists diagnosed clozapine-induced cardiomyopathy. Clozapine was discontinued, and intravenous steroid injection was initiated. Four days after clozapine was discontinued, a UCG indicated improvement of the left ventricular EF of 38%, and administration of olanzapine at 20 mg/day was restarted. Thirteen days after discontinuation, a UCG indicated an improvement of left ventricular EF of 75%. Twenty days after discontinuation of clozapine, the patient was discharged from the hospital with preadmission-equivalent symptoms. During the subsequent 1-year follow-up, neither fever nor cardiac function depression was observed. Prescription of clozapine has increased because of efficacy and fewer extrapyramidal adverse effects, hyperprolactinemia, and tardive dyskinesia. However, clozapine is notorious for adverse effects such as agranulocytosis and cardiovascular adverse effects. Clozapine-induced

N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: Case reports and methods for detection

The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is suspected of having encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder) were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related encephalitis would give essential clues for the research of schizophrenia, catatonia, and atypical psychosis.

Orexin/hypocretin levels in the cerebrospinal fluid and characteristics of patients with myotonic dystrophy type 1 with excessive daytime sleepiness

Purpose Myotonic dystrophy type 1 (DM1) is often characterized by excessive daytime sleepiness (EDS) and sleep-onset rapid eye movement periods caused by muscleblind-like protein 2. The EDS tends to persist even after treatment of sleep apnea. We measured the cerebrospinal fluid (CSF) orexin levels in DM1 patients with EDS and compared the clinical characteristics with narcolepsy type 1 and idiopathic hypersomnia (IHS) patients. Patients and methods We measured the CSF orexin levels in 17 DM1 patients with EDS and evaluated subjective sleepiness using the Epworth Sleepiness Scale (ESS), objective sleepiness using mean sleep latency (MSL), and sleep apnea using apnea-hypopnea index (AHI). We compared the ESS scores and MSL between decreased (≤200 pg/mL) and normal (>200 pg/mL) CSF orexin group in DM1 patients. Furthermore, we compared the CSF orexin levels, ESS scores, MSL, and AHI among patients with DM1, narcolepsy type 1 (n=46), and IHS (n=30). Results Seven DM1 patients showed decreased CSF orexin levels. There were significant differences in the ESS scores and MSL between decreased and normal CSF orexin groups in DM1 patients. The ESS scores showed no significant difference among patients with DM1, narcolepsy type 1, and IHS. The MSL in DM1 and IHS patients were significantly higher than narcolepsy type 1 patients (p=0.01, p<0.001). The AHI in DM1 patients was significantly higher than narcolepsy type 1 patients (p=0.042) and was insignificantly different from IHS patients. The CSF orexin levels in DM1 patients were significantly lower than IHS patients and higher than narcolepsy type 1 patients (p<0.001, p<0.001). Conclusion The CSF orexin levels of DM1 patients moderately decreased compared to those of IHS patients as the control group. However, the EDS of DM1 patients may not be explained by only orexin deficiency.

Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation

Objectives Delayed sleep phase syndrome (DSPS) is a chronic dysfunction of circadian rhythm of the subject that impairs functioning in social, occupational, or other spheres. High rate of depression is found among DSPS patients. Aripiprazole (APZ), a second-generation antipsychotic, is effective in treatment of depression as well as schizophrenia. Recently, few case reports show the effectiveness of APZ in treating DSPS and non-24-hour sleep–wake rhythm disorder. Therefore, we tried to treat DSPS with depression using APZ. Methods Twelve subjects (including four women) aged 19–64 years were included. The subjects were prescribed initially 0.5–3 mg of APZ once a day with subsequent dose adjustments. Results Sleep onset, midpoint of sleep, and sleep offset were significantly advanced by 1.1, 1.8, and 2.5 hours, respectively. Unexpectedly, sleep duration became significantly shorter by 1.3 hours after treatment. Their depressive moods showed an unremarkable change. Conclusion Low dose of APZ advanced the sleep rhythm and reduced nocturnal sleep time in the subjects with DSPS. Since it is not easy for physicians to treat prolonged sleep duration often associated with DSPS, this medication would become a new therapeutic option for these patients.

Clozapine Induced EEG Abnormalities and the Serum Concentration of Clozapine in Japanese Patients with Schizophrenia

Introduction Clozapine-induced electroencephalography (EEG) abnormalities are common. It has been reported that clozapine-induced EEG abnormalities occur in a dose-dependent manner and correlate with the serum concentration of clozapine (C-CLZ). However, the oppositional results were also reported. Objectives The objective of this study was to investigate the relationship between serum level of clozapine and EEG abnormalities. Methods Twenty-eight patients were recruited in this study, but five patients were excluded because clozapine was discontinued before post-treatment EEG measurement or measurement of C-CLZ. Ultimately, 23 patients (6 males, 17 females) with an average age of 35 years were enrolled. The subjects were divided into EEG normal and abnormal group. C-CLZ and the serum concentration of metabolite of clozapine (N-CLZ) were measured. The correlation between C-CLZ and daily dose of CLZ (D-CLZ), N-CLZ and D-CLZ were evaluated in each group. C-CLZ per D-CLZ (C/D), N-CLZ per D-CLZ (N/D) and the ratio of C-CLZ to N-CLZ (C/N) were compared between the two groups. Results 74 serum levels were measured. All patients had normal baseline EEGs, and 10 patients later showed EEG abnormalities. There were a significant correlation between C-CLZ and D-CLZ (EEG normal: rs 0.58, p Conclusion There was no relationship between the serum concentration of clozapine and EEG abnormalities.