Yuka Kikuchi

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

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.

Successful Management of Clozapine-induced Akathisia with Gabapentin Enacarbil: A Case Report

The management of clozapine (CLZ)-induced adverse events affects patient prognoses. Akathisia is a relatively rare adverse event related to CLZ administration and thus the management of this syndrome is not well established. Here, we report a case of treatment-resistant schizophrenia wherein CLZ-induced akathisia was successfully managed with gabapentin enacarbil (GE). The patient was a 39-year-old woman who had been treated with atypical antipsychotics other than CLZ for three years with poor tolerability. Initiation of CLZ (400 mg/day) attenuated her psychotic symptoms, but was followed by moderate akathisia. Neither benzodiazepines nor biperiden improved the akathisia; however, akathisia was finally diminished with co-administration of GE. GE facilitated a dosage increase in CLZ (450 mg/day) for the improved management of pyschotic symptoms, and thus indirectly contributed to treatment of the patient’s schizophrenia. We suggest that GE is a useful candidate for the management of CLZ-induced akathisia. The improved management of treatment-induced akathisia and other adverse events can extend the potential application of CLZ for treatment-resistant schizophrenia.

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.