Long-term oral blonanserin treatment for schizophrenia: a review of Japanese long-term studies.

In general, the course of schizophrenia is chronic accompanied not only by positive and negative symptoms but also by cognitive dysfunction associated with psychosocial disability, and thus treatment combining antipsychotics and psychological therapy is considered promising. This review focused on two prospective, open-label, multicenter, phase 3 long-term studies for approval of oral blonanserin for the treatment of schizophrenia. These two studies included both inpatients and outpatients with variable disease duration or symptom prominence according to the Positive and Negative Syndrome Scale (PANSS). The selected two studies consisted of almost the same study schedule and eligibility criteria but different protocols regarding prior medications and concomitant antipsychotics. The proportion of patients who had a baseline PANSS negative score higher than the positive score was 82.2 and 67.2% in the two studies. In both studies, patients with an illness duration of ≥ 10 years were the most common. Based on the clinical symptoms at baseline, the physician determined the treatment: blonanserin monotherapy, blonanserin in combination with the existing antipsychotic medication, or therapy simplified to haloperidol together with blonanserin. The 28-week completion rate for long-term blonanserin treatment was high in both studies (82.2 and 78.7%). The types of adverse events in both studies were similar to those in the preceding 8-week randomized, active-controlled studies in Japan, which were included in the application package for the approval of oral blonanserin for patients with schizophrenia. Long-term blonanserin use did not increase the risk of extrapyramidal symptoms but reduced the dose of antiparkinsonian drugs, minimally affecting functioning. In both studies, the PANSS total score, positive score, and negative score were improved at the last observation carried forward compared with those at baseline. In conclusion, blonanserin is useful for long-term treatment of chronic schizophrenic patients when the appropriate management of clinical symptoms and adverse drug reactions are applied. Blonanserin might represent a promising treatment option that partially or completely relieves patients with chronic schizophrenia of polypharmacy. Blonanserin may possibly fit both the current real-world clinical setting and the currently recommended approach to antipsychotic medication.

Long-term mood/antidepressant effects of quetiapine extended-release formulation: an open-label, non-controlled extension study in Japanese patients with bipolar depression.

BACKGROUND: In an 8-week, randomized, placebo-controlled, double-blind study, an extended-release formulation of quetiapine, quetiapine XR, demonstrated efficacy and safety in Japanese patients with bipolar depression. Bipolar disorder is a chronic disease requiring continuous treatment. METHODS: This was a long-term (52-week), open-label, non-controlled extension study to evaluate the long-term safety and efficacy of quetiapine XR in Japanese patients with bipolar depression who had previously completed the initial 8-week double-blind study. Efficacy was determined by the Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Depression Scale 17-item (HAM-D17), and Clinical Global Impressions-Bipolar scale (CGI-BP). Safety evaluations included analysis of adverse events, clinical laboratory measures, vital signs, Drug-induced Extrapyramidal Symptoms Scale, Young Mania Rating Scale, and the Columbia Suicide Severity Rating Scale. RESULTS: The mean (SD) MADRS total score decreased from 30.9 (6.9) at baseline to 16.1 (10.6) at week 8, and eventually to 9.1 (8.7) at week 52. The sustained efficacy of quetiapine XR treatment was also shown using HAM-D17 total scores, CGI-BP-Severity and Change evaluations. The most common adverse events were somnolence, nasopharyngitis, and thirst. Long-term treatment with quetiapine XR caused no substantial changes in the safety profiles, including clinical laboratory parameters, and no new safety concerns were identified. CONCLUSIONS: The efficacy of quetiapine XR was sustained long-term and no new safety concerns were identified in Japanese patients with bipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov Registration: NCT01725308. Date of registration; 12th November 2012 (retrospectively registered).

Screening for diabetes using Japanese monitoring guidance in schizophrenia patients treated with second-generation antipsychotics: a cross-sectional study using baseline data.

AIM: The Japanese blood glucose monitoring guidance for patients receiving second-generation antipsychotics has been newly developed. We aimed to report a cross-sectional study using the baseline data of the Japanese monitoring guidance to find undiagnosed hyperglycemia systematically as a routine clinical practice and to quantify the frequency of glucose abnormalities in schizophrenia patients treated with second-generation antipsychotics. METHODS: Data for 537 patients with schizophrenia, who had not been diagnosed as having diabetes prior to baseline screening and started the monitoring between June 2008 and January 2009, were collected from medical records in 25 hospitals. Blood glucose (fasting or casual), hemoglobin(A1c) , serum lipids, height/weight, clinical diabetic symptoms, and family history of diabetes were assessed. Patients were classified into normal, pre-diabetic or probable diabetic type based on their values of blood glucose or hemoglobin(A1c) , and various background characteristics and serum lipid values were compared among the three types. RESULTS: Out of 537 patients, 13 (2.4%) met criteria for probable diabetic type, 51 (9.5%) for pre-diabetic type, and 473 (88.1%) for normal type. Individuals categorized as probable diabetic type had a higher body mass index and higher frequency of family history of diabetes mellitus than those with normal type. CONCLUSION: Glucose abnormalities were newly detected in 11.9% of schizophrenia patients treated with second-generation antipsychotics by the baseline monitoring. To assess the detective power and usefulness of the guidance, longitudinal investigations are necessary.

Blonanserin versus haloperidol in Japanese patients with schizophrenia: A phase 3, 8-week, double-blind, multicenter, randomized controlled study.

OBJECTIVE: This Japanese, multicenter, randomized, double-blind trial, evaluating the efficacy and safety of blonanserin compared with haloperidol in patients with schizophrenia, was previously published by Murasaki in the Japanese language. In this article, we present the results of the trial based on full analysis dataset instead of per protocol dataset formerly reported and discuss the findings in light of the latest knowledge of pharmacological treatment for schizophrenia. METHODS: A total of 265 patients were randomized to receive blonanserin (8 to 24 mg/d) or haloperidol (4 to 12 mg/d) twice daily for 8 weeks. Efficacy assessments included the Clinical Global Impressions-Improvement (CGI-I) and the Positive and Negative Syndrome Scale (PANSS). RESULTS: Blonanserin was not inferior to haloperidol with a margin of 10% with respect to the improvement rate on CGI-I at end of study (60.5% vs 50.0%, P < 0.001). The decrease in the PANSS total score did not differ between the drugs (-10.3 vs -7.1). For the PANSS negative symptom score, the decrease was significantly greater with blonanserin than with haloperidol (P = 0.006). Blonanserin was well tolerated. The incidence of adverse events was similar for the two drugs. Extrapyramidal adverse events, sedation, hypotension, and prolactin increase were rarer with blonanserin than with haloperidol. No clinically important weight gain was observed. CONCLUSIONS: Blonanserin is as effective as haloperidol for the treatment of schizophrenia. Blonanserin is more effective for negative symptoms with a lower risk of extrapyramidal symptoms compared with haloperidol.

Multi-center, randomized, double-blind, placebo-controlled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

RATIONALE: Quetiapine fumarate is an atypical antipsychotic indicated for various mental disorders, but it has not been studied in Japanese patients with bipolar depression. OBJECTIVES: To evaluate the efficacy and safety of quetiapine XR (extended release) in Japanese patients with bipolar depression. METHODS: In this multi-center, randomized, double-blind, placebo-controlled, fixed-dose study of 431 Japanese adults with bipolar I or II disorder, efficacy was determined by analyzing the mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary end points included MADRS response and remission rates, Hamilton Depression Scale 17-Item (HAM-D17), and Clinical Global Impressions-Bipolar (CGI-BP) scale scores. Safety was determined by monitoring adverse events and clinical assessments. RESULTS: This study revealed a statistically significantly greater decrease in MADRS total score after 8 weeks of quetiapine XR 300 mg/day monotherapy compared with placebo (- 12.6 vs. - 10.1; p = 0.034). There were also improvements in MADRS response (44.1 vs. 35.6%) and remission (38.0 vs. 26.6%) rates as well as in HAM-D17 and CGI-BP scale scores compared with placebo. In the subgroup analysis of patients with bipolar I or II disorder, the adjusted mean changes in MADRS total score compared to placebo were - 2.3 and - 2.1, respectively. Adverse events occurred in 149 patients (83.2%) receiving quetiapine XR 300 mg/day and in 81 patients (45.8%) receiving placebo. The most common adverse events were somnolence and thirst, which is consistent with the previously reported safety profile. CONCLUSIONS: Once-daily monotherapy with quetiapine XR is an effective and well-tolerated treatment for bipolar depression in Japanese patients.

Correction to: Multi-center, randomized, double-blind, placebocontrolled study of quetiapine extended-release formulation in Japanese patients with bipolar depression.

The original version of this article contained a mistake in Table 5. Correct version is presented here.

[Reconsideration of psychomotor seizure--importance of medio-dorsal thalmic nucleus].

Recently, to my regret, the opportunities for psychiatrists to join in clinical and experimental activities to combat epilepsy are decreasing. In the period of 1960-1980, experimental epileptology was one of the main areas in the field of psychiatry. Now, I have been given an opportunity to reevaluate my paper, entitled "Role of the Mediodorsal Thalamic Nucleus in Temporal Lobe Seizures--An Experimental Study", published in this journal in 1968. Therefore, I would like to reconsider psychomotor seizures, which are classified as complex partial seizures at present. The psychomotor seizures mentioned above are so-called amygdalo hippocampal seizures. At first, I was very much interested in the amygdala and hippocampus, because these seizures are quite similar to psychomotor seizures which are clinically observed in epileptics. I observed a lot of important phenomena. A amygdaloid and hippocampal seizures are quite different from each other, both regarding their behavior and EEG findings which are observed during the attacks. Hippocampal seizures consisted of staring in the arrest reaction. On the contrary, amygdaloid seizures showed typical automatisms, such as facial and behavioral automatisms. From these results, it was considered that the clinically observed psychomotor seizures began in the hippocampus and immediately induced the self-sustained amygdaloid seizures. In my experiments, I often observed that self-sustained amygdaloid seizures were easily induced by hippocampal seizures. Moreover, I noted the fact that stimulation of the mediodorsal thalamic nucleus elicited both amygdaloid and hippocampal seizures. By means of stimulation and surgical interruption methods among the dorsomedial thalamic nucleus, amygdala, and hippocampus, I found that the dorsomedial thalamic nucleus plays the main role in amygdalo-hippocampal seizures. According to my experiments, the thalamic nucleus controls the limbic seizures. So, I concluded that the therapeutic approach to the mediodorsal thalamic nucleus is clinically very important. I think that, through these experimental studies, I could profoundly understand epilepsy itself and the development of seizure discharge in the brain, and put this understanding to good use in my clinical activities. It is my belief that experiments which are performed by clinicians field useful results which can be utilized clinically.

Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia.

The aim of this study was to evaluate the efficacy and safety of ramelteon 4, 8, 16 or 32 mg and placebo in Japanese patients with chronic insomnia using a randomized, double-blind, five-period crossover design. A total of 65 Japanese patients with chronic primary insomnia received ramelteon or placebo for two nights each in sleep laboratories. Changes in sleep parameters were assessed objectively by polysomnography and subjectively by postsleep questionnaires. Safety and tolerability was evaluated by assessment of the occurrence of adverse events, next-day residual effects and laboratory and ECG investigations. Ramelteon 8 and 32 mg significantly shortened the mean latency to persistent sleep in comparison with placebo, and there was a statistically significant trend for linear dose-response for this sleep parameter. Overall changes in sleep architecture were modest (<3% changes vs placebo), with increases in stage 1 and decreases in stage 3/4. Ramelteon was well tolerated, the most common adverse effect being somnolence, which was similar to placebo at doses up to 8 mg, but increased with higher doses. Next-day residual effects occurred no more frequently with ramelteon at any dose than with placebo. When compared with sleep latency data from a similarly-designed US study, there was no evidence of any ethnic differences in the efficacy of ramelteon between Japanese and US patients. Overall, ramelteon 8 mg showed the most favorable balance between sleep-promoting effects and tolerability. The unique efficacy profile of ramelteon, promoting sleep initiation without affecting other sleep parameters, may be due to its circadian shifting effect.

Paroxetine in the treatment of obsessive-compulsive disorder: randomized, double-blind, placebo-controlled study in Japanese patients.

The efficacy of paroxetine in the treatment of obsessive-compulsive disorder in Western populations is well established. The present study compares the efficacy and safety of paroxetine with placebo in the treatment of obsessive-compulsive disorder in Japanese patients. Patients aged 16 years or older who met Diagnostic and Statistical Manual of Mental Disorders (4th edn; DSM-IV) criteria for obsessive-compulsive disorder and had a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of >/=16 were randomized to receive 12 weeks' therapy in a double-blind manner. Paroxetine 20-50 mg/day or placebo was administered following a 1 week, placebo run-in phase. One hundred and ninety-one patients were randomized to either paroxetine or placebo, 188 patients were assessed as the full analysis set (FAS) and 144 patients completed the 12 week study. After adjustment for the Y-BOCS total score at baseline, reductions in obsessive-compulsive total score at week 6 and at the end of therapy were significantly greater in the paroxetine group than the placebo group. Most of the adverse events that occurred during the study were of mild to moderate intensity. Paroxetine is effective and well tolerated in Japanese adult patients with obsessive-compulsive disorder.