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Safe and effective administration of clozapine requires careful monitoring for inflammatory reactions during the initial titration. The concentration-to-dose (C/D) ratio must be taken into account, which may vary among ethnicities. In this retrospective study, 1408 Korean schizophrenia inpatients were examined for during the first 8 weeks of clozapine titration. The average doses of clozapine administered during weeks 1, 2, 4, and 8 were 77.37, 137.73, 193.20, and 212.83 mg/day, with significantly lower doses for females than males. The average C/D ratio was significantly higher in females (1.75 ± 1.04 and 1.11 ± 0.67 ng/mL per mg/day). Patients with higher C/D ratios were more likely to experience fever and were prescribed lower doses of clozapine starting from week 4. In total, 22.1 % of patients developed a fever at an average of 15.74 days after initiating clozapine. Patients who developed a fever were younger, used more antipsychotics at baseline, had a higher C/D ratio, and had a higher incidence of an elevated C-reactive protein level. A higher C/D ratio, use of a greater number of antipsychotics at baseline, and concomitant olanzapine use were risk factors for the development of inflammatory reactions. The incidence of pneumonia, agranulocytosis, and myocarditis within 8 weeks were 3.7 %, 0.3 %, and 0.1 %. In summary, the target dose of clozapine titration is lower for Korean schizophrenia patients, with a higher C/D ratio and more frequent fever compared to Western patients; however, myocarditis occurs rarely. Our findings may contribute to the titration methods for clozapine for the East Asian population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest concerning the subject of the study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pneumonia is a significant adverse drug reaction (ADR) associated with clozapine, characterized by high mortality and potential linkage with other inflammatory responses. Despite the critical nature, research regarding the development of pneumonia during initial clozapine titration remains limited. This retrospective study included 1408 Korean inpatients with schizophrenia spectrum disorders. Data were collected from January 2000 to January 2023. Pneumonia developed in 3.5 % of patients within 8 weeks of clozapine initiation. Patients who developed pneumonia were taking a greater number and higher dose of antipsychotics at baseline (2.14 vs. 1.58, p < 0.001; 25.64 vs. 19.34, p = 0.012). The average onset occurred 17.24 days after initiation, on an average dose of 151.28 mg/day. Titration was either paused or slowed in most of these patients, with no reported fatalities. The types of pneumonia included aspiration pneumonia, mycoplasma pneumonia, bronchopneumonia, and COVID-19 pneumonia. Myocarditis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and urinary tract infections were also identified. Logistic regression analysis revealed that a greater number of concomitant antipsychotics (odds ratio [OR] = 1.59, p = 0.027) and concomitant benzodiazepine use (OR = 2.33, p = 0.005) at baseline were associated with an increased risk of pneumonia. Overall, pneumonia development during clozapine titration is linked with other inflammatory ADRs, suggesting a shared immunological mechanism. Close monitoring is recommended, especially for patients taking multiple antipsychotics and benzodiazepines. Further studies involving repeated measures of clozapine concentrations at trough and steady state, along with a more detailed description of pneumonia types, are warranted., Competing Interests: Declaration of competing interest The authors have no conflicts of interest concerning the subject of the study., (Copyright © 2023 Elsevier B.V. All rights reserved.)

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P  = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear., Objectives: To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia., Methods: Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted., Results: Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E., Conclusions: E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Corrected QT-interval (QTc) prolongation (QTP) is a rare but fatal adverse effect of antipsychotics. Clozapine is the only antipsychotic recommended for treatment of resistant schizophrenia; however, clozapine has been reported to cause QTP. We sought factors predictive of QTP in patients who had antipsychotic polypharmacy involving clozapine. We explored whether the clozapine blood concentration might predict QTP., Methods: We included 133 patients with schizophrenia spectrum disorder who had antipsychotic polypharmacy involving clozapine. We used the χ2 and nonparametric tests to compare clozapine therapeutic drug monitoring (TDM) values and QTc-prolonged person (QTPP) status. Multivariate regression and mediator models were used to identify risk factors for QTPP status and QTP., Results: In total, 111 patients were prescribed clozapine. The QTPP rates were 31.3% (20) for men and 23.2% (16) for women. Compared with the non-QTPP group, the QTPP group exhibited significantly higher daily dose of all antipsychotics including clozapine, a higher clozapine dose, and elevated clozapine and norclozapine TDM values. Furthermore, such patients were prescribed a greater number of antipsychotics. Multivariate logistic regression revealed that only the clozapine TDM value could be predictive factor for QTPP status (P = 0.018). A clozapine TDM value above the therapeutic range (>600 mg/dL) was associated with a high risk of QTPP status (adjusted odds ratio, 6.5; 95% confidence interval, 1.7-25.2; P = 0.006). The mediator model revealed that the clozapine TDM values completely mediated the association between the clozapine dose and the QTc interval., Conclusions: The clozapine blood concentration reliably predicts QTP in patients with clozapine use., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration., Competing Interests: In the last 3 years, the following authors had no conflict of interest: Drs. de Leon, Schoretsanitis, Molden, Smith, Solismaa, Švancer, Olmos, Ricciardi, Iglesias-Garcia, Iglesias-Alonso, Spina, Ruan, Chuan-Yue Wang, Gang Wang, Tang, Lin, Lane, Rajkumar, González-Esquivel, Jung-Cook, Baptista, Rohde, Nielsen, Verdoux, Quiles, Sanz, De las Cuevas, Cohen, Schulte, Chopra, McCollum, Shelton, Kaithi, Farooq, McGrane, Lana, Arrojo-Romero, Rădulescu, Every-Palmer, Bebawi, Bhattacharya, Otsuka, Lazary, Torres, Yecora, Motuca, Chan, Zolezzi, Ouanes, De Berardis, Grover, Kirilochev, Soloviev, Ayub, Silva, Bonelli, Temmingh, Decloedt, Pedro, Pacheco Palha, LLerena, Fernandez-Egea, Siskind, Masmoudi, Mohd Saffian, Leung and Buckley. In the last 3 years several authors report conflicts of interests. Dr. Seppälä is permanent medical advisor, received lecture fees and is an advisory board member from Viatris that markets clozapine in Finland and other European countries. Dr. Kopeček participated in speakers/advisory boards and lectured with the support of Angelini, Janssen Pharmaceuticals, Lundbeck and Richter Gedeon. Dr. Yong Sik Kim received grants, research support and honoraria from Janssen, Otsuka, Whan in Pharm and Bukwang Pharm (Sumitomo Dannipon Pharma). Dr. Se Hyun Kim received research grants from and/or served as a lecturer for Janssen, Eli Lilly, and Dongwha. Dr. Ertuğrul has received speaker’s honoraria from Abdi İbrahim Otsuka. Dr. Anıl Yağcıoğlu has received speaker’s honoraria and consulting fees from Janssen and Abdi İbrahim Otsuka. Dr. Cotes has received research funding from Otsuka, Lundbeck, Roche, Alkermes, and is a consultant for Saladax Biomedical. Dr. Kane reports personal fees from Alkermes, personal fees from Allergan, personal fees from Bristol-Myers Squibb, personal fees from IntraCellular Therapies, Janssen, Lundbeck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Sunovion, Takeda, Teva, outside-the-submitted work from LB Pharma, MedAvante and The Vanguard Research Group. Dr. Ng had served as consultant for Grunbiotics, Lundbeck, Servier, and Janssen-Cilag, and received research speaker honoraria from Servier, Janssen-Cilag and Pfizer.IMcG received royalties from Hogrefe Publishing Corp. T.L. Dr. Bilbily is supported by the National Institute on Drug Abuse training grant 5T32DA007261-30 (MPI). Dr. Hiemke received speaker’s honoraria from Otsuka. Dr. López-Jaramillo reports financial support for research from Financial support from the National Institute of Mental Health, USA, MinCiencias, Colombia and the Universidad de Antioquia, Colombia. Dr. Eap received honoraria for conferences or teaching CME courses from Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Vifor-Pharma, and Zeller. Dr. Seifritz has received honoraria from Schwabe GmbH for educational lectures. He has further received educational grants and consulting fees from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Recordati, Vifor, Sunovion, and Mepha. Dr. Bousman is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Pharmacogene Variation Consortium (PharmVar). Dr. Kelly has served as a consultant for Alkermes, Lyndra and Sunovion. Dr. Procyshyn has been on the speaker's bureau and attended advisory board meetings for Janssen, Lundbeck, and Otsuka. Dr. Adebayo was on the advisory board of Janssen for a Long Acting Injectable Paliperidone palmitate in Nigeria. Janssen is not involved in Clozapine in Nigeria. Dr. Fountoulakis has received grants in the past, served as consultant, advisor or CME speaker, or received support to attend congresses by the following entities: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Pfizer, the Pfizer Foundation, Sanofi-Aventis, Servier, Shire and others. Since January 2020 he has been the director of Cochrane Greece and completely free from any conflict of interest. Dr. Wilkowska has received research support from Angelini, Biogen, Eli Lilly and Company, Janssen-Cilag, Lundbeck, Polpharma, Sanofi and Valeant. Dr. Cubała has received research support from Alkermes, Allergan, Auspex, Biogen, Celon, Ferrier, Forest Laboratories, Janssen, Otsuka, and Sanofi; he has served on speaker bureaus for Angelini, Celon, Janssen, and Sanofi, and he has served as a consultant for GW Pharmaceuticals, Janssen, Celon and Sanofi. Dr. Villagrán-Moreno has received speakerʼs honoraria from Janssen and have developed lectures and presented clozapine lectures for Adamed, which sells clozapine in Spain; he has participated in advisory boards for Rovi and in research projects for Otsuka. Dr. Crespo-Facorro has received funding unrelated to the present work for research projects and/or honoraria as a consultant or speaker from the following entities: Angelini, Janssen-Cilag, Lundbeck, Otsuka, Mylan, Sanofi-Aventis, ADAMED, Agencia Española de Investigacion, Instituto de Salud Carlos III, the EU Seventh Framework Program and Horizon 2020. Dr. Takeuchi has received speaker’s fees from EA Pharma, Kyowa, Janssen, Lundbeck, Meiji Seika Pharma, Mochida, Otsuka, Sumitomo Dainippon Pharma, Takeda, and Yoshitomiyakuhin. Dr. Tsukahara has received speaker's honoraria from Eisai Inc. Dr. Gründer has served as a consultant for Allergan (Dublin, Ireland), Boehringer Ingelheim (Ingelheim, Germany), Institute for Quality and Efficiency in Health Care (IQWiG, Cologne, Germany), Janssen-Cilag (Neuss, Germany), Lundbeck (Copenhagen, Denmark), Otsuka (Chiyoda, Japan), Recordati (Milan, Italy), Sage (Cambridge, USA), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Gedeon Richter (Budapest, Hungary), Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax (Bethlehem, USA). He is co-founder and/or shareholder of Mind and Brain Institute GmbH (Zornheim, Germany), Brainfoods GmbH (Zornheim, Germany), OVID Health Systems GmbH (Berlin, Germany) and MIND Foundation gGmbH (Berlin, Germany). Dr. Sagud participated in lectures for the following companies: Alkaloid, Belupo, Elli Lilly, Gedeon Richter, Jadran Galenski Laboratorij, Johnson / Johnson, Lundbeck, Makpharm, Pliva, Stada and participated in the clinical trial: Eli Lilly, Krka and Gedeon Richter. Dr. Celofiga received speaker’s honoraria from Ely Lilly, Lundbeck, Richter Gedeon, Krka, Lek, Pliva, Angelini Pharma and participated in advisory boards for Janssen Pharmaceuticals and Lundbeck. Dr. Ignjatovic Ristic developed and presented clozapine lectures with the support of Mylan, received speakerʼs honoraria from Mylan, Teva Serbia, Pharm Swiss, Krka and Janssen. Dr. Ortiz has been a consultant and has received honoraria from Janssen-Cilag. Dr. Elkis received research grants from the São Paulo Research Support Foundation (FAPESP) and honoraria for participation as a member of advisory boards, speaker, or travel support from the following pharmaceutical companies: Aché, Cristalia, Daiichi-Sankyo, Janssen, Mantecorp-Hypera, Sandoz, and Teva. Dr. Weizman received speakerʼs honoraria from Lundbeck, Lilly, Teva, Trima, Jansen, Medison, Novartis and AstraZeneca. These activities were unrelated to the current study. Dr Marder reports consultation fees from Roche, Sunovion, Merck, Boehringer Ingelheim and Otsuka. He reports research support from Boehringer-Ingelheim, and GW Pharma. Dr. Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: AbbVie, Acadia, Alexza, Alkermes, Allergan, Angelini, Astellas, AstraZeneca, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Bristol-Myers Squibb, Cadent Therapeutics, Eisai, Eli Lilly, Forum, Genentech, Impel, Indivior, Intra-Cellular Therapies, Janssen, Jazz, Karuna, Lundbeck, Luye, Lyndra, Medavante-Prophase, Meiji, Merck, Medivation, Mylan, Neurocrine, NeuroRx, Novartis, Noven, Osmotica, Otsuka, Pfizer, Reckitt Benckiser, Relmada, Reviva, Sage, Shire, Sunovion, Takeda, Teva, University of Arizona, Valeant, Vanda, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research. Dr. Freudenreich has the following financial relationship with a commercial interest to disclose (recipient SELF; content area SCHIZOPHRENIA): Alkermes – Research grant (to institution), consultant honoraria (Advisory Board); Avanir – Research grant (to institution); Janssen – Research grant (to institution), consultant honoraria (Advisory Board); Integral - Consultant honoraria; Neurocrine – Consultant honoraria (Advisory Board); Novartis – Consultant honoraria; Otsuka – Research grant (to institution); Roche – Consultant honoraria; Springer Verlag – Royalties (medical writer); Elsevier – Honoraria (medical editing); Global Medical Education – Honoraria (CME speaker and content developer); Medscape – Honoraria (CME speaker); American Psychiatric Association – Consultant honoraria (SMI Adviser); Wolters-Kluwer – Royalties (content developer); UpToDate – Royalties, honoraria (content developer and editor, including for a chapter on clozapine). Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Damitsa, Gedeon Richter, Hikma, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of LB Pharma. Dr. Müller reports he has been a co-investigator for two pharmacogenetic studies where genetic test kits were provided as an in-kind contribution by Myriad Neuroscience. He did not receive any payments or any equity, stocks, or options from any pharmacogenetic companies. He is also a co-inventor of two patents assessing risk for antipsychotic-induced weight gain (pending)., (Thieme. All rights reserved.)

Background: Patients treated with antipsychotics experience significant weight gain and accompanying metabolic disorders. We investigated the efficacy of liraglutide 3.0 mg in reducing the weight of antipsychotic-treated obese patients., Method: We retrospectively reviewed 16 obese patients with schizophrenia or bipolar disorder who were treated with 3.0 mg of liraglutide each. During the 16 weeks of treatment, changes in body weight and Clinical Global Impression-Severity scale (CGI-S) were analyzed. The participants were divided into responders (lost at least 5% of body weight) and non-responders for analysis., Results: Treatment with liraglutide 3.0 mg significantly decreased body weight (estimated marginal mean, 93.2 kg at baseline and 88.9 kg at 16 weeks; p < 0.001) as well as waist circumference, BMI and plasma glucose levels. Six of 16 patients (37.5%) complained of a modest degree of nausea. Six of the 12 subjects (50%) completing 16 weeks of treatment were responders. There were no significant differences in baseline characteristics between responders and non-responders. There was no worsening of CGI-S scores., Conclusion: Liraglutide 3.0 mg significantly decreased body weight in obese patients treated with antipsychotics without altering the status of psychiatric diseases. A randomized controlled study is required to corroborate the results of this study., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Electroconvulsive therapy (ECT) has been suggested as a treatment for augmenting the response to clozapine in patients that do not respond well to clozapine alone and maintenance ECT (M-ECT) had also been recommended to sustain improvement. This retrospective study of up to 2 years of observation was conducted to explore whether M-ECT is beneficial for long-term maintenance of the symptom remission elicited by acute ECT. Positive and Negative Syndrome Scale (PANSS) were plotted for each patient and compared using a linear mixed-effect model. A total of thirty-eight patients were followed and classified into three groups: (1) clozapine alone (CZP, n = 15), (2) acute ECT only (A-ECT, n = 11), and (3) acute ECT with M-ECT (M-ECT, n = 12). The mean number and interval of ECT sessions during the maintenance period in the M-ECT group were 39.0 ± 26.7 and 15.6 ± 8.4 days, respectively. The slope of the M-ECT group eventually declined, but that of the A-ECT group gradually increased back to the pre-ECT level. No persistent or serious adverse effects were observed. In conclusion, A-ECT augmented the effect of clozapine, but M-ECT was required for sustaining symptom improvement., (Copyright © 2019. Published by Elsevier B.V.)

Clozapine, a representative atypical antipsychotic, has superior efficacy compared to other antipsychotic agents and is used for the treatment of severe psychotic disorders. Therefore, studies on its mechanisms of action are important for understanding the mechanisms of therapeutic approaches to psychosis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine-threonine kinase that plays a major role in maintaining metabolic homeostasis. Unc-51-like kinase 1 (ULK1) and Beclin1 are downstream substrates of AMPK and activate the autophagic process. In this study, we examined the effects of clozapine on the AMPK-ULK1-Beclin1 signaling pathway and autophagy in the frontal cortex of the rat. Clozapine (10mg/kg) administration increased the immunoreactivity of p-Thr172-AMPKα in the rat frontal cortex at 1, 2, and 4h after injection, as we previously reported. The immunoreactivity of p-Ser317-ULK1 and p-Ser93-Beclin1 was also increased at 2 and 4h after clozapine injection. At the same time, the immunoreactivity of LC3-II and the Atg5-Atg12 conjugate, which indicate activation of autophagy, was increased. Transmission electron microscopy clearly showed an increase in autophagosome number in the rat frontal cortex at 2h after clozapine injection. To investigate the role of AMPK in clozapine-induced autophagy, the effects of intracerebroventricular injection of compound C, an AMPK inhibitor, were examined. Administration of compound C attenuated the clozapine-induced increase in ULK1 and Beclin1 phosphorylation, as well the protein levels of LC3-II and the Atg5-Atg12 conjugate in the frontal cortex. In summary, the results showed that clozapine activates autophagy through the AMPK-ULK1-Beclin1 signaling pathway in the frontal cortex of the rat., (Copyright © 2017. Published by Elsevier Inc.)

The aim of this study was to explore the longitudinal trends in the relationship between personal and social functioning and drug-induced extrapyramidal symptoms (DIEPS). The baseline sample included 484 patients with schizophrenia. Participants were assessed at baseline, weeks 4 (time 2), 8 (time 3), and 12 (time 4) regarding social functioning, and DIEPS. In latent growth analysis, the path coefficient between the intercept for the DIEPSS and the intercept for the PSP indicated a significant cross-sectional relationship between these two variables. And the path coefficient between the intercept of the DIEPSS and the slope of the PSP was also significant, indicating that patients who initially had more serious side effects tended to exhibit less improvement in their personal and social functioning over time. Similarly, a significant path coefficient between the slopes of the two variables indicated a dynamic and possibly reciprocal association over time. In addition, K-PSP scale showed good construct validity and reliability. Based on the standardized PSP scale, our results demonstrate DIEPSS induced by antipsychotic treatment dynamically affect personal and social functioning over time, a negative association between psychosocial aspects and the DIEPS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The aim of the present study was to refine the 20-item Subjective Well-Being under Neuroleptic Treatment Scale (SWN-20) using the Rasch rating model to validate measurements of subjective well-being in patients with schizophrenia undergoing antipsychotic treatment., Methods: In total, 854 (403 males, 451 females) inpatients (n=213) and outpatients (n=641) with schizophrenia participated in this study, which was designed as an open-label investigation of paliperidone extended release. The participants completed the Korean version of the SWN-20 themselves. Refinement of the Korean version of the SWN-20 was accomplished using the Rasch rating model., Results: Infit and outfit statistics for all 20 items satisfied the criterion for construct validity. Second, all items except items 2 and 20 had suitable point-measure correlations, reflecting content validity. Third, item characteristic curves indicated that roughly 18 items were evenly distributed along the person ability continuum. Finally, option analysis of the category characteristics showed that categories 3 and 4 in the SWN-20 response format were unnecessary., Conclusions: We offer several recommendations for improving the SWN-20: (a) items 2 and 20 should be omitted to ensure construct validity; (b) easier items would be added related to the person ability estimates in the process of validating a short form of the SWN scale based on item response theory; and (c) the number of response categories should be reduced for schizophrenic patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: Antipsychotic-induced autonomic dysregulation may lead to a wide range of subjective side-effects in schizophrenia patients. Using heart rate variability (HRV) measures, we prospectively examined the relationship between subjective side-effects and cardiac autonomic regulation in unmedicated schizophrenia patients., Methods: Forty-five unmedicated schizophrenia patients were assessed for antipsychotic-associated side-effects and HRV parameters at baseline and after 6 weeks of treatment. Psychiatric symptoms and subjective side-effects were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Liverpool University Neuroleptic Side-effect Rating Scale (LUNSERS)., Results: Correlations between subjective adverse effects and HRV measures at baseline and at week 6 varied. Nonetheless, the changes in the psychic side-effects domain were significantly correlated with the changes in time-domain HRV measures and sample entropy (SampEn). In addition, the change in SampEn was significantly associated with that in the scores of extrapyramidal, anticholinergic, miscellaneous, and red herring domains as well as the mean total LUNSERS score., Conclusion: Baseline HRV measures may predict clinical response and adverse events associated with treatment adherence. Also, subjective side-effects may correspond well with the changes in neurocardiac dynamics, and the changes in SampEn may effectively reflect subjective discomfort in patients receiving antipsychotic treatment., (© 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.)

Objectives: Second-generation antipsychotic drugs, such as clozapine, were reported to enhance neurite outgrowth by nerve growth factor in PC12 cells. The authors previously showed that chloride channel 4 (CLC-4) is responsible for nerve growth factor-induced neurite outgrowth in neuronal cells. In this study, we examined whether clozapine induces CLC-4 in neuroblastoma and glioma cells., Methods: The effect of clozapine on CLC-4 expression was examined in neuroblastoma (SH-SY5Y) and glioma (U87) cells. To investigate the signaling pathway responsible for clozapine-induced CLC-4 expression, the phosphorylation of cAMP response element-binding protein (CREB), which binds CRE in the promoter of the human CLC-4 gene, was examined. To identify the target of clozapine induced CLC-4, CLC-4 siRNA was introduced to neuroblastoma and glioma cells for functional knockdown., Results: We observed that clozapine increased CLC-4 expression in both SH-SY5Y and U87 cells. Clozapine induced CREB phosphorylation, but in the presence of inhibitor of protein kinase A (an upstream kinase of CREB) clozapine-induced CLC-4 expression was suppressed. Finally, we found that CLC-4 knockdown suppressed clozapine-induced cyclin-dependent kinase 5 (CDK5) expression in SH-SY5Y and U-87 cells suggesting CDK5 as potential molecular target of clozapine induced CLC-4 expression., Conclusions: The results of the present study suggest that clozapine's therapeutic effect may include the induction of CLC-4 which is dependent on CREB activation via PKA. We also found that functional knockdown of CLC-4 resulted in reduction of CDK5 expression, which may also be implicated in clozapine's therapeutic effect., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study was designed to investigate long-term clinical outcomes of risperidone long-acting injectable (RLAI) in patients with schizophrenia or schizoaffective disorder. An open-label, 48-week, prospective study of RLAI treatment was carried out at 63 centers in South Korea. Initial and maintenance dosage of RLAI were adjusted according to clinical judgment. Efficacy was measured by the remission rate, continuation rate, and changes in the clinical measurements such as eight items of the Positive and Negative Symptom Scale (PANSS), the Clinical Global Impression - Severity, and the Schizophrenia Quality of Life Scale. In terms of the safety, Simpson-Angus rating Scale, adverse events (AEs), and BMI were investigated. Of the 522 patients who were enrolled, 472 patients who had been assessed on the eight items of PANSS at baseline and at least once during RLAI treatment were included in the intention-to-treat (ITT) population. The per-protocol (PP) population included 184 patients (39.0%), who completed all assessments during 48 weeks of the follow-up period. Total scores of eight items of PANSS, Clinical Global Impression - Severity, and Schizophrenia Quality of Life Scale were reduced significantly from baseline to endpoint in both ITT and PP populations. The mean dose (SD) of RLAI was 33.2 (7.6) mg. In the PP population, the number of patients who scored 1-3 on eight items of PANSS were 47 (25.5%) at baseline and 144 (78.3%) at 48 weeks. According to the remission defining as scores 1-3 on eight items of PANSS sustaining of at least 6 months' duration by Andreasen, the numbers of patients who achieved remission were 45 (24.5%) at 24 weeks and 120 (65.2%) at 48 weeks. A significant decrease in the mean score of Simpson-Angus rating Scale and a significant increase in BMI over time in last observation carried forward were observed, and patients who fulfilled the remission criteria during the study showed more weight gain than those who did not. During the study period, a total of 645 AEs were noted in 233 patients (49.3%) who were included in the ITT population. Sixty-nine serious AEs in 51 patients were reported, but all of them were not directly attributable to administration of RLAI. This prospective, open-label study showed improvements in symptom and AEs and a significant increase in BMI during 48 weeks of biweekly RLAI treatment. The rate of study completion was 39.0% and the remission rate among those who completed the study was 65.2%. None of the serious AEs were directly related to the administration of RLAI.

Rationale: Clozapine affects the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in the brain, which plays an important role in its antipsychotic action. However, previous findings are inconsistent, and related molecular mechanisms require further clarification., Objectives: Time- and dose-dependent effects of clozapine on the ERK1/2 pathway and its regulatory mechanism were investigated in rat frontal cortex., Methods and Results: At 15, 30, 60, and 120 min after intraperitoneal injection of clozapine (5, 10, and 20 mg/kg), changes in ERK1/2, its upstream canonical kinases (Raf1 and mitogen-activated protein kinase kinase 1/2 [MEK1/2]), and its downstream molecule (p90 ribosomal S6 kinase [p90RSK]) were investigated in rat frontal cortex. At 15 min, p-Raf1, p-MEK1/2, p-ERK1/2, and p-p90RSK all increased dose-dependently. At 30 min, p-ERK1/2 and p-p90RSK showed no significant changes, while dose-dependent increases in p-Raf1 and p-MEK1/2 were found. At 60 and 120 min, although p-ERK1/2 and p-p90RSK decreased, increases in p-Raf1 and p-MEK1/2 were maintained. A clozapine-induced reduction in ERK1/2 phosphorylation was evident at both tyrosine and threonine residues, suggesting the involvement of dual specificity phosphatases (DUSPs; mitogen-activated protein kinase phosphatases [MKPs]). mRNA expression of seven Dusps that can dephosphorylate ERK1/2 were examined; Mkp-1 (Dusp1) mRNA increased following clozapine treatment. Moreover, MKP-1 protein and phosphatase activity increased, and binding of MKP-1 to ERK1/2 was also upregulated by clozapine administration., Conclusions: In rat frontal cortex, clozapine regulates ERK1/2 phosphorylation via MKP-1, which induces uncoupling between Raf1-MEK1/2 and ERK1/2-p90RSK activity. These findings suggest an important role of MKP-1 in the mechanism of action of clozapine.

Objective: The current study compared the long-term effectiveness, safety, and tolerability of paliperidone extended-release (ER) among patients with schizophrenia who had switched from risperidone (risperidone group) or other antipsychotic medications (non-risperidone group) due to lack of efficacy, intolerability, or non-adherence., Research Design and Methods: This open-label, prospective, multicenter, 48 week study utilized the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity scale (CGI-S), the Personal and Social Performance scale (PSP), and the Subjective Well-being under Neuroleptics scale (SWN) to assess patients with schizophrenia. Additionally, extrapyramidal symptoms (EPS) and subjective side effects were evaluated with validated scales., Clinical Trial Registration: Clinicaltrials.gov identifier: NCT00864045., Results: The completion rate for this study was 51.6% (95/184), and 169 patients finished with ≥1 post-baseline assessment (81 patients in the risperidone group, 88 in the non-risperidone group). The mean (SD) PANSS total score decreased significantly from 78.3 (18.8) to 65.5 (19.7) in the risperidone group and from 79.1 (19.8) to 65.4 (20.8) in the other group (all p < 0.001). Similar to PANSS, the severity rating for overall scores of the CGI-S and the PSP scores improved significantly from baseline (all p < 0.001). The magnitude of improvement in all effectiveness measures at 48 weeks did not differ between the two groups. EPS and subjective side effects improved significantly for all patients. Akathisia (18.5%) and increased weight (14.1%) were the main adverse events. Elevated prolactin levels were identified in female subjects in the non-risperidone group., Conclusions: Switching from previously unsuccessful antipsychotic treatments to paliperidone ER can be a useful option to achieve long-term improvement in symptoms and functioning for patients with schizophrenia. The clinical effectiveness appeared to be similar in patients who previously received risperidone and those treated with other antipsychotic medications. The open-label design and lack of a placebo group were limitations.

Objective: This study assessed whether the subjective experience of patients with schizophrenia improved after switching from an oral antipsychotic to flexibly-dosed paliperidone extended-release., Methods: We conducted a 24-week, multicenter, non-comparative, open-label trial. A total of 387 patients with schizophrenia participated the study. The primary study outcome was the change in subjective symptoms measured by the Symptom Checklist-90-Revised version (SCL-90-R) from baseline. Visual analogue scales were used for sleep and daytime somnolence as secondary subjective assessments. The clinical global impression-schizophrenia-severity scale was used to assess overall symptom severity. Social functioning was evaluated by the personal and social performance scale. Adverse events were also evaluated., Results: All subjective symptoms measured by the SCL-90-R improved significantly. The early responders, who achieved >20% reduction in the SCL-90-R within 1 week, maintained significantly lower severity through the 24 weeks. The clinical global impression-schizophrenia-severity scale and personal and social performance scores also improved significantly. The visual analogue scales revealed that daytime somnolence improved significantly, whereas nocturnal sleep quality was unaltered., Conclusion: Our results suggest that switching to paliperidone extended-release was associated with improvements in various subjective symptoms, decreased overall symptom severity, and increased social functioning. The results also suggest that early detection and reduction of subjective symptoms are important for treatment outcome., (Copyright © 2013 John Wiley & Sons, Ltd.)

Previous studies have suggested the utility of nonlinear complexity measures of heart rate variability (HRV) in evaluating the regulatory capacity of the neuroautonomic system. The purpose of the present study was to investigate the effects of clozapine on the nonlinear complexity measures of HRV in patients with treatment-resistant schizophrenia to find novel electrophysiological markers that indicate response to clozapine treatment. Forty patients with treatment-resistant schizophrenia were evaluated during 8 weeks of clozapine monotherapy. For nonlinear complexity measures of HRV, the approximate entropy (ApEn) and sample entropy (SampEn) values were obtained. The response rate to clozapine was 37.5%. The results of multivariate analysis of covariance revealed that the ApEn and the SampEn values of HRV at week 8 were significantly higher in the responders than in the nonresponders. Repeated-measures analysis of covariance showed a significant group by time interaction effect in the ApEn and SampEn indices. The responder group showed an increasing pattern of change in these complexity measures after administration of clozapine, whereas the nonresponder group showed a decreasing pattern of change. These results suggest that the nonlinear dynamic complexity measures of HRV, which indicate the irregularity and complexity of the biosystem, may be useful in evaluating the therapeutic changes of neuroautonomic function in schizophrenia. The response to clozapine treatment is expected to be more favorable when the plasticity of the neuroautonomic system reflected in the nonlinear complexity measures is high.

Aims: The effects of antipsychotics on various gene expressions through change in DNA methylation have been reported. Dual-specificity phosphatase 6 (DUSP6) is an extracellular signal regulated kinase 1/2 (ERK1/2)-selective phosphatase, and its expression can be suppressed by intronic methylation. Antipsychotic agent haloperidol affects ERK1/2 activity and could induce changes in DNA methylation as well as histone acetylation. In this study, we examined the effects of haloperidol on DUSP6 expression related to DNA methylation changes., Main Methods: The effects of haloperidol and 5-azacytidine, a demethylating agent, on expression and methylation of DUSP6 were quantitatively measured in MIA PaCa-2 human pancreatic carcinoma cells, in which DUSP6 expression is suppressed due to intronic hypermethylation. The growth rate of MIA PaCa-2 cells was also examined after treatment with haloperidol or 5-azacytidine., Key Findings: Haloperidol increased DUSP6 expression in a concentration-dependent manner and inhibited MIA PaCa-2 cell proliferation; effects were comparable to those of 5-azacytidine. However, haloperidol did not induce DUSP6 expression in PANC-1 cells, another pancreatic cancer cell line without transcriptional suppression of DUSP6. Pyrosequencing methylation analysis confirmed the intronic hypermethylation of DUSP6 in MIA PaCa-2 and revealed that haloperidol and 5-azcytidine induced demethylation of CpG sequences in this region., Significance: Haloperidol induced DUSP6 expression related to intronic demethylation and inhibited MIA PaCa-2 cell proliferation, which suggests demethylating activity and anti-cancer effects of haloperidol. These findings suggest the possible involvement of epigenetic regulatory mechanisms in the action mechanism of haloperidol., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Metabolic syndrome and antipsychotic medications are associated with inflammation. This study investigated the relationship between inflammation and metabolic syndrome in patients with schizophrenia. It also examined the effects of paliperidone extended release (ER) treatment on metabolic parameters., Methods: Data were analyzed from schizophrenic patients who participated in a multi-center, open-label, non-comparative clinical trial. Anthropomorphic measurements (i.e., weight, waist circumference, and blood pressure) were assessed along with fasting laboratory values, including white blood cell (WBC) count, glucose, high-density lipoprotein, and triglycerides., Results: Among the 225 patients at baseline, the group with the highest WBC count displayed a 5.9-fold risk for metabolic syndrome compared with that of the lowest group. An increase of 10(3)WBCs/μL was associated with a 1.4-fold increased risk for metabolic syndrome. After 24weeks of treatment with paliperidone ER, significant increases were observed in waist circumference and body weight. Changes in WBC count were positively correlated with changes in waist circumference., Conclusions: Schizophrenic patients with high levels of inflammation should be carefully monitored for metabolic syndrome. Moreover, strategies to reduce inflammation and obesity may prevent metabolic syndrome in patients with schizophrenia who take atypical antipsychotic medication., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate the subjective well-being and attitudes toward antipsychotic medication of patients with schizophrenia who had switched to paliperidone extended release (ER)., Methods: A total of 291 patients with schizophrenia treated with antipsychotics participated in this open-label, 24-week switching study. The primary outcome measures were the Subjective Well-Being under Neuroleptic Treatment Scale-short version (SWN-K) and the Drug Attitude Inventory (DAI). The Krawiecka scale, Clinical Global Impression-Schizophrenia (CGI-SCH), Personal and Social Performance scale (PSP) were used to evaluate psychopathology and psychosocial functioning, respectively., Results: Data from a total of 243 subjects who received the study medication and had at least one follow-up assessment without a major protocol violation were analyzed. Scores on the DAI and SWN-K showed significant improvement between baseline and end-point measurements beginning during the second week. Scores on the Krawiecka scale, all five subscales of the CGI-SCH scale, and the PSP scale were also significantly improved at the end point compared with the baseline. Significant predictors of improvements in the SWN-K and DAI after a switch to paliperidone ER were baseline scores, reductions in scores on the Krawiecka scale, and previous risperidone use. A clinically relevant increase in body weight (≥7% weight gain) occurred in one-fourth of the participants who completed the 24-week study., Conclusion: Switching to paliperidone ER improved the subjective well-being and attitudes towards antipsychotic medication in patients with schizophrenia. Exploratory analyses revealed that these improvements were particularly pronounced in patients who had been treated with risperidone before treatment with paliperidone ER., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Clozapine is an antipsychotic drug that has a greater efficacy than other medications in some contexts, especially for the treatment of treatment-resistant schizophrenia. However, clozapine induces more metabolic side-effects involving abnormality in lipid metabolism compared to other antipsychotics. AMP-activated protein kinase (AMPK) plays a central role in controlling lipid metabolism through modulating the downstream acetyl CoA carboxylase (ACC) and carnitine palmitoyl transferase 1 (CPT1) pathway. In this study, we investigated the effect of a single intraperitoneal injection of clozapine on the AMPK-ACC-CPT1 pathway in the rat frontal cortex, which has been implicated as a target site for this antipsychotic drug. At 2 h after injection, the clinically relevant dose of clozapine had activated AMPK, with increased phosphorylation of AMPKα at Thr(172), and had inactivated ACC, with increased phosphorylation of ACC at Ser(79). In addition, clozapine activated the brain-specific isoform of CPT1, CPT1c, whose activity is inhibited by unphosphorylated ACC, in the rat frontal cortex. Immunohistochemistry and immunofluorescence analysis showed that clozapine induced an increase in number of p-AMPKα (Thr(172))- and p-ACC (Ser(79))-positive cells among the neurons of the rat frontal cortex. Taken together, these results show that clozapine activated the AMPK-ACC-CPT1 pathway in the neurons of the rat frontal cortex. These findings indicate that the antipsychotic agent clozapine affects the lipid regulatory system of neurons in the brain.

The etiology of side effects of antipsychotic medications can be conceptualized as involving both specific pharmacological actions of a drug and any mental and physical states attributed by the patient. Both factors are likely to be linked with neurocognitive functioning which may largely affect the subjective experience of side effects in patients with schizophrenia. In this study, we examined whether baseline neurocognitive functions, such as IQ, attention, executive functioning, and short-term memory, are associated with baseline and 6-month follow-up measures of self-reported Liverpool University Neuroleptics Side Effects Scale (LUNSERS) and clinician-rated Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). At the baseline, anxiety and depression were significantly associated with LUNSERS red herring (RH) and total side effects (SE) but not with DIEPSS. There was no association between LUNSERS and DIEPSS. Controlling for anxiety and depression, IQ was significantly correlated with DIEPSS, while choice reaction time (CRT) and stop signal task (SST) direction errors correlated with RH, and intra-extradimensional set-shifting (IED) total errors and pre-extradimensional set-shifting (pre-EDs) errors correlated with SE. The baseline SST direction errors further correlated significantly with RH and SE and DIEPSS total score of 6-month follow-up, and CRT mean and SD correct latency also correlated with DIEPSS. The correlations between the 6-month changes (Δ) in the same side effects measures and baseline neurocognitive measures were also significant, except that between RH and SST direction errors. Such evidences supported association between both self-rated and clinician-rated side effects and selective impairments in attention and executive functioning., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Although ethnicity also contributes to MetS risk, the majority of the studies on the relationship of SGAs to this syndrome come from Western countries, whereas few reports have come from Asian countries, especially regarding patients taking a single SGA. We reviewed the electronic medical records of patients with schizophrenia who received aripiprazole, olanzapine or risperidone monotherapies for at least three months. We evaluated the prevalence of MetS in our sample as well as the indirect standardized prevalence ratio (ISPR) using data from the 4th Korean National Health and Nutrition Examination Survey (KNHNES, 2007). The prevalence of MetS in our sample (n=145) was 31.7%, and the ISPR was 2.09. Male patients had a higher prevalence of MetS than female patients (odds ratio [OR]=4.18, 95% CI=1.93-9.03). The ISPR of male patients was 2.67 and statistically significant, whereas the ISPR of female patients was not significant. In our sample, the frequency of abnormal MetS subcomponents occurred in descending order: increased waist circumference, increased triglyceride levels, decreased HDL-cholesterol levels, elevated blood pressure and elevated fasting blood glucose levels. Patients who received aripiprazole were significantly less likely to have MetS. However, a logistic regression showed that age and sex, but not the type of antipsychotic, its dose or the use of antidepressants, were significantly related to the presence of MetS. There were no statistically significant differences among SGAs in terms of MetS subcomponent abnormalities of after adjusting for age and sex. In conclusion, only male Korean patients with schizophrenia who received a monotherapy of aripiprazole, olanzapine or risperidone for more than three months were more likely to have MetS than the general population., (Copyright © 2011. Published by Elsevier Inc.)

This study was conducted to delineate the relationship between self-reported side effects and psychopathology in schizophrenia patients. Patients with schizophrenia completed the Liverpool University Neuroleptic Side Effects Rating Scale for subjective side effects and were evaluated with the Positive and Negative Syndrome Scale for their psychopathology. Based on a series of multiple linear regression analyses, we derived a model accounting for the relationships among the specific domains of psychopathology and red herring (RH) items of the Liverpool University Neuroleptic Side Effects Rating Scale in predicting subjective side effects. The model with anxiety/depressive symptoms and RH serving as mediators between positive symptoms and side effects was found to show good fit. Positive symptoms caused mostly anxiety symptoms and tendency to report RH items, whereby resulting in over-generalized reporting of subjective side effects. However, a large proportion of variance of side effects was explained by RH, which was only partially explained by positive symptoms alone. Therefore, patients with severe levels of positive and anxiety/depressive symptoms may be prone to nocebo-like effects of antipsychotics. Studies that include acute stage patients presenting severe levels of these symptoms should not rely only on the subjective report of side effects but also apply objective measures.

We examined short- and long-term changes in neurocognitive functions in patients with schizophrenia who were either started or switched to amisulpride in comparison with the normal controls. Fifty-seven patients treated with amisulpride and 60 normal controls completed a comprehensive neurocognitive function test battery at the baseline, the 8-week, and the 1-year follow-up. We conducted and compared the results of both intention-to-treat (ITT) and per-protocol (PP) analyses to account for the follow-up loss. Three general results obtained were as follows: (1) the degree of the improvements in neurocognitive function was comparable to those of other second-generation antipsychotics in both ITT and PP analysis; (2) in light of the relative effect size, the composite effect size and the effect size in most measures in both ITT and PP analyses were smaller for the patient group than those of the control group, signifying that improvement in performance may be largely attributable to practice effects; and (3) nonetheless, there were evidences of both short- and long-term improvements in some cognitive tasks, such as in the Korean-Wechsler Adult Intelligence Scale vocabulary subtest and the Trail Making Test, that may not be accounted by practice effect. These results suggest the need to include a healthy control group to validate the medication effect of cognitive improvements in patients with schizophrenia and to consider practice effect in interpreting the results of repeated administration of neurocognitive function tests.

Urinary incontinence and enuresis are well-known side effects of clozapine. However, clinical experience has shown that patients also suffer from diverse lower urinary tract symptoms (LUTS). The natural course of clozapine-related LUTS is unclear. Thus, a longitudinal follow-up study is needed. A total of 101 subjects who were taking clozapine initially participated. Their LUTS were evaluated using the International Prostate Symptom Score (IPSS), other questionnaires, and a medical records review. After 2 years, 87 of the original subjects could be contacted, and the status of their LUTS was re-evaluated. The average IPSS total was 7.4 +/- 5.9 at the initial evaluation. Although only 11 subjects (10.9%) reported actual incontinence, 42 subjects (41.6%) were found to have clinically significant LUTS (IPSS total score > or =8). No influencing factors could be found among the demographic and clinical variables. At the follow-up, the average IPSS total (7.9 +/- 6.0) and the percentage of subjects with clinically significant LUTS (43.7%) had both increased, although the change was not statistically significant. The prevalence of LUTS in clozapine-medicated patients was higher than in the general population of the same age. However, the prevalence of incontinence was only a quarter of that of LUTS. If clinicians focus only on incontinence, distress from LUTS will not receive appropriate attention. Furthermore, contrary to literature observations, clozapine-related LUTS did not remit easily but rather persisted even into the long-term maintenance phase. More concern should be directed at these troublesome and often neglected side effects.

Haloperidol, a classical antipsychotic drug, affects the extracellular signal-regulated kinase (ERK) pathway in the brain. However, findings are inconsistent and the mechanism by which haloperidol regulates ERK is poorly understood. Therefore, we examined the ERK pathway and the related protein phosphatase 2A (PP2A) in detail after haloperidol administration. Haloperidol (0.5 and 1 mg/kg) induced biphasic changes in the phosphorylation level of mitogen-activated protein kinase kinase (MEK), ERK, and p90 ribosomal S6 kinase (p90RSK) without changing Raf-1 phosphorylation. Fifteen minutes after haloperidol administration, MEK-ERK-p90RSK phosphorylation increased, whilst PP2A activity decreased. At 60 min, the reverse was observed and the binding of PP2A to MEK and ERK increased. Higher dosages of haloperidol (2 and 4 mg/kg), affected neither MEK-ERK-p90RSK phosphorylation nor PP2A activity. Accordingly, PP2A regulates acute dose- and time-dependent changes in MEK-ERK-p90RSK phosphorylation after haloperidol treatment. These findings suggest the involvement of a dephosphorylating mechanism in the acute action of haloperidol.

Objective: Inadequate response to clozapine poses a substantial problem in the pharmaco-therapy of refractory schizophrenia. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia., Method: Patients with DSM-IV schizophrenia who had a history of treatment failure or partial response to long-term clozapine treatment were recruited. A total of 62 patients with either a baseline Brief Psychiatric Rating Scale (BPRS) score of at least 35 or more than 2 Schedule for Assessment of Negative Symptoms (SANS) global rating item scores of at least 3 were randomly assigned to double-blind augmentation treatment with either aripiprazole (5-30 mg/day) or placebo over 8 weeks. The primary outcome measure was change in BPRS total score from baseline. The study was conducted between December 1, 2005, and December 10, 2006., Results: There was no significant difference in the primary outcome measure between the 2 groups. In secondary analyses, improvement was significantly greater with aripiprazole treatment than with placebo for negative symptoms assessed by both the BPRS negative symptom sub-scale and the SANS total score but not for positive symptoms. Prolactin and triglyceride levels were significantly lower in the aripiprazole group than in the placebo group. No significant differences between the 2 groups were observed in adverse effects, including extrapyramidal symptoms and serum glucose levels., Conclusion: Although aripiprazole augmentation of clozapine did not lead to a significant improvement of total symptom severity in schizophrenia, a favorable change in the negative symptom domain was observed.

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

The relationship between antipsychotic-induced extrapyramidal syndrome (EPS) and the autonomic neurocardiac function was examined in 57 schizophrenic patients treated with atypical antipsychotics. Comprehensive assessments of EPS and heart rate dynamics were performed. There was a significant negative correlation of non-hypokinetic parkinsonism, akathisia, and dyskinesia with several linear and novel non-linear heart rate dynamics measures, suggesting reduced neurocardiac dynamics associated with some forms of EPS. Assessment of heart rate dynamics may be useful for the detection of these adverse effects and may serve as a useful non-invasive method providing a dynamic window into the alterations of complex neuronal activity.

The purpose of the present study was to compare the subjective response and attitude towards antipsychotic treatment between schizophrenic patients receiving clozapine and those receiving risperidone. Ninety-four outpatients who had been on a stable drug dosage were evaluated (clozapine group: n=57, mean dose=254.1 mg/day; risperidone group: n=37, mean dose=3.0 mg/day). Subjective response to antipsychotic treatment was assessed using the Drug Attitude Inventory (DAI). The two treatment groups had a positive total mean score, indicating that both groups had a positive subjective view of drug treatment. The proportion of subjects who had a positive total score was not different between the two groups. In subscale scores, multivariate analysis revealed that clozapine group tended to have a higher score on the subjective positive response subscale (P=0.06). The scores of subjective negative response or attitude to medication subscales were not different between groups. In conclusion, there was no marked difference between stabilized outpatients taking clozapine and risperidone in terms of subjective response and attitude towards antipsychotic treatment. Considering that subjects treated with clozapine were treatment resistant patients, equal DAI score might indicate a more favorable subjective experience of clozapine. Further prospective studies on subjective response to various atypical agents are required to obtain valuable insight into how best to use these drugs from the patient's perspective.

We compared the severity of subjective and objective symptomatology of akathisia between the acute and chronic subtypes of neuroleptic-induced akathisia. Sixty-one schizophrenic subjects were evaluated. Multivariate analysis revealed that motor manifestations and distress of akathisia were less severe in chronic akathisia than in acute akathisia. The severity of subjective restlessness was not significantly different between the two groups. In conclusion, there were differences in the severity of symptoms and signs between the acute and chronic subtypes of akathisia, suggesting that the severity of the subjective and objective components of akathisia may be differentially affected by the duration of akathisia.

The present study aimed to elucidate the effectiveness of clozapine treatment in reducing the disabling period of chronically ill schizophrenic patients by investigating their rehospitalization status. Of 232 schizophrenic patients with a history of clozapine use who were recruited from the clinic at Seoul National University Hospital, 117 were selected who had been followed up for more than 1 year with respect to rehospitalization. To obtain information about the period before the clozapine change, a chart review of these 117 patients was conducted. The number and length of hospitalizations of the patients significantly decreased after clozapine treatment compared to the same period before clozapine treatment. The hospital days per year of the patients were also decreased significantly after clozapine introduction. By analysing 38 patients who were followed up for more than 5 years, it was suggested that the decrease in the number and length of hospitalizations was substantially sustained for up to 5 years after clozapine treatment. This study showed that the number and length of hospitalizations are significantly decreased by long-term clozapine treatment and that this effect can positively affect the social outcome of schizophrenic patients.

The primary distinguishing features of akathisia in comparison with other extrapyramidal syndromes are the prominent subjective manifestations, which include various sensory symptoms. The sensory symptoms are multidimensional in nature and encompass various forms of bodily and mental sensations. The purpose of the present study was to elucidate the multidimensional aspects of the sensory phenomena associated with antipsychotic-induced akathisia. Seventy stable and chronic schizophrenic subjects receiving maintenance antipsychotic treatment were evaluated for akathisia and other extrapyramidal side effects. Subjective sensory phenomena were evaluated in 3 dimensions (ie, bodily sensations, mental sensations, and autonomic sensations). The frequency of each dimension of these sensory phenomena was compared between the groups with and without akathisia using chi test with Bonferroni correction. The akathisia group (n = 29) reported significantly more frequent focal or generalized bodily sensations than the non-akathisia group (n = 41) (P < 0.001). The akathisia group also showed significantly more frequent mental sensations such as mental urge and a feeling of inner tension/pressure (P < 0.001). In autonomic phenomena, there was a trend for the akathisia group to show more frequent autonomic sensations. The most common autonomic phenomena associated with akathisia were palpitation and difficulty breathing. The results of the present study suggest that the sensory phenomena of antipsychotic-induced akathisia are characterized by multidimensional features such as bodily sensations, mental sensations, and several autonomic sensations. The assessment of these multidimensional sensory phenomena would be useful in evaluating the important phenotypic features of akathisia.

According to the recommended guidelines by Novartis, neutropenia in the range of a white blood cell count less than 3000 per mm, or an absolute neutrophil count (ANC) less than 1500 per mm, is classified as being in the 'red-alert zone' during clozapine treatment. If a patient's blood test result falls into this zone, immediate discontinuation of clozapine is recommended, and reinstitution is prohibited. However, in some patients, it is not entirely feasible to implement this standard guideline because of the lack of effective alternatives to clozapine treatment. Through retrospective chart reviews, five patients who had been maintained on clozapine treatment despite red-alert zone neutropenia were selected. The haematological and clinical courses of these patients were followed for more than 600 days and were compared with those of two control patients who discontinued clozapine due to neutropenia. In all five patients, no additional episodes of neutropenia occurred during the observation period despite continued clozapine treatment. However, three of them maintained a lower neutrophil count for the remaining observation period. Four patients responded favourably to clozapine treatment as judged by Clinical Global Impression score. Given the limitations of a retrospective chart review and the small number of patients, we cannot draw any definite conclusions. However, while the guidelines for the prevention of agranulocytosis should be generally followed, it may be that judicious continuation of clozapine treatment is less risk-prone than previously considered in selected cases where only a few feasible alternatives to clozapine are available. Moreover, there is an apparent necessity to develop new measures or methods that can differentiate between benign neutropenia and that leading to fatal agranulocytosis.

The analysis of heart rate variability (HRV) has proven to be useful in evaluating the neuroautonomic dysfunctions associated with various clinical conditions. The purpose of this study was to investigate the linear and non-linear dynamic measures of HRV, and to evaluate their relationship with the psychotic symptom severity, in clozapine-treated schizophrenic subjects. Fifty schizophrenic patients treated with clozapine as monotherapy and 50 normal control subjects were evaluated for HRV analysis. The HRV measurements were obtained from a 30-min resting electrocardiogram (ECG). The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). In the patient group, the complexity and symbolic dynamics measures as well as the time and frequency domain measures of HRV were significantly lower than in the control group (P<0.01). The intermediate-term fractal scaling component value was significantly higher in the patient group (P<0.01). The PANSS total score and the positive symptom subscale score had significant negative correlations with the sample entropy (SampEn) value (P<0.01). In conclusion, schizophrenic patients treated with clozapine had markedly different heart rate dynamics compared to normal control subjects. The severity of psychotic symptoms was associated with the SampEn value, suggesting that the non-linear complexity measure might be useful in assessing the neuroautonomic dysfunction in schizophrenia.

The metric properties of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were examined in 182 subjects treated with antipsychotics. Inter-rater reliability, test-retest reliability, and concurrent validity with other rating scales for EPS were high. Four factors were identified and the optimal diagnostic cut-off scores were obtained. These results suggest that the DIEPSS is a reliable and valid multidimensional rating scale., (Copyright 2002 Movement Disorder Society)

Polygalasaponins were extracted from a plant (Polygala tenuifolia Willdenow) that has been prescribed for hundreds of years to treat psychotic illnesses in Korean traditional medicine. Previous in vitro binding studies suggested a potential mechanism for its antipsychotic action, as polygalasaponin was shown to have an affinity for both dopamine and serotonin receptors [Psychopharmacol. Bull. 31 (1995) 139.]. In the present study we have investigated the functional in vivo actions of this material in tests that are predictive of dopamine and serotonin antagonist activities. Polygalasaponin (25-500 mg/kg) was shown to produce a dose-related reduction in the apomorphine-induced climbing behaviour (minimum effective dose [ED(min)] 25 mg/kg ip, 250 mg/kg sc and po), the 5-hydroxytryptamine (5-HTP)-induced serotonin syndrome (ED(min) 50 mg/kg ip) and the MK-801-induced hyperactivity (ED(min) 25 mg/kg ip) in mice. This compound also reduced the cocaine-induced hyperactivity (ED(min) 25 mg/kg ip) in rats. These results demonstrated that polygalasaponin has dopamine and serotonin receptor antagonist properties in vivo. This might suggest its possible utility as an antipsychotic agent.

This study investigated the incidence and nature of clozapine-associated electroencephalographic (EEG) abnormalities and the relationship between EEG abnormality and clozapine dosage in Korean schizophrenic patients. Fifty schizophrenic patients with normal baseline EEG and with additional EEG record examined during clozapine treatment more than once were included. Thirty-one patients (62%) showed abnormal EEGs after clozapine treatment, and two of them had seizures. The majority of EEG abnormalities presented as nonspecific slow waves (SW). Spikes (or spike and wave complexes; SP) and frontal intermittent rhythmic delta activity (FIRDA) were relatively rarely observed. The probability of EEG abnormality was linearly dependent on the daily dose of clozapine and patient's age. Our results can be summarized as follows: (1) a substantial proportion of Korean patients treated with clozapine develops EEG abnormalities, and its incidence is comparable to the published results in Caucasian patients; (2) EEG abnormalities occurred in a dose-dependent manner; and (3) the occurrence of EEG abnormalities did not necessarily lead to future seizure development, except in a small number of cases.

Abstract: Repeated administration of NMDA antagonists can induce behavioral alterations that mimic symptoms of psychosis, as seen in schizophrenia. JNK, one of the MAPKs, and c-Jun, its downstream target molecule, play important roles in regulating apoptosis in neural cells, and have been suggested as being associated with the pathophysiology of psychosis and the mechanism of action of some antipsychotics. We investigated changes in the JNK–c-Jun pathway and other Jun family proteins in the rat frontal cortex after single and repeated administration of MK-801 to examine acute and chronic responses. Neither the protein level nor the phosphorylation of JNK changed after single or repeated doses of MK-801. However, after repeated treatments, but not a single treatment, with MK-801, a down-regulation occurred in the protein level and of Ser73 phosphorylation of c-Jun in the rat frontal cortex. Other members of the Jun family, JunB and JunD, were unchanged. Repeated exposure to MK-801 down-regulated the phosphorylation and protein level of c-Jun in the rat frontal cortex, which may be related to the long-term effects of chronic treatment with MK-801. [Copyright &y& Elsevier]

Abstract: Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3β pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3β and increased GSK-3β kinase activity. A voltage-sensitive Ca2+ channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca2+ concentration prevented CZP-induced dephosphorylation of Akt and GSK-3β, suggesting that Ca2+/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3β, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca2+ concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3β pathway by counteracting Ca2+/CaM in PTEN-negative U-87MG glioblastoma cells. [Copyright &y& Elsevier]

Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol. [ABSTRACT FROM AUTHOR]