Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine‑resistant treatment‑refractory schizophrenia:a 12‑week randomized,double‑blind,placebo‑controlled trial

Background:Although clozapine is an effective option for treatment-resistant schizophrenia(TRS),there are still 1/3 to 1/2 of TRS patients who do not respond to clozapine.The main purpose of this randomized,double-blind,placebocontrolled trial was to explore the amisulpride augmentation efficacy on the psychopathological symptoms and cognitive function of clozapine-resistant treatment-refractory schizophrenia(CTRS)patients.Methods:A total of 80 patients were recruited and randomly assigned to receive initial clozapine plus amisulpride(amisulpride group)or clozapine plus placebo(placebo group).Positive and Negative Syndrome Scale(PANSS),Scale for the Assessment of Negative Symptoms(SANS),Clinical Global Impression(CGI)scale scores,Repeatable Battery for the Assessment of Neuropsychological Status(RBANS),Treatment Emergent Symptom Scale(TESS),laboratory measurements,and electrocardiograms(ECG)were performed at baseline,week 6,and week 12.Results:Compared with the placebo group,amisulpride group had a lower PANSS total score,positive subscore,and general psychopathology subscore at week 6 and week 12(PBonferroni<0.01).Furthermore,compared with the placebo group,the amisulpride group showed an improved RBANS language score at week 12(PBonferroni<0.001).Amisulpride group had a higher treatment response rate(P=0.04),lower scores of CGI severity and CGI efficacy at week 6 and week 12 than placebo group(PBonferroni<0.05).There were no differences between the groups in body mass index(BMI),corrected QT(QTc)intervals,and laboratory measurements.This study demonstrates that amisulpride augmentation therapy can safely improve the psychiatric symptoms and cognitive performance of CTRS patients.

Dispersive Liquid-liquid Microextraction Combined with High-performance Liquid Chromatography for the Determination of Clozapine and Chlorpromazine in Urine

A simple method has been proposed for the determination of clozapine （CLZ） and chlorpromazine （CPZ） in human urine by dispersive liquid-liquid microextraction （DLLME） in combination with high-performance liquid chromatography-ultraviolet detector （HPLC-UV）. All important variables influencing the extraction efficiency, such as pH, types of the extraction solvent and the disperser solvent and their volume, ionic strength and centrifugation time were investigated and optimized. Under the optimal conditions, the limit of detection （LODs） and quantification （LOQs） of the method were 13 and 39 ng/mL for CLZ, and 2 and 6 ng/mL for CPZ, respectively. The relative standard deviations （RSDs） of the targets were less than 5.1% （C=0.100 μg/mL, n=9）. Good linear behaviors over the tested concentration ranges were obtained with the values of R20.999 for the targets. The absolute extraction efficiencies of CLZ and CPZ from the spiked blank urine samples were 98.3% and 97.8%, respectively. The applicability of the technique was validated by analyzing urine samples and the mean recoveries for spiked urine samples ranged from 93.3% to 105.0%. The method was successfully applied for the determination of CLZ and CPZ in real human urine.

Effects of acute and chronic administration of MK-801 on c-Fos protein expression in mice brain regions implicated in schizophrenia and antagonistic action of clozapine

Objective To investigate the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice and an-tagonistic action of clozapine.Methods Immunohistochemistry was used to detect the expression of c-Fos protein.Results MK-801(0.6 mg·kg-1)acute administration produced a significant increase in the expression of c-Fos protein in the layers Ⅲ-Ⅳ of posterior cingulate and retrosplenial(PC/RS)cortex,which was consistent with the previous reports.Moreover,we presented a new finding that MK-801(0.6 mg·kg-1)chronic administration for 8 days produced a significant increase of c-Fos protein expression in the PC/RS cortex,prefrontal cortex(PFC)and hypothalamus of mice.Among that,c-Fos protein expression in the PC/RS cortex of mice was most significant.Compared acute administration with chronic administration,we found that MK-801 chronic administration significantly increased the expression of c-Fos protein in the PC/RS cortex,PFC and hypothalamus.Furthermore,pretreatment of mice with clozapine significantly decreased the expression of c-Fos protein induced by MK-801 acute and chronic administration.Conclusions Marked expression of c-Fos protein induced by MK-801 is associated with neurotransmitters' change noted in our previous studies,and c-Fos protein,the marker of neuronal activation,might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist.

Case Report: Augmentation with Blonanserin for a Schizophrenia Patient with Insufficient Response to Clozapine

Background: Clozapine is the most efficacious among antipsychotics for patients with schizophrenia. Nevertheless, clozapine is not effective in more than about 50% of treatment refractory schizophrenia patients, and several pharmacological strategies are used to augment it. Several reviews including meta-analyses have been published, but the efficacy of augmentation therapy for clozapine-resistant patients is not adequately supported. Though there is a weak connection between the oral dose and plasma concentration of clozapine, there is no report of augmentation therapy considering the plasma concentration of clozapine. Blonanserin is reported to be effective in treatment of both positive and negative symptoms of schizophrenia and well tolerated. Methods: We obtained consent to evaluate clinical presentations and clozapine plasma concentrations at the Okayama Psychiatric Medical Center and had not identified the individual for ethical reasons. This is a case report. Results: This case fulfilled the diagnostic criteria of neuroleptic-induced dopamine supersensitivity psychosis. Monotherapy with blonanserin was not effective, but augmentation of blonanserin with clozapine was effective and well tolerated by a clozapine-resistant schizophrenia patient. Conclusion: Because clozapine may ameliorate dopamine supersensitivity psychosis, the addition of blonanserin to clozapine may be effective even if monotherapy with blonanserin was not.

Effect of clozapine on the serum total bile acid, glucose and lipid metabolism in patients with schizophrenia

Objective:To observe the effect of clozapine on the serum total bile acid (TBA), glucose and lipid metabolism in patients with schizophrenia.Methods:A total of 80 patients with first-episode schizophrenia who were admitted in our hospital from January, 2015 to January, 2016 were included in the study and randomized into the observation group and the control group with 40 cases in each group. The patients in the observation group were given clozapine, while the patients in the control group were given risperidone. The serum TBA, T-Bil, D-Bil, I-Bil, glucose and lipid metabolism before and after treatment in the two groups were compared. Results:The comparison of TBA before and after treatment between the two groups was not statistically significant (P>0.05). T-Bil, D-Bil, and I-Bil after treatment were significantly reduced when compared with before treatment (P<0.05), but the comparison between the two groups was not statistically significant (P>0.05). BMI, waistline, hipline, and waist-hip ratio after treatment in the two groups were significantly elevated when compared with before treatment (P<0.05), and BMI, waistline, hipline, and waist-hip ratio after treatment in the observation group were significantly higher than those in the control group (P<0.05). The comparison of FBS, TC, TG, HDL-C, and LDL-C levels before treatment between the two groups was not statistically significant (P>0.05). FBS, TC, TG, and LDL-C levels 12 months after treatment were significantly elevated when compared with before treatment (P<0.05), but HDL-C was significantly reduced when compared with before treatment (P<0.05). FBS, TC, TG, and LDL-C levels 12 months after treatment in the observation group were significantly higher than those in the control group (P<0.05), but HDL-C was significantly lower than that in the control group (P<0.05).Conclusions:Clozapine has no obvious effect on TBA in patients with schizophrenia. Both of the two medications can produce effects on the glucose and lipid metabolism, but the effect by clozapine is more obvious;therefore, it should be paid attention in the clinical application.

Curcumin Inhibits Adipogenesis Elicited by Clozapine in 3T3-L1 Cells

Although clozapine (CZP), which is used for schizophrenia treatment, causes weight gain, the mechanism remains unclear. We recently reported that the naturally occurring compound curcumin (CUR) suppresses adipogenesis in 3T3-L1 cells. The aims of the present study were to determine the mechanism by which CZP induces adipocyte differentiation of 3T3-L1 cells, and whether CUR reduces CZP-induced adipogenesis. We found that cells grown in the presence of CZP had significantly higher triacylglycerol levels, numbers of lipid-filled adipocytes, and mRNA expression levels of CCAAT-enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) than those grown without CZP. Treatment with CZP plus CUR resulted in major reductions in these four parameters. These results suggest that CZP enhances adipogenesis in 3T3-L1 cells via the C/EBPα-PPARγ pathway and that by interrupting CZP’s effects, CUR might be a potent agent for preventing CZP-induced weight gain.

Relationships between clozapine and norclozapine plasma concentrations, clozapine dose, and clinical response in Tunisian patients with schizophrenia-treatment resistance

The present study investigated relationships between clozapine dose, clozapine and norclozapine plasma concentrations, and clinical responses to clozapine treatment in Tunisian schizophrenics. Fourteen schizophrenia-treatment resistant patients, recruited for this study, were treated with clozapine for 45 days. Patient health improvement was assessed before and after each cycle of two weeks of clozapine therapy, using the Brief Psychiatric Rating Scale (BPRS). Plasma clozapine and norclozapine concentrations were determined by high-performance liquid chromatography (HPLC). No significant correlations between plasma clozapine and norclozapine concentrations and clinical health improvement among our schizophrenic patients were found. However, a significant correlation was observed between clinical health improvement given by BPRS scores and norclozapine plasma concentration to daily clozapine dose ratio (NCZ/D). Despite the small sample size of our study, our findings suggest that the clozapine therapy response variations observed in our patients may be, in part, explained by the interindividual differences in plasma norclozapine concentration to clozapine dose ratio (NCZ/D). So the NCZ/D parameter could be used as a good indicator for adjusting the clozapine dose-adaptation strategy and consequently for improving the clinical psychopathological state of schizophrenia-treatment resistant patients.

Delaying clozapine: how long is too long?

Background Although clozapine is the most effective drug for treatment-resistant schizophrenia,its use remains restricted in clinical practice in India.The delay in initiating treatment with clozapine and its impact on disease outcome needs evaluation.Aim To identify the implications of delaying clozapine initiation in clinical outcomes among people with treatment-resistant schizophrenia.Methods Subjects with treatment-resistant schizophrenia,stabilised on clozapine monotherapy,were recruited from the outpatient clinic of a general hospital psychiatry unit offering tertiary care services in Thrissur district,Kerala,India.A retrospective cohort design was employed,and information on duration of illness,total duration of treatment and duration of treatment with clozapine was collected.Present symptom status was measured using the Positive and Negative Syndrome Scale.Factors associated with higher symptom scores were analysed using an independent sample f test,Spearman correlation and multiple linear regression.Results Forty subjects stabilised on long-term clozapine therapy formed the study sample.The mean dose of clozapine used in the study population was 200 mg.The mean duration of antipsychotic treatment before starting clozapine was 89.3 months(7.4 years).The duration of treatment before starting clozapine was found to have a significant positive association with the total Positive and Negative Syndrome Scale score(correlation coefficient 0.40;p=0.01)and negative symptom score(correlation coefficient 0.33;p=0.04).The multiple regression analysis adjusting for covariates showed that the duration of treatment before starting clozapine was an independent factor associated with a higher negative symptom score in the Positive and Negative Syndrome Scale(slope p=0.05;p=0.02;R2=0.27).Conclusion Poor treatment outcomes in treatmentresistant schizophrenia could be secondary to a delay in initiating clozapine therapy.

Acute onset clozapine-induced hyperglycaemia: A case report

Clozapine is an atypical antipsychotic which is described to have higher efficacy among all available antipsychotic medications. Clozapine is reserved especially for resistant schizophrenia due to its side effects. Clozapine-induced metabolic syndrome and hyperglycaemia are common longterm side effects and are responsible for increased mortality in patients with schizophrenia. In this case, a patient with resistant schizophrenia was presented with acute-onset hyperglycaemia and delirium with the use of clozapine within a week. Withdrawal of clozapine in the patient led to the improvement in delirium and hyperglycaemia without the use of any hypoglycaemic agent. This case s叩ports the notion that in certain cases clozapine can induce hyperglycemia through possible direct pathophysiological mechanisms within a shorter time frame.

Re-Challenge with Clozapine after Neuroleptic Malignant Syndrome and Seizure in a Patient with Di-George Syndrome: Case Report and Review of Literature

Background: Individuals with 22q11.2DS, a genetic subtype of Schizophrenia, respond as well to clozapine as those with other forms of Schizophrenia. It has been reported that serious and rare adverse events like seizures, and myocarditis have been associated with clozapine treatment in this population. To the best of our knowledge, the incidence of neuroleptic malignant syndrome (NMS) as an adverse effect of antipsychotic use in patients with this disorder has not yet been reported. Aim: In this article, we discuss a case of clozapine-induced NMS and subsequent re-challenge in a patient with 22q11.2DS-associated schizophrenia. The aim of this study is to accumulate scientific data about rare presentations, and serve as a major educational tool, and highlight the unique challenges faced when using clozapine in a patient with DiGeorge Syndrome. Methods: This is a descriptive case report of a patient encountered in the inpatient unit which includes retrospective review of the patient’s electronic medical record and a literature review of antipsychotic medications-induced NMS. Conclusion: This study demonstrates a successful re-challenge with clozapine after the patient developed NMS and seizures during the initial treatment and also highlights how, in addition to drug level monitoring, considering pharmacogenetic testing early in treatment might help minimize adverse drug reactions in individuals with known genetic disorders such as 22q11.2DS.

Novartis公司的抗神经病药物Clozaril（clozapine）和EliLilly的Zyprexa（olanzapine）可能增加糖尿病的危险

在一项有36例非肥胖患者参加的临床研究中，受试者被给予该2种药物和risperidone。患者在用餐后被要求禁止进食12h，然后被进行静脉血糖耐受性试验。Clozaril和Zyprexa组患者的胰岛素耐受性和血糖效价偏差比risperidone组患者要显著大得多。因此Novartis建议服用该2种药物的患者应当被常规性地监督血糖状态，以降低不良作用的危险性和及时采取相应的医疗措施。

Difference between treatment-resistant schizophrenia and clozapineresistant schizophrenia

We read the impressive review article“Clozapine resistant schizophrenia:Newer avenues of management”with great enthusiasm and appreciation.The author believes that preventing clozapine resistance from developing may be the most effective treatment strategy for patients with clozapine-resistant schizophrenia(CRS),and optimizing clozapine treatment is a key component.Disentangling the differences between treatment-resistant schizophrenia and CRS is important for studies addressing treatment strategies for these difficult-to-treat populations.

Clinical Study on Fuzi Lizhong Pill in Treating Salivation after Taking Clozapine for Schizophrenia

[Objectives]To observe the clinical effect of Fuzi Lizhong pills for salivation after taking clozapine in schizophrenia.[Methods]A total of 45 cases of schizophrenia patients with salivation after taking clozapine only were selected as the study subjects and randomly divided into two groups according to enrollment order.The control group(22 cases)was treated with propantheline bromide tablets and the treatment group(23 cases)were treated with Fuzi Lizhong pills combined with propantheline bromide tablets.Clinical effects and adverse reactions were compared between the two groups.Chinese medicine syndrome scores,scores of severe degree of salivation and levels of serum cholinesterase were compared between the two groups before treatment,after one-week treatment and after two-week treatment.[Results]The total clinical effective rate was 86.96%in the treatment group,higher than that of 59.09%in the control group(P<0.05).When compared with those before treatment,Chinese medicine syndrome scores of short breath and lack of strength,lassitude of spirit and somnolence,poor appetite,spontaneous sweating and dyspnea,and salivation as well as scores of salivation in Rating Scale for Extrapyramdal Side Effects(RSESE)and the severe degree of salivation in the two groups were decreased after 1 week and 2 weeks treatment(P<0.05),and levels of serum cholinesterase were increased(P<0.05).When compared with those in the control group after one-week and two-week treatment,Chinese medicine syndrome scores of short breath and lack of strength,lassitude of spirit and somnolence,poor appetite,spontaneous sweating and dyspnea,and salivation as well as scores of salivation in RSESE and the severe degree of salivation in the treatment group at the same period were lower(P<0.05),and level of serum cholinesterase was higher(P<0.05).There was no significant difference in the comparison of incidence of adverse reactions between the two groups(P>0.05).[Conclusions]Fuzi Lizhong pills combined with propantheline bromide tablets can improve clinical symptoms of schizophrenia patients with salivation after taking clozapine,and enhance level of serum cholinesterase and clinical effect.

Case Reports: Treatment-Resistant Schizophrenia with Severe Type 2 Diabetes Mellitus Treated with Clozapine

Objective: Clozapine is regarded as the most effective drug for treatment of schizophrenia but has complex adverse effects associated with hyperglycemia and diabetes mellitus. Method: We report that clozapine was very effective to treat positive, negative, and cognitive symptoms and well tolerated to a treatment-resistant schizophrenia patient with severe type 2 diabetes mellitus (DM) under cautious blood-sugar monitoring. Results: Clozapine itself and discontinuation of other psychotropic and anticholinergic agents after switching may improve cognitive function and adherence to the treatment regimens for schizophrenia and DM. Conclusion: Clozapine can be administered to treatment-resistant schizophrenia patients even with severe DM with caution.

Hyperglycemia induced by clozapine and its alternativetherapy:a case report

Clozapine has been recognized as the best drug for the treatment of refractory schizophrenia,but its clinical use is very cautious.Clozapine has many side effects,among which agranulocytosis is fatal.And it often causes glucose intolerance,leading to type 2 di-abetes.The treatment plan for elevated blood glucose in clozapine patients is still unclear.This paper will report one case of glucose intolerance caused by clozapine and its alternative treatment,and discuss the treatment plan.

氯氮平联合齐拉西酮治疗精神分裂症患者的效果

目的:探讨氯氮平联合齐拉西酮治疗精神分裂症患者的效果。方法:选择2021年6月—2023年8月黄山市第二人民医院收治的80例精神分裂症患者作为研究对象,通过随机数表法将患者分为对照组与观察组,各40例。对照组采用氯氮平联合利培酮治疗,观察组采用氯氮平联合齐拉西酮治疗,比较两组精神状况[简明精神病评定量表(BPRS)、社会功能缺陷量表(SDSS)、治疗时出现的症状量表(TESS)]、肾功能指标、血脂水平、血清水平及糖代谢。结果:两组治疗前SDSS评分、血脂水平、载脂蛋白B(Apo-B)水平、糖代谢指标比较,差异无统计学意义(P>0.05);观察组治疗后SDSS评分、TESS评分、总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、Apo-B、前白蛋白(PA)、糖化血清蛋白(GSP)、空腹血糖(FBG)低于对照组,高密度脂蛋白胆固醇(HDL-C)高于对照组,差异有统计学意义(P<0.05)。两组治疗前后BPRS评分、尿素氮(BUN)、肌酐(Cr)、尿酸(UA)、载脂蛋白A1(Apo-A1)、β2-微球蛋白(β2-MG)比较,差异无统计学意义(P>0.05)。结论:在精神分裂症患者治疗中,氯氮平联合齐拉西酮与氯氮平联合利培酮的疗效相近,但氯氮平联合齐拉西酮能显著改善患者的SDSS评分和TESS评分,优化血脂水平和糖代谢指标,降低心血管疾病风险,且对肾功能无明显不良影响。

团体绘画疗法联合氯氮平治疗慢性精神分裂症疗效观察

目的观察团体绘画疗法联合氯氮平治疗慢性精神分裂症的临床疗效。方法选取2019年2月至2023年2月上海市民政第二精神卫生中心收治的100例慢性精神分裂症患者作为研究对象,按随机数表法均分为对照组和观察组各50例。对照组患者采用氯氮平治疗,观察组患者在对照组治疗的基础上联合团体绘画疗法治疗。两组患者均持续治疗6周,于治疗结束后比较两组患者的临床疗效,以及治疗前后的阳性和阴性症状量表(PANSS)、精神分裂症患者生活质量量表(SQLS)和住院精神患者社会功能评定量表(SSPI)评分,同时比较两组患者的不良反应发生情况。结果观察组患者的治疗总有效率为84.00%,明显高于对照组的66.00%,差异有统计学意义(P<0.05);治疗后,观察组患者的阳性因子评分、阴性因子评分、一般精神病理评分和总分明显低于对照组,差异均有统计学意义(P<0.05);治疗后,观察组患者的心理社会、精力与动力、症状及副反应评分和总分明显低于对照组,差异均有统计学意义(P<0.05);治疗后,观察组患者的日常生活功能、动性及交往情况、社会活动技能评分和总分明显高于对照组,差异均有统计学意义(P<0.05);治疗期间,观察组患者的不良反应总发生率为14.00%,略低于对照组的18.00%,但差异无统计学意义(P>0.05)。结论团体绘画疗法联合氯氮平治疗能够改善慢性精神分裂症患者的阳性/阴性症状,提高其生活质量和社会功能,具有疗效好和安全性高等特点,值得临床推广应用。

阿立哌唑或利培酮联合氯氮平治疗难治性精神分裂症的疗效分析

目的:探讨阿立哌唑或利培酮联合氯氮平治疗难治性精神分裂症的疗效。方法:回顾性分析2021年5月至2022年5月于天津市滨海新区塘沽安定医院接受治疗的90例难治性精神分裂症患者的临床资料,依据采用的药物治疗方案分为氯氮平组、阿立哌唑+氯氮平组、利培酮+氯氮平组,各30例,比较3组治疗前后阳性和阴性症状量表(PANSS)评分、临床疗效和不良反应总发生率。结果:治疗后3组PANSS总分及分量表得分均较治疗前降低(P<0.05),且治疗后阿立哌唑+氯氮平组、利培酮+氯氮平组PANSS总分及分量表得分低于氯氮平组,阿立哌唑+氯氮平组低于利培酮+氯氮平组(P<0.05);治疗后阿立哌唑+氯氮平组、利培酮+氯氮平组治疗总有效率均高于氯氮平组,阿立哌唑+氯氮平组高于利培酮+氯氮平组(P<0.05);3组不良反应总发生率相近(P>0.05)。结论:在难治性精神分裂症治疗中阿立哌唑联合氯氮平的疗效总体优于利培酮联合氯氮平和单用氯氮平治疗,可作为优选治疗方案加以推广使用。

氯氮平与阿立哌唑治疗中青年精神分裂症的疗效及对其代谢综合征的影响

目的 探讨氯氮平与阿立哌唑治疗中青年精神分裂症的疗效及对其代谢综合征的影响。方法 将2022 年4 月至2023 年4 月吉安市第三人民医院收治的80 例中青年精神分裂症患者随机数字表法分成两组,各40 例。对照组接受氯氮平治疗,观察组接受氯氮平联合阿立哌唑治疗。比较两组患者治疗结束后的临床疗效、服药期间不良反应以及入组时与疗程结束时阳性与阴性症状量表评分、代谢相关指标的变化情况。结果 观察组临床总有效率为92.50%,高于对照组的75.00%,差异有统计学意义(P<0.05)。治疗后,观察组阳性量表评分、阴性量表评分、一般精神病理评分均低于对照组,差异有统计学意义(P<0.05);观察组体质量指数、空腹血糖、甘油三酯、低密度脂蛋白胆固醇水平均低于对照组,高密度脂蛋白胆固醇水平高于对照组,差异有统计学意义(P<0.05)。两组服药期间不良反应总发生率比较,差异无统计学意义(P>0.05)。结论 氯氮平联合阿立哌唑治疗中青年精神分裂症效果显著,相比于单用氯氮平不会明显影响患者的代谢相关指标且安全性较好,值得临床推荐。