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.

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.

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.

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.

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。

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.

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.

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.

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.

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.

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.

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.

Multiple therapies relieve long-term tardive dyskinesia in a patient with chronic schizophrenia:A case report

BACKGROUND Tardive dyskinesia(TD)is a serious and disabling movement disorder;it impairs social function and quality of life and increases the mortality rate.TD is usually induced by the use of antipsychotic drugs;however,the underlying mechanism remains unclear.Pharmacotherapy of TD includes cholinergic drugs,benzodiazepines,ginkgo biloba extract(GBE),antioxidants,amantadine,propanolol,botulinum toxin,valbenazine,and deutetrabenazine,whereas the non-pharmacotherapy approach includes modified electroconvulsive therapy(MECT)and deep brain stimulation.We successfully treated a chronic schizophrenia patient with comorbid long-term severe TD using deutetrabenazine,clozapine,and MECT.CASE SUMMARY A 69-year-old woman who was diagnosed as having schizophrenia 16 years ago developed severe TD after 6-mo prescription of risperidone oral solution.Her TD symptoms did not resolve despite various treatments,such as GBE,vitamin E,trihexyphenidyl,promethazine,benzodiazepines,and switching to quetiapine and olanzapine.After admission,she was given deutetrabenazine 6 mg bid.Her buccal tremor was slightly resolved 3 d later;however,her tongue remained protruded and could not be retracted.Quetiapine was switched to clozapine on day 4,and the buccal tremor remarkably resolved,and the tongue could be retracted into the mouth from day 6 onward.After three sessions of MECT,the buccal tremor resolved further.Since then,she has been able to take a semifluid diet,and her quality of life improved remarkably during 6 mo of follow-up.CONCLUSION TD is a serious condition which could be caused by antipsychotic medications;however,the best strategy against TD is prevention and monitoring during using antipsychotics.For patients with TD caused by antipsychotic medication use,multiple measures should be considered like switching to clozapine,adjunction with deutetrabenazine,or even MECT.

氯氮平急性中毒的抢救(附5例报告)

氯氮平(Clozapine)为较新一代的抗精神病药,治疗效果较好。我们近两年共收治5例急性中毒病人,用洗胃,加速排泄药物,腹膜透析,支持疗法治疗,效果良好,现报告如下: 病历摘要 例1 女性30岁,精神分裂症病史3年,持续服用氯氮平50mg/日。因受精神刺激一次服用氯氮平2000mg,1小时后被送入医院,患者当时面色苍白,大汗淋漓,口鼻流出大量白色泡沫样分泌物,T36.4℃,P104次/分,BP 14/10kPa,R40次/分,深昏迷状态,双瞳孔等大等圆,直径1.5mm。

Cognitive-behavioural therapy for obsessive-compulsive disorder co-occurring with psychosis: Systematic review of evidence

AIM To review available evidence on the use of cognitive behavioural therapy(CBT) for treating obsessive compulsive disorder co-occurring with psychosis.METHODS In this paper we present a detailed and comprehensive review of the current literature focusing on CBT treatment of obsessive compulsive disorder(OCD) co-occurring with schizophrenia or schizoaffective disorder. We identified relevant literature published between 2001 and May 2016 through MEDLINE/PubM ed search using as search string("obsessive compulsive disorders" or "obsessive compulsive symptoms") and("schizophrenia" or "schizoaffective disorder" or "psychosis") and("cognitive behavioural therapy"). Other citations of interest were further identified from references reported in the accessed articles. The search was limited to studies written in English and carried out in adult patients. A total of 9 studies, 8 case reports and 1 case series, were found.RESULTS The reviewed evidence indicates that CBT is:(1) safe, i.e., does not worsen psychotic symptoms;(2) well accepted, with a discontinuation rate quite similar to that reported for patients with OCD without psychosis comorbidity;(3) effective, with a symptom reduction quite similar to that reported for patients with OCD without psychosis and for SRIs treatment of OCD cooccurring with psychosis; and(4) effective in patients with OCD induced by second-generation antipsychotic as well as in patients with OCD not induced by secondgeneration antipsychotic. Alcohol/substance use disorder comorbidity and OCD onset preceding that of SCH/SA was predictors of poor outcome. These results are derived only by additional studies with adequate sample size.CONCLUSION Our results support the use of CBT for OCD in patients with psychosis.

尿液中氯氮平的GC-MS法快速检验

Clozapine was directly extracted in human urine by using liquid-liquid extraction method,and determined by gas chromatography-mass spectrometry.The method established in this paper can be applied in detection of clozapine in test cases with high speed and precision.

Antipsychotics preserve telomere length in peripheral blood mononuclear cells after acute oxidative stress injury

Antipsychotics may prolong or retain telomere length,affect mitochondrial function,and then affect the metabolism of nerve cells.To validate the hypothesis that antipsychotics can prolong telomere length after oxidative stress injury,leukocytes from healthy volunteers were extracted using Ficoll-Histopaque density gradient.The mononuclear cells layer was resuspended in cell culture medium.Oxidative stress was induced with hydrogen peroxide in cultured leukocytes.Four days later,leukocytes were treated with aripiprazole,haloperidol or clozapine for 7 days.Real-time PCR revealed that treatments with aripiprazole and haloperidol increased the telomere length by 23%and 20%in peripheral blood mononuclear cells after acute oxidative stress injury.These results suggest that haloperidol and aripiprazole can reduce the damage to telomeres induced by oxidative stress.The experiment procedure was approved by the Ethics Committee of Faculty of Medicine of the University of Sao Paulo(FMUSP/CAAE approval No.52622616.8.0000.0065).