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

Ming-Huan Zhu; Zhen-Jing Liu; Qiong-Yue Hu; Jia-Yu Yang; Ying Jin; Na Zhu; Ying Huang; Dian-Hong Shi; Min-Jia Liu; Hong-Yang Tan; Lei Zhao; Qin-Yu Lv; Zheng-Hui Yi; Feng-Chun Wu; Ze-Zhi Li

doi:10.1186/s40779-022-00420-0

Your Location：

Home >

Browse articles >

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

RESEARCH | Updated：2023-09-05

- Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial
- Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial
- MMR 2023年10卷第4期页码：431-443
- Affiliations：
  
  1.Clinical Research Center for Mental Disorders, School of Medicine, Shanghai Pudong New Area Mental Health Center, Tongji University, Shanghai 200124, China
  2.Qingdao Mental Health Center, Qingdao 266034, Shandong, China
  3.Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
  4.Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou 510370, China
  5.Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou 510370, China
- Author bio：
  
  * 13580380071@163.com;
  biolpsychiatry@126.com
- Funds：
  
  the National Natural Science Foundation of China(81401127);the Clinical Research Project of Shanghai Municipal Health Commission(20204Y0173);the Open Project Program of State Key Laboratory of Virtual Reality Technology and Systems, Beihang University(VRLAB2022 B02);the Shanghai Key Laboratory of Psychotic Disorders Open Grant(21-K03);the Scientific Research Project of Traditional Chinese Medicine of Guangdong(20192070);the Guangzhou Municipal Key Discipline in Medicine(2021–2023);the Science and Technology Plan Project of Guangdong Province(2019B030316001)
- DOI：10.1186/s40779-022-00420-0
  中图分类号：
- 纸质出版：2023-08
- Accepted：
Scan QR Code
Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial[J]. MMR, 2023,10(4):431-443.

Zhu MH, Liu ZJ, Hu QY, Yang JY, Jin Y, Zhu N, et al. Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial. Mil Med Res. 2022;9(1):59.
Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial[J]. MMR, 2023,10(4):431-443. DOI： 10.1186/s40779-022-00420-0.

Zhu MH, Liu ZJ, Hu QY, Yang JY, Jin Y, Zhu N, et al. Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia: a 12-week randomized, double-blind, placebo-controlled trial. Mil Med Res. 2022;9(1):59. DOI： 10.1186/s40779-022-00420-0.

摘要

Abstract

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 (

Bonferroni

0.01). Furthermore

compared with the placebo group

the amisulpride group showed an improved RBANS language score at week 12 (

Bonferroni

0.001). Amisulpride group had a higher treatment response rate (

=0.04)

lower scores of CGI severity and CGI efficacy at week 6 and week 12 than placebo group (

Bonferroni

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.

Conclusions:

This study indicates that amisulpride augmentation therapy has important clinical significance for treating CTRS to improve clinical symptoms and cognitive function with tolerability and safety.

Trial registration:

Clinicaltrials.gov identifier- NCT03652974. Registered August 31

2018

https://clinicaltrials.gov/ct2/show/NCT03652974

关键词

Keywords

references

He Q , Jantac Mam-Lam-Fook C , Chaignaud J , Danset-Alexandre C , Iftimovici A , Gradels Hauguel J , et al . Influence of polygenic risk scores for schizophrenia and resilience on the cognition of individuals at-risk for psychosis . Transl Psychiatry . 2021 ; 11 ( 1 ): 518 .

Pardinas AF , Holmans P , Pocklington AJ , Escott-Price V , Ripke S , Carrera N , et al . Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection . Nat Genet . 2018 ; 50 ( 3 ): 381 - 9 .

Rodrigues-Silva C , Semedo AT , Neri H , Vianello RP , Galaviz-Hernandez C , Sosa-Macias M , et al . The CYP2C19*2 and CYP2C19*17 polymorphisms influence responses to clozapine for the treatment of schizophrenia . Neuropsychiatr Dis Treat . 2020 ; 16 : 427 - 32 .

Nucifora FC Jr , Woznica E , Lee BJ , Cascella N , Sawa A . Treatment resistant schizophrenia: clinical, biological, and therapeutic perspectives . Neurobiol Dis . 2019 ; 131 : 104257 .

Zhuo C , Xu Y , Hou W , Chen J , Li Q , Liu Z , et al . Mechanistic/mammalian target of rapamycin and side effects of antipsychotics: insights into mechanisms and implications for therapy . Transl Psychiatry . 2022 ; 12 ( 1 ): 13 .

Vita A , Minelli A , Barlati S , Deste G , Giacopuzzi E , Valsecchi P , et al . Treatment-resistant schizophrenia: genetic and neuroimaging correlates . Front Pharmacol . 2019 ; 10 : 402 .

Roerig JL . Clozapine augmentation strategies . Ment Health Clin . 2019 ; 9 ( 6 ): 336 - 48 .

Bioque M , Parellada E , García-Rizo C , Amoretti S , Fortea A , Oriolo G , et al . Clozapine and paliperidone palmitate antipsychotic combination in treatment-resistant schizophrenia and other psychotic disorders: a retrospective 6-month mirror-image study . Eur Psychiatry . 2020 ; 63 ( 1 ): e71 .

Kane JM . Treatment-resistant schizophrenic patients . J Clin Psychiatry . 1996 ; 57 ( Suppl 9 ): 35 - 40 .

Honer WG , Thornton AE , Chen EY , Chan RC , Wong JO , Bergmann A , et al . Clozapine alone versus clozapine and risperidone with refractory schizophrenia . N Engl J Med . 2006 ; 354 ( 5 ): 472 - 82 .

National Collaborating Centre for Mental H . National institute for health and clinical excellence: guidance . Psychosis and Schizophrenia in Adults: Treatment and management: Updated edition 2014 . London ; National Institute for Health and Care Excellence (UK) ; 2014 .

Naguy A , Alamiri B . Ultra-treatment resistant schizophrenia- Where do we stand? Asian J Psychiatr . 2019 ; 44 : 95 - 6 .

Yilmaz Z , Zai CC , Hwang R , Mann S , Arenovich T , Remington G , et al . Antipsychotics, dopamine D(2) receptor occupancy and clinical improvement in schizophrenia: a meta-analysis . Schizophr Res . 2012 ; 140 ( 1–3 ): 214 - 20 .

De Gregorio D , Comai S , Posa L , Gobbi G . d-Lysergic acid diethylamide (LSD) as a model of psychosis: mechanism of action and pharmacology . Int J Mol Sci . 2016 ; 17 ( 11 ): 1953 .

Lin CH , Chan HY , Hsu CC , Chen FC . Temporal trends in clozapine use at time of discharge among people with schizophrenia at two public psychiatric hospitals in Taiwan, 2006–2017 . Sci Rep . 2020 ; 10 ( 1 ): 17984 .

Gao L , Hao C , Ma R , Chen J , Zhang G , Chen Y . Synthesis and biological evaluation of a new class of multi-target heterocycle piperazine derivatives as potential antipsychotics . RSC Adv . 2021 ; 11 ( 28 ): 16931 - 41 .

Kang C , Shirley M . Amisulpride: a review in post-operative nausea and vomiting . Drugs . 2021 ; 81 ( 3 ): 367 - 75 .

Genc Y , Taner E , Candansayar S . Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single-blind randomized study . Adv Ther . 2007 ; 24 ( 1 ): 1 - 13 .

Barnes TRE , Leeson V , Paton C , Marston L , Osborn DP , Kumar R , et al . Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial . Ther Adv Psychopharmacol . 2018 ; 8 ( 7 ): 185 - 97 .

Leucht S , Cipriani A , Spineli L , Mavridis D , Orey D , Richter F , et al . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis . Lancet . 2013 ; 382 ( 9896 ): 951 - 62 .

Assion HJ , Reinbold H , Lemanski S , Basilowski M , Juckel G . Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial . Pharmacopsychiatry . 2008 ; 41 ( 1 ): 24 - 8 .

Meltzer HY . Suicide in schizophrenia: risk factors and clozapine treatment . J Clin Psychiatry . 1998 ; 59 ( Suppl 3 ): 15 - 20 .

Meltzer HY . Treatment of the neuroleptic-nonresponsive schizophrenic patient . Schizophr Bull . 1992 ; 18 ( 3 ): 515 - 42 .

Zhou Y , Li Y , Meng Y , Wang J , Wu F , Ning Y , et al . Neuregulin 3 rs10748842 polymorphism contributes to the effect of body mass index on cognitive impairment in patients with schizophrenia . Transl Psychiatry . 2020 ; 10 ( 1 ): 62 .

Ang MJ , Lee S , Kim JC , Kim SH , Moon C . Behavioral tasks evaluating schizophrenia-like symptoms in animal models: a recent update . Curr Neuropharmacol . 2021 ; 19 ( 5 ): 641 - 64 .

Lang X , Zhang W , Song X , Zhang G , Du X , Zhou Y , et al . FOXP2 contributes to the cognitive impairment in chronic patients with schizophrenia . Aging . 2019 ; 11 ( 16 ): 6440 - 8 .

Li Z , Liu L , Lin W , Zhou Y , Zhang G , Du X , et al . NRG3 contributes to cognitive deficits in chronic patients with schizophrenia . Schizophr Res . 2020 ; 215 : 134 - 9 .

Kay SR , Opler LA , Lindenmayer JP . Reliability and validity of the positive and negative syndrome scale for schizophrenics . Psychiatry Res . 1988 ; 23 ( 1 ): 99 - 110 .

Leucht S , Davis JM , Engel RR , Kane JM , Wagenpfeil S . Defining “response” in antipsychotic drug trials: recommendations for the use of scalederived cutoffs . Neuropsychopharmacology . 2007 ; 32 ( 9 ): 1903 - 10 .

Mondelli V , Ciufolini S , Belvederi Murri M , Bonaccorso S , Di Forti M , Giordano A , et al . Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis . Schizophr Bull . 2015 ; 41 ( 5 ): 1162 - 70 .

Chen H , Fan Y , Zhao L , Hao Y , Zhou X , Guan Y , et al . Successful treatment with risperidone increases 5-HT 3A receptor gene expression in patients with paranoid schizophrenia—data from a prospective study . Brain Behav . 2017 ; 7 ( 9 ): e00798 .

Munro J , Matthiasson P , Osborne S , Travis M , Purcell S , Cobb AM , et al . Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine . Acta Psychiatr Scand . 2004 ; 110 ( 4 ): 292 - 8 .

Vauquelin G , Bostoen S , Vanderheyden P , Seeman P . Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism . Naunyn Schmiedebergs Arch Pharmacol . 2012 ; 385 ( 4 ): 337 - 72 .

Khokhar JY , Henricks AM , Sullivan EDK , Green AI . Unique effects of clozapine: a pharmacological perspective . Adv Pharmacol . 2018 ; 82 : 137 - 62 .

de Araújo AN , do Nascimento MA , de Sena EP , Baptista AF . Temporomandibular disorders in patients with schizophrenia using antipsychotic agents: a discussion paper . Drug Healthc Patient Saf . 2014 ; 6 : 21 - 7 .

Hopkins SC , Wilkinson S , Corriveau TJ , Nishikawa H , Nakamichi K , Loebel A , et al . Discovery of nonracemic amisulpride to maximize benefit/risk of 5-HT7 and D2 receptor antagonism for the treatment of mood disorders . Clin Pharmacol Ther . 2021 ; 110 ( 3 ): 808 - 15 .

Alm PA . The dopamine system and automatization of movement sequences: a review with relevance for speech and stuttering . Front Hum Neurosci . 2021 ; 15 : 661880 .

Gross G , Drescher K . The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions . Handb Exp Pharmacol . 2012 ; 213 : 167 - 210 .

Laszlovszky I , Barabassy A , Nemeth G . Cariprazine, a broad-spectrum antipsychotic for the treatment of schizophrenia: pharmacology, efficacy, and safety . Adv Ther . 2021 ; 38 ( 7 ): 3652 - 73 .

Dubertret C , Gorwood P , Ades J , Feingold J , Schwartz J , Sokoloff P . Meta-analysis of DRD3 gene and schizophrenia: ethnic heterogeneity and significant association in Caucasians . Am J Med Genet . 1998 ; 81 ( 4 ): 318 - 22 .

Morozova A , Zorkina Y , Pavlov K , Pavlova O , Storozheva Z , Zubkov E , et al . Association of rs4680 COMT, rs6280 DRD3, and rs7322347 5HT2A with clinical features of youth-onset schizophrenia . Front Psychiatry . 2019 ; 10 : 830 .

Moritz AE , Free RB , Sibley DR . Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds . Cell Signal . 2018 ; 41 : 75 - 81 .

Stahl S . Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes . CNS Spectr . 2017 ; 22 ( 5 ): 375 - 84 .

Werner F . Neural networks in neurological and psychiatric diseases . Curr Pharm Des . 2019 ; 25 ( 4 ): 374 - 5 .

Bitter I , Lieberman JA , Gaudoux F , Sokoloff P , Groc M , Chavda R , et al . Randomized, double-blind, placebo-controlled study of F17464, a preferential D3 antagonist, in the treatment of acute exacerbation of schizophrenia . Neuropsychopharmacology . 2019 ; 44 ( 11 ): 1917 - 24 .

Zhou X , Wang X , Li R , Yan J , Xiao Y , Li W , et al . Neutrophil-to-Lymphocyte ratio is independently associated with severe psychopathology in schizophrenia and is changed by antipsychotic administration: a largescale cross-sectional retrospective study . Front Psychiatry . 2020 ; 11 : 581061 .

Liang Y , Yu X . Effectiveness of amisulpride in Chinese patients with predominantly negative symptoms of schizophrenia: a subanalysis of the ESCAPE study . Neuropsychiatr Dis Treat . 2017 ; 13 : 1703 - 12 .

Wang YT , Chiu NY , Jou SH , Kuang Yang Y , Hui Lee I , Wang CC , et al . Effects of amisulpride on the cognitive function of patients with schizophrenia who switched from risperidone . Int J Psychiatry Clin Pract . 2008 ; 12 ( 3 ): 180 - 6 .

Kumar S , Chaudhury S . Efficacy of amisulpride and olanzapine for negative symptoms and cognitive impairments: an open-label clinical study . Ind Psychiatry J . 2014 ; 23 ( 1 ): 27 - 35 .

Park JH , Hong JS , Kim SM , Min KJ , Chung US , Han DH . Effects of amisulpride adjunctive therapy on working memory and brain metabolism in the frontal cortex of patients with schizophrenia: a preliminary positron emission tomography/computerized tomography investigation . Clin Psychopharmacol Neurosci . 2019 ; 17 ( 2 ): 250 - 60 .

Molina JD , Quintero J , Garcia-Laredo E , Lopez-Munoz F , Correas-Lauffer J , Barbudo E , et al . Cognitive effects of combined amisulpride and quetiapine treatment in patients with refractory schizophrenia: A naturalistic, prospective study . Am J Ther . 2020 ; 27 ( 4 ): e346 - 55 .

Salmazo-Silva H , Parente MA , Rocha MS , Baradel RR , Cravo AM , Sato JR , et al . Lexical-retrieval and semantic memory in Parkinson’s disease: the question of noun and verb dissociation . Brain Lang . 2017 ; 165 : 10 - 20 .

de Boer J , Brederoo S , Voppel A , Sommer I . Anomalies in language as a biomarker for schizophrenia . Curr Opin Psychiatry . 2020 ; 33 ( 3 ): 212 - 8 .

Talati P , Rane S , Skinner J , Gore J , Heckers S . Increased hippocampal blood volume and normal blood flow in schizophrenia . Psychiatry Res . 2015 ; 232 ( 3 ): 219 - 25 .

Schobel SA , Chaudhury NH , Khan UA , Paniagua B , Styner MA , Asllani I , et al . Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver . Neuron . 2013 ; 78 ( 1 ): 81 - 93 .

Shin W , Bang M , Kim A , Cho DY , Lee SH . Influence of cytochrome P450 2D6 polymorphism on hippocampal white matter and treatment response in schizophrenia . NPJ Schizophr . 2021 ; 7 ( 1 ): 5 .

Tregellas JR , Smucny J , Harris JG , Olincy A , Maharajh K , Kronberg E , et al . Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia . Am J Psychiatry . 2014 ; 171 ( 5 ): 549 - 56 .

Heckers S , Konradi C . GABAergic mechanisms of hippocampal hyperactivity in schizophrenia . Schizophr Res . 2015 ; 167 ( 1–3 ): 4 - 11 .

Shin S , Kim S , Seo S , Lee J , Howes O , Kim E , et al . The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [ 11 C]-raclopride PET study with aripiprazole . Transl Psychiatry . 2018 ; 8 ( 1 ): 87 .

Kvachnina E , Liu G , Dityatev A , Renner U , Dumuis A , Richter D , et al . 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology . J Neurosci . 2005 ; 25 ( 34 ): 7821 - 30 .

Kobe F , Guseva D , Jensen TP , Wirth A , Renner U , Hess D , et al . 5-HT7R/G12 signaling regulates neuronal morphology and function in an agedependent manner . J Neurosci . 2012 ; 32 ( 9 ): 2915 - 30 .

Costa L , Sardone LM , Bonaccorso CM , D’Antoni S , Spatuzza M , Gulisano W , et al . Activation of serotonin 5-HT(7) receptors modulates hippocampal synaptic plasticity by stimulation of adenylate cyclases and rescues learning and behavior in a mouse model of fragile X syndrome . Front Mol Neurosci . 2018 ; 11 : 353 .

Juruena MF , de Sena EP , de Oliveira IR . Safety and tolerability of antipsychotics: focus on amisulpride . Drug Healthc Patient Saf . 2010 ; 2 : 205 - 11 .

Nikiforuk A , Popik P . Amisulpride promotes cognitive flexibility in rats: the role of 5-HT7 receptors . Behav Brain Res . 2013 ; 248 : 136 - 40 .

Sokoloff P , Le Foll B . The dopamine D3 receptor, a quarter century later . Eur J Neurosci . 2017 ; 45 ( 1 ): 2 - 19 .

Lemercier CE , Schulz SB , Heidmann KE , Kovács R , Gerevich Z . Dopamine D3 receptors inhibit hippocampal gamma oscillations by disturbing CA3 pyramidal cell firing synchrony . Front Pharmacol . 2015 ; 6 : 297 .

Papp M , Gruca P , Lason-Tyburkiewicz M , Litwa E , Niemczyk M , Tota-Glowczyk K , et al . Dopaminergic mechanisms in memory consolidation and antidepressant reversal of a chronic mild stress-induced cognitive impairment` . Psychopharmacology . 2017 ; 234 ( 17 ): 2571 - 85 .

Gou HY , Sun X , Li F , Wang ZY , Wu N , Su RB , et al . The antipsychotic-like effects in rodents of YQA31 involve dopamine D3 and 5-HT1A receptor . Pharmacol Rep . 2017 ; 69 ( 6 ): 1125 - 30 .

Newcomer JW . Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review . CNS Drugs . 2005 ; 19 ( Suppl 1 ): 1 - 93 .

McKeage K , Plosker G . Amisulpride: a review of its use in the management of schizophrenia . CNS Drugs . 2004 ; 18 ( 13 ): 933 - 56 .

浏览量

Downloads

CSCD

文章被引用时，请邮件提醒。

Submit

工具集

关联资源

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis

基于图像识别的轮轨冲角测量系统研究

3D轴焊接构架式转向架重车过曲线轮轨横向力超标原因分析

开裂预应力混凝土梁的检测、评估和加固