Negative Symptoms of Schizophrenia: New Prospects of Cariprazine Treatment

Abstract

Background. Cariprazine is a new piperazine derivative atypical antipsychotic, like aripiprazole and brexpiprazole. It has been approved for treating schizophrenia in many countries and has recently been included on the List of Essential Medicines in Russia. Unlike most other atypical antipsychotics, it shows high in vivo occupancy of dopamine D2 and D3 receptors at clinically relevant doses. In animal models, cariprazine has demonstrated dopamine D3 receptor- dependent pro-cognitive and anti-anhedonic effects, suggesting its potential for treating negative symptoms. This review summarizes the efficacy of cariprazine in the treatment of negative symptoms of schizophrenia.

Methods. A literature search of databases covering international and Russian journals, for articles published between 1st January 2010 and 1st June 2020.

Results. Cariprazine demonstrated at least comparable efficacy in the treatment of schizophrenia symptoms to active comparators including risperidone, olanzapine or aripiprazole. The drug has a good safety profile. It appeared to be associated with a lower risk of metabolic syndromes and most extrapyramidal symptoms. The positive effect of cariprazine on the negative symptoms of schizophrenia may be associated with the elimination of secondary negative symptoms. However, of all the atypical antipsychotics to date, only cariprazine has a convincingly, methodologically robust proven advantage over risperidone in eliminating the predominant negative symptoms of schizophrenia. Yet only four studies have investigated the effect of cariprazine on the negative symptoms of schizophrenia. There is a lack of research into its direct impact on emotional-volitional disorders, anhedonia, cognitive symptoms and personality changes. However, there is evidence to suggest cariprazine is effective in treatment-resistant cases, but this requires further confirmation.

Conclusion. Cariprazine is an effective and well-tolerated agent for the treatment of schizophrenia and may be effective in cases where other antipsychotics have failed. Cariprazine has been shown to have a positive effect on negative symptoms. Further studies are needed to collect more data on long-term treatment of schizophrenia and especially negative symptoms.

Keywords

cariprazine / negative symptoms / schizophrenia / mental disorders / treatment

References

[1] Kraepelin E. Psychiatrie: Ein Lehrbuch für Studirende und Aerzte. Leipzig: Verlag von J.A. Barth; 1899. https://archive.org/details/psychiatrieeinle02krae/page/n7/mode/2up

[2] Jackson JH. A dynamic interplay between positive and negative factors in insanity. Levels of dissolution and mental symptoms. Dialogues in philosophy, mental and neuro sciences. 2020; 13 (1): 23-31. http://www.crossingdialogues.com/Ms-E20-01.htm

[3] Reinolds JR. Epilepsy: its symptoms, treatment, and relation to other chronic convulsive diseases. London: John Churchill, New Burlington street, 1861. https://archive.org/details/b21496134/page/n5/mode/2up

[4] van Rooijen G, Isvoranu AM, Meijer CJ, et al. A symptom network structure of the psychosis spectrum. Schizophr Res. 2017; 189: 75-83. doi:10.1016/j.schres.2017.02.018.

[5] Hawkins KA, McGlashan TH, Quinlan D, et al. Factorial structure of the Scale of Prodromal Symptoms. Schizophr Res. 2004;68(2-3):339-347. doi:10.1016/S0920-9964(03)00053-7.

[6] Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull. 2006;32(2):214-219. doi:10.1093/schbul/sbj053.

[7] Sayers SL, Curran PJ, Mueser KT. Factor structure and construct validity of the scale for the assessment of negative symptoms. Psychol Assessment. 1996; 8: 269–280. doi: 10.1037/1040-3590.8.3.269.

[8] Шмуклер А.Б. Шизофрения. М.: ГЭОТАР-Медиа, 2017. – 176 с. [Shmukler AB. Shizofreniya. M.: GEOTAR-Media, 2017. (In Russian)].

[9] Снежневский А.В. (1966) О течении и нозологическом единстве шизофрении (Методика и результаты исследования). Вестник Академии медицинский наук СССР. 3: 3-10. [Snezhnevskij AV. On the course and nosological unity of schizophrenia (Methodology and research results). O techenii i nozologicheskom edinstve shizofrenii (Metodika i rezul'taty issledovaniya). Vestnik Akademii medicinskij nauk SSSR. 1966; 3: 3-10. (In Russian)].

[10] Снежневский А.В. (1969) Шизофрения и проблемы общей патологии. Вестник Академии медицинский наук СССР. 4: 3-8. [Snezhnevskij AV. Schisophrenia and problems of general pathology. Shizofreniya i problemy obshchej patologii. Vestnik Akademii medicinskij nauk SSSR. 1969: 4: 3-8. (In Russian)].

[11] Foussias G, Remington G. Negative symptoms in schizophrenia: avolition and Occam's razor. Schizophr Bull. 2010;36(2):359-369. doi:10.1093/schbul/sbn094.

[12] Strauss JS, Carpenter WT, Bartko JJ. An approach to the diagnosis and understanding of schizophrenia: part III. speculations on the processes that underlie schizophrenic symptoms and signs. Schizophrenia Bulletin. 1974; 1 (11): 61–75. doi: https://doi.org/10.1093/schbul/1.11.61.

[13] Смулевич А.Б., Клюшник Т.П., Лобанова В.М., Воронова Е.И. Негативные и позитивные расстройства при шизофрении (аспекты созависимости, психопатологии, патогенеза). Журнал неврологии и психиатрии им. С.С. Корсакова. 2020; 120 (6 вып 2.): 13-22. [Smulevich AB, Kluschnik ТP, Lobanova VМ, Voronova ЕI. Negative and positive disorders of schizophrenia (issues of co-dependence, psychopathology and pathogenesis). S.S. Korsakov Journal of Neurology and Psychiatry = Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2020; 120 (6): 13-22 (In Russian)]. doi: 10.17116/jnevro202012006213.

[14] Hunter R, Barry S. Negative symptoms and psychosocial functioning in schizophrenia: neglected but important targets for treatment. Eur Psychiatry. 2012;27(6):432-436. doi:10.1016/j.eurpsy.2011.02.015.

[15] Marder SR, Galderisi S. The current conceptualization of negative symptoms in schizophrenia. World Psychiatry. 2017; 16(1): 14-24. doi:10.1002/wps.20385.

[16] Milev P, Ho BC, Arndt S, Andreasen NC. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005; 162(3): 495-506. doi:10.1176/appi.ajp.162.3.495.

[17] Rabinowitz J, Berardo CG, Bugarski-Kirola D, Marder S. Association of prominent positive and prominent negative symptoms and functional health, well-being, healthcare-related quality of life and family burden: a CATIE analysis. Schizophr Res. 2013;150(2-3):339-342. doi:10.1016/j.schres.2013.07.014.

[18] Rabinowitz J, Werbeloff N, Caers I, et al. Negative symptoms in schizophrenia--the remarkable impact of inclusion definitions in clinical trials and their consequences. Schizophr Res. 2013; 150 (2-3): 334-338. doi:10.1016/j.schres.2013.06.023.

[19] Suttajit S, Pilakanta S. Predictors of quality of life among individuals with schizophrenia. Neuropsychiatr Dis Treat. 2015;11:1371-1379. Published 2015 May 28. doi:10.2147/NDT.S81024

[20] Boonstra N, Klaassen R, Sytema S, et al. Duration of untreated psychosis and negative symptoms--a systematic review and meta-analysis of individual patient data. Schizophr Res. 2012;142(1-3):12-19. doi:10.1016/j.schres.2012.08.017

[21] Бархатова А.Н. Прогностическое значение психопатологической структуры ремиссий в инициальной стадии шизофрении. Журнал неврологии и психиатрии им. С.С. Корсакова. 2019; 119 (3): 5-11. [Barkhatova AN. Prognostic importance of the psychopathological remission structure at the initial stage of schizophrenia. S.S. Korsakov Journal of Neurology and Psychiatry. 2019; 119 (3): 5-11. (In Russian)]. doi: 10.17116/jnevro20191190315.

[22] Kirkpatrick B, Buchanan RW, Ross DE, Carpenter J. A separate disease within the syndrome of schizophrenia. Arch Gen Psychiatry. 2001; 58 (2): 165–1671. doi: 10.1001/archpsyc.58.2.165.

[23] Galderisi S, Mucci A, Buchanan RW, Arango C. Negative symptoms of schizophrenia: new developments and unanswered research questions. Lancet Psychiatry. 2018;5(8):664-677. doi:10.1016/S2215-0366(18)30050-6

[24] Наджаров Р.А. Формы течения шизофрении. Шизофрения: мультидисциплинарное исследование. Под ред. А.В. Снежневского. М.: Медицина, 1972. [Nadzharov RA. Formy techeniya shizofrenii. Shizofreniya: mul'tidisciplinarnoe issledovanie. Pod red. A.V. Snezhnevskogo. M.: Medicina, 1972. (In Russian)].

[25] Наджаров Р.А., Смулевич А.Б. Клинические проявления шизофрении. Формы течения. Руководство по психиатрии. Под ред. А.В. Снежневского. – Т. 1. М.: Медицина, 1983. [Nadzharov RA, Smulevich AB. Klinicheskie proyavleniya shizofrenii. Formy techeniya. Rukovodstvo po psihiatrii. Pod red. A.V. Snezhnevskogo. = Clinical manifestations of schizophrenia. Flow forms. Psychiatric Guide. Ed. A.V. Snezhnevsky. – T. 1. M.: Medicina, 1983. (In Russian)].

[26] Kao YC, Liu YP. Effects of age of onset on clinical characteristics in schizophrenia spectrum disorders. BMC Psychiatry. 2010;10:63. Published 2010 Aug 18. doi:10.1186/1471-244X-10-63

[27] Immonen J, Jääskeläinen E, Korpela H, Miettunen J. Age at onset and the outcomes of schizophrenia: A systematic review and meta-analysis. Early Interv Psychiatry. 2017;11(6):453-460. doi:10.1111/eip.12412

[28] Murru A, Carpiniello B. Duration of untreated illness as a key to early intervention in schizophrenia: A review. Neurosci Lett. 2018;669:59-67. doi:10.1016/j.neulet.2016.10.003

[29] Molnar MJ, Jimoh IJ, Zeke H, Palásti Á, Fedor M. Early-Onset Schizophrenia With Predominantly Negative Symptoms: A Case Study of a Drug-Naive Female Patient Treated With Cariprazine. Front Pharmacol. 2020;11:477. Published 2020 Apr 23. doi:10.3389/fphar.2020.00477

[30] Perkins DO, Gu H, Boteva K, Lieberman JA. Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry. 2005;162(10):1785-1804. doi:10.1176/appi.ajp.162.10.1785

[31] Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. What does the PANSS mean? Schizophr Res. 2005; 79 (2-3): 231-238. doi:10.1016/j.schres.2005.04.008

[32] Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry. 2009;14(4):429-447. doi:10.1038/sj.mp.4002136Epub 2008 Jan 8. PMID: 18180760.

[33] Быков Ю.В., Беккер Р.А., Морозов П.В. Эффективность карипразина в лечении шизофрении, особенно с преобладанием негативной симптоматики. Психиатрия и психофармакотерапия. 2018; 20 (5): 27-37 [Bykov YU.R., Bekker R.A., Morozov P.V. The effectiveness of cariprazine in the treatment of schizophrenia, especially with a predominance of negative symptoms. Psihiatriya i psihofarmakoterapiya = Psychiatry and Psychopharmacology. 2018; 20 (5): 27-37. In Russian]. https://con-med.ru/magazines/psikhiatriya_i_psikhofarmakoterapiya_im_p_b_ganushkina/psikhiatriya_i_psikhofarmakoterapiya_im_p_b_ganushkina-02-2020/kariprazin_kak_sotsializiruyushchiy_preparat_pri_shizofrenii_ obzor_literatury/. Russian.

[34] Solmi M, Murru A, Pacchiarotti I, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017; 29;13: 757-777. doi: 10.2147/TCRM.S117321.

[35] Мосолов С.Н., Капителли С.Г., Цукарзи Э.Э. Антипсихотическая фармакотерапия шизофрении: от научных данных к клиническим рекомендациям. Биологические методы терапии психических расстройств (доказательная медицина – клинической практике). Под ред. С.Н. Мосолова. – М.: Изд-во «Социально-политическая мысль», 2012. – С. 11–60. [Mosolov SN, Kapitelli SG, Cukarzi EE. Antipsychotic Pharmacotherapy for schizophrenia: from scientific evidence to clinical guidelines. Biologicheskie metody terapii psihicheskih rasstrojstv (dokazatel'naya medicina – klinicheskoj praktike). Pod red. S.N. Mosolova = Biological methods of therapy for mental disorders (evidence-based medicine - clinical practice). Ed. S.N. Mosolov. – M.: Izd-vo «Social'no-politicheskaya mysl'», 2012. In Russian].

[36] Keefe RS, Bilder RM, Davis SM, et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry. 2007;64(6):633-647. doi:10.1001/archpsyc.64.6.633

[37] Nasrallah H, Tandon R, Keshavan M. Beyond the facts in schizophrenia: closing the gaps in diagnosis, pathophysiology, and treatment. Epidemiol Psychiatr Sci. 2011;20(4):317-327. doi:10.1017/s204579601100062x

[38] Earley W, Guo H, Daniel D, et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data. Schizophr Res. 2019;204:282-288. doi:10.1016/j.schres.2018.08.020

[39] Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31-41. doi:10.1016/S0140-6736(08)61764-X

[40] Gross G, Drescher K. The role of dopamine D(3) receptors in antipsychotic activity and cognitive functions. Handb Exp Pharmacol. 2012;(213):167-210. doi:10.1007/978-3-642-25758-2_7

[41] Gyertyán I, Sághy K, Laszy J, et al. Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(5):529-539. doi:10.1007/s00210-008-0311-x

[42] Joyce JN, Millan MJ. Dopamine D3 receptor antagonists as therapeutic agents. Drug Discov Today. 2005;10(13):917-925. doi:10.1016/S1359-6446(05)03491-4

[43] Kiss B, Laszlovszky I, Horváth A, et al. Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: I. neurochemical characterisation of RG-15. Naunyn Schmiedebergs Arch Pharmacol. 2008;378(5):515-528. doi:10.1007/s00210-008-0308-5

[44] Laszy J, Laszlovszky I, Gyertyán I. Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl). 2005;179(3):567-575. doi:10.1007/s00213-004-2096-z

[45] Leggio GM, Salomone S, Bucolo C, et al. Dopamine D(3) receptor as a new pharmacological target for the treatment of depression. Eur J Pharmacol. 2013;719(1-3):25-33. doi:10.1016/j.ejphar.2013.07.022

[46] Aretha CW, Sinha A, Galloway MP. Dopamine D3-preferring ligands act at synthesis modulating autoreceptors. J Pharmacol Exp Ther. 1995;274(2):609-613.

[47] Millan MJ, Svenningsson P, Ashby CR Jr, et al. S33138 [N-[4-[2-[(3aS,9bR)-8- cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2((3H)-yl)-ethyl] phenylacetamide]]], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent. II. A neurochemical, electrophysiological and behavioral characterization in vivo. J Pharmacol Exp Ther. 2008; 324 (2), 600–611. doi: 10.1124/jpet.107.134536.

[48] Pugsley TA, Davis MD, Akunne HC, et al. Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907. J Pharmacol Exp Ther. 1995;275(3):1355-1366.

[49] Lacroix LP, Hows ME, Shah AJ, Hagan JJ, Heidbreder CA. Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the rat anterior cingulate cortex. Neuropsychopharmacology. 2003;28(5):839-849. doi:10.1038/sj.npp.1300114

[50] Stahl SM. Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr. 2017 Oct;22(5):375-384. doi: 10.1017/S1092852917000608. PMID: 28965530.

[51] Gyertyán I, Kiss B, Sághy K, et al. Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents. Neurochem Int. 2011;59(6):925-935. doi:10.1016/j.neuint.2011.07.002

[52] Roberts RJ, Findlay LJ, El-Mallakh PL, El-Mallakh RS. Update on schizophrenia and bipolar disorder: focus on cariprazine. Neuropsychiatr Dis Treat. 2016;12:1837-1842. Published 2016 Jul 25. doi:10.2147/NDT.S97616

[53] Girgis RR, Slifstein M, D'Souza D, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO. Psychopharmacology (Berl). 2016;233(19-20):3503-3512. doi:10.1007/s00213-016-4382-y

[54] Duric V, Banasr M, Franklin T, et al. Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model. Int J Neuropsychopharmacol. 2017;20(10):788-796. doi:10.1093/ijnp/pyx038

[55] Zimnisky R, Chang G, Gyertyán I, et al. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013;226(1):91-100. doi:10.1007/s00213-012-2896-5

[56] McCormick PN, Kapur S, Graff-Guerrero A, et al. The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro. Neuropsychopharmacology. 2010;35(8):1826-1835. doi:10.1038/npp.2010.50

[57] Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013;9(2):193-206. doi:10.1517/17425255.2013.759211

[58] Werner FM, Coveñas R. New developments in the management of schizophrenia and bipolar disorder: potential use of cariprazine. Ther Clin Risk Manag. 2015;11:1657-1661. Published 2015 Nov 2. doi:10.2147/TCRM.S64915

[59] Potkin S, Keator D, Mukherjee J, et al. Dopamine D3 and D2 receptor occupancy of cariprazine in schizophrenic patients. Europ. Neuropsychopharmacol. 2009; 19 (3): 316. doi: 10.1016/S0924-977X(09)70472-9.

[60] Seneca N, Finnema SJ, Laszlovszky I, et al. Occupancy of dopamine D₂ and D₃ and serotonin 5-HT₁A receptors by the novel antipsychotic drug candidate, cariprazine (RGH-188), in monkey brain measured using positron emission tomography. Psychopharmacology (Berl). 2011;218(3):579-587. doi:10.1007/s00213-011-2343-z

[61] Choi YK, Adham N, Kiss B, Gyertyán I, Tarazi FI. Long-term effects of cariprazine exposure on dopamine receptor subtypes. CNS Spectr. 2014;19(3):268-277. doi:10.1017/S1092852913000680

[62] Caccia S, Invernizzi RW, Nobili A, Pasina L. A new generation of antipsychotics: pharmacology and clinical utility of cariprazine in schizophrenia. Ther Clin Risk Manag. 2013;9:319-328. doi:10.2147/TCRM.S35137

[63] De Deurwaerdère P. Cariprazine: New dopamine biased agonist for neuropsychiatric disorders. Drugs Today (Barc). 2016; 52 (2): 97-110. doi:10.1358/dot.2016.52.2.2461868

[64] Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res. 2014; 152 (2-3): 450-457. doi:10.1016/j.schres.2013.11.041

[65] Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial [published correction appears in Schizophr Res. 2018 Feb;192:493]. Schizophr Res. 2016; 176 (2-3): 264-271. doi:10.1016/j.schres.2016.06.030

[66] Медведев А.Е. Карипразин – новый антипсихотик для лечения шизофрении. Современная терапия психических расстройств. 2019; 1: 22-29. [Medvedev AE. Cariprazine – Novel Antipsychotic for the Treatment of Schizophrenia. Sovremennaya terapiya psihicheskih rasstrojstv = The Journal of Current Therapy of Mental Disorders. 2019; 1: 22-29. In Russian]. doi: https://doi.org/10.21265/PSYPH.2019.59.55.004.

[67] Шмуклер АБ. Карипразин – антипсихотик с новыми уникальными потенциальными возможностями для лечения шизофрении и аффективных расстройств. Социальная и клиническая психиатрия. 2014; 24 (2): 72–5. [Shmukler AB. Kariprazin – antipsikhotik s novymi unikal'nymi potentsial'nymi vozmozhnostiami dlia lecheniia shizofrenii i affektivnykh rasstroistv. Socialnaya i klinicheskaya psihiatriya = Social and Clinical Psychiatry. 2014; 24 (2): 72–5. In Russian]. https://psychiatr.ru/magazine/scp/39/737

[68] Kane JM, Zukin S, Wang Y, et al. Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results From an International, Phase III Clinical Trial. J Clin Psychopharmacol. 2015;35(4):367-373. doi:10.1097/JCP.0000000000000346

[69] Cutler AJ, Durgam S, Wang Y, et al. Evaluation of the long-term safety and tolerability of cariprazine in patients with schizophrenia: results from a 1-year open-label study. CNS Spectr. 2018;23(1):39-50. doi:10.1017/S1092852917000220

[70] Durgam S, Greenberg WM, Li D, et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl). 2017;234(2):199-209. doi:10.1007/s00213-016-4450-3

[71] Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial [published correction appears in Lancet. 2017 Mar 18;389(10074):1102]. Lancet. 2017;389(10074):1103-1113. doi:10.1016/S0140-6736(17)30060-0

[72] Németh B, Molnár A, Akehurst R, et al. Quality-adjusted life year difference in patients with predominant negative symptoms of schizophrenia treated with cariprazine and risperidone. J Comp Eff Res. 2017;6(8):639-648. doi:10.2217/cer-2017-0024

[73] Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2018;268(7):625-639. doi:10.1007/s00406-018-0869-3

[74] Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials [published correction appears in J Clin Psychiatry 1998 Apr;59(4):200]. J Clin Psychiatry. 1997;58(12):538-546. doi:10.4088/jcp.v58n1205

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