Efficacy and safety of clozapine combination with different antipsychotics in schizophrenia: a systematic review

  • Maria Sri Ayu Mustikawati Master of Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta
  • Bambang Hastha Yoga Legowo Budiman Departement of Psychiatry Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta
  • Zullies Ikawati Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta
Keywords: clozapine combination, efficacy, safety, schizophrenia, clinical outcome


Schizophrenia is a severe and chronic mental disorder, where antipsychotics are used as the main therapy. Antipsychotics are commonly used in combination, especially in refractory patients. Clozapine is one of antipsychotics that is often used in combination with other antipsychotic to achieve more effective treatment. However, the effectiveness and safety of the clozapine combination are still inconclusive. This review aimed to evaluate the efficacy and safety evidence of clozapine combination therapy with different other antipsychotics. Relevant articles were collected from Google Scholar, Scopus, and PubMed, and published in 2000-2020. Five studies concerning the effectiveness and safety of clozapine in combination with different other antipsychotics were evaluated. No significant difference in the effectiveness of clozapine in combination with other antipsychotics was observed in 4 studies. No significant difference in the safety of all clozapine combinations was observed in 3 studies. Only 2 studies reported that the clozapine-atypical antipsychotic combination (clozapine-aripiprazole) is more tolerable compared to the clozapine-typical antipsychotic. In conclusion, the efficacy and safety of clozapine in combination with different other antipsychotics have not been definitively conclusive, yet.


Peritogiannis V, Ninou A, Samakouri M. Mortality in schizophrenia-spectrum disorders: recent advances in understanding and management. Healthcare 2022;10(12):2366. https://doi.org/10.3390/healthcare10122366

Marder SR, Cannon TD. Schizophrenia. N Engl J Med 2019;381(18):1753-61.


Kirkbride JB, Fearon P, Morgan C, Dazzan P, Morgan K, Tarran J, et al. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. Arch Gen Psychiatry 2006;63(3):250-8.

https://doi.org/ 10.1001/archpsyc.63.3.250. PMID: 16520429.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathophysiologic approach. 11th eds. New York: McGraw Hill Medical; 2020.

Genç 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. https://doi.org/10.1007/BF02849987

Bighelli I, Wallis S, Reitmeir C, Schwermann F, Salahuddin NH, Leucht S. Effects of psychological treatments on functioning in people with Schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Eur Arch Psychiatry Clin Neurosci. 2023;273(4):779-810.


Ereshefsky L. Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. J Clin Psychiatry1999; 60(10):20-30.

Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations: Antipsychotic combination therapy in schizophrenia. Acta Psychiatr Scand. 2002;106(5):323-330.


Kapur S, Roy P, Daskalakis J, Remington G, Zipursky R. Increased dopamine D2 receptor occupancy and elevated prolactin level associated with addition of haloperidol to clozapine. Am J Psychiatry 2001;158(2):311-14.


Ritsner MS. Polypharmacy in psychiatry practice, Volume II: use of polypharmacy in the “real world.” Netherlands: Springer 2013.


Lähteenvuo M, Tiihonen J. Antipsychotic polypharmacy for the management of schizophrenia: evidence and recommendations. Drugs 2021;81(11):1273-84. https://doi.org/10.1007/s40265-021-01556-4

Indriani A, Ardiningrum W, Febrianti Y. Studi penggunaan kombinasi antipsikotik pada pasien skizofrenia di Rumah Sakit Yogyakarta. Majalah Farmasetika 2020;4. https://doi.org/10.24198/mfarmasetika.v4i0.25882

Purwandityo AG, Febrianti Y, Sari CP, Ningrum VDA. The influence of antipsychotic to decrease the score of the positive and negative syndrome scale-excited component. Indones J Clin Pharm. 2018;7(1):19-29.

https://doi.org. 10.15416/ijcp.2018.7.1.19

Barber S, Olotu U, Corsi M, Cipriani A. Clozapine combined with different antipsychotic drugs for treatment-resistant schizophrenia. Cochrane Schizophrenia Group, ed. Cochrane Database Syst Rev. 2017;2017(3).


Zink M, Kuwilsky A, Krumm B, Dressing H. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Pychopharmacol (Oxf). 2009;23(3):305-14. https://doi.org/10.1177/0269881108089593

Kuwilsky A, Krumm B, Englisch S, Dressing H, Zink M. Long-term efficacy and tolerability of clozapine combined with ziprasidone or risperidone. Pharmacopsychiatry 2010;43(06):216-20.


Barbui C, Accordini S, Nosè M, Stroup S, Purgato M, Girlanda F, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol 2011;31(3):266-273. https://doi.org/10.1097/JCP.0b013e318219cba3

Cipriani A, Accordini S, Nosè M, Purgato M, Girlanda F, Tansella M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial. J Clin Psychopharmacol. 2013;33(4):533-7. https://doi.org/10.1097/JCP.0b013e318296884f

Keepers GA, Fochtmann LJ, Anzia JM, Benjamin S, Lyness JM, Mojtabai R, et al. The American Psychiatric Association Practice Guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872.


McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J. American Psychiatric Association; Steering Committee on Practice Guidelines. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1-56. PMID: 15000267.

Stahl SM, Shayegan DK. Describing an atypical antipsychotic: receptor binding and its role in pathophysiology. CNS Spectrum 2004; 9(10): 5-14.

Nasrallah HA, Targum SD, Tandon R, McCombs JS, Ross R. Defining and measuring clinical effectiveness in the treatment of schizophrenia. Psychiatr Serv 2005;56(3):273-282.


Kumari S, Mph M, Malik M, Manalai P, Sonje S. An assessment of five (PANSS, SAPS, SANS, NSA-16, CGI-SCH) commonly used symptoms rating scales in schizophrenia and comparison to newer scales (CAINS, BNSS). J Addict Res Ther. 2017;08(03). https://doi.org/10.4172/2155-6105.1000324

Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999;156(2):286-293.


Nordström AL, Farde L, Wiesel FA, Forslund K, Pauli S, Halldin C, et al. Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry. 1993;33(4):227-235.


Gründer G, Carlsson A, Wong DF. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry. 2003;60(10):974. https://doi.org/10.1001/archpsyc.60.10.974

Zuo L, Luo X, Krystal JH, Cramer J, Charney DS, Gelernter J. The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation. Pharmacogenet Genomics. 2009;19(6):437-46.


Stomski NJ, Morrison P, Meyer A. Antipsychotic medication side effect assessment tools: A systematic review. Aust N Z J Psychiatry. 2016;50(5):399-409. https://doi.org/10.1177/0004867415608244

Swartz MS, Perkins DO, Stroup TS, McEvoy JP, Nieri JM, Haak DC. Assessing clinical and functional outcomes in the clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial. Schizophr Bull 2003;29(1):33-43. htpps://doi.org/10.1093/oxfordjournals.schbul.a006989

Blom MT, Cohen D, Seldenrijk A, Penninx BW, Nijpels G, Stehouwer CD, et al. Brugada syndrome ECG is highly prevalent in schizophrenia. Circ Arrhythm Electrophysiol 2014;7(3):384-91.


Muench J, Hamer AM. Adverse effects of antipsychotic medications. Am Fam Phys 2010;81(5):617-22.

Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158(11):1774-82. https://doi.org/10.1176/appi.ajp.158.11.1774

Tsuboi T, Bies RR, Suzuki T, Mamo DC, Pollock BG, Graff-Guerrero A, et al. Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:178-82.


Farde L. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49(7):538. https://doi.org/10.1001/archpsyc.1992.01820070032005

Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, 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;13:757-77. https://doi.org/10.2147/TCRM.S117321

Schotte A, Janssen PFM, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996;124(1-2):57-73. https://doi.org/10.1007/BF02245606

Muscatello MRA, Bruno A, Pandolfo G, Micò U, Scimeca G, Di Nardo F, et al. Effect of aripiprazole augmentation of clozapine in schizophrenia: A double-blind, placebo-controlled study. Schizophr Res. 2011;127(1-3):93-9.


Kamin J, Manwani S, Hughes D. Emergency psychiatry: extrapyramidal side effects in the psychiatric emergency service. Psychiatr Serv 2000;51(3):287-89. https://doi.org/10.1176/appi.ps.51.3.287

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. The Lancet 2013;382(9896):951-62.


Wadenberg M. Dopamine D2 receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 2001;25(5):633-41.