Clozapine Research: The 25 Most-Cited Studies and the Newest Evidence

The most-cited clozapine study in schizophrenia research is Kane and colleagues' 1988 trial in the Archives of General Psychiatry, with 4,203 citations. It showed a 30% response rate in patients who had not responded to other antipsychotics, compared with 4% on chlorpromazine. The label cites a trial of this design as the basis for the treatment-resistance indication.^{1, 2}

This page lists the 25 most-cited clozapine papers in human schizophrenia research and the 25 most-cited published from 2024 to 2026. It is a reading list for clinicians, trainees, and families who want the primary sources.

How the lists were built

Papers were identified in OpenAlex by searching for clozapine in the title and ranking by citation count, retrieved on November 12, 2026. Each record was then checked against PubMed, and the titles, journals, and years below are PubMed's. Animal and molecular studies, drug formulation, assay, and dosing-model papers, and studies of clozapine in Parkinson's disease were excluded. Citation counts from Google Scholar run higher. Counts for the newest papers are low and their order will change.

The 25 most-cited clozapine studies

1. Kane J et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45(9):789-96. 4,203 citations
   The trial behind the treatment-resistance indication. Among 268 patients who had not responded to other antipsychotics, 30% responded to clozapine in six weeks and 4% to chlorpromazine.
2. Farde L et al. 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):538-44. 1,424 citations
3. Meltzer HY et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91. 1,421 citations
   InterSePT. In 980 high-risk patients, suicidal behavior was 24% lower with clozapine than with olanzapine over two years. The basis for the FDA suicide indication.
4. Meltzer HY et al. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull. 1999;25(2):233-55. 1,025 citations
5. McEvoy JP et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600-10. 1,019 citations
   From the CATIE study. Patients who had stopped a newer antipsychotic stayed on clozapine for a median of 10.5 months, longer than on quetiapine or risperidone.
6. Alvir JM et al. Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med. 1993;329(3):162-7. 976 citations
   The first US surveillance data: 11,555 patients, agranulocytosis in 0.80% at one year, most cases within three months.
7. Kapur S et al. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry. 1999;156(2):286-93. 719 citations
8. Henderson DC et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry. 2000;157(6):975-81. 697 citations
   A five-year naturalistic study of 82 outpatients. 36.6% were diagnosed with diabetes during follow-up.
9. Baldessarini RJ et al. Clozapine. A novel antipsychotic agent. N Engl J Med. 1991;324(11):746-54. 697 citations
10. Siskind D et al. Clozapine v. first- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2016;209(5):385-392. 660 citations
    Meta-analysis covering 21 papers and 25 comparisons in treatment-refractory schizophrenia. Number needed to treat of 9.
11. Woodward ND et al. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharmacol. 2005;8(3):457-72. 613 citations
12. Meltzer HY Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl). 1989;99 Suppl:S18-27. 601 citations
13. Kilian JG et al. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841-5. 539 citations
    The Australian series that defined early myocarditis: 15 cases among 8,000 patients, all within three weeks of starting.
14. Bilder RM et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002;159(6):1018-28. 537 citations
15. Rosenheck R et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. N Engl J Med. 1997;337(12):809-15. 516 citations
16. Meltzer HY Treatment-resistant schizophrenia--the role of clozapine. Curr Med Res Opin. 1997;14(1):1-20. 503 citations
17. Meltzer HY et al. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. Am J Psychiatry. 1995;152(2):183-90. 440 citations
18. Lewis SW et al. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006;32(4):715-23. 422 citations
19. Siskind D et al. Clozapine Response Rates among People with Treatment-Resistant Schizophrenia: Data from a Systematic Review and Meta-Analysis. Can J Psychiatry. 2017;62(11):772-777. 417 citations
    Pooled response rate of 40.1% in treatment-resistant schizophrenia.
20. Volavka J et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry. 2002;159(2):255-62. 412 citations
21. Kumra S et al. Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry. 1996;53(12):1090-7. 412 citations
22. Hagger C et al. Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry. 1993;34(10):702-12. 396 citations
23. Lieberman JA et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry. 1994;151(12):1744-52. 393 citations
24. Breier A et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry. 1994;151(1):20-6. 390 citations
25. Petrides G et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: a prospective, randomized study. Am J Psychiatry. 2015;172(1):52-8. 365 citations
    Randomized trial of ECT added to clozapine in 39 clozapine-resistant patients. 50% responded, compared with none on clozapine alone.

The 25 most-cited clozapine papers, 2024 to 2026

The recent literature has moved from whether clozapine works to how to use it safely: blood count rules, constipation and pneumonia, myocarditis screening, and weight.

1. Siskind D et al. Efficacy and safety of semaglutide versus placebo for people with schizophrenia on clozapine with obesity (COaST): a phase 2, multi-centre, participant and investigator- blinded, randomised controlled trial in Australia. Lancet Psychiatry. 2025;12(7):493-503. 77 citations
   COaST. Semaglutide produced 13.9% weight loss at 36 weeks in 31 adults on clozapine, compared with 0.4% on placebo.
2. Rubio JM et al. Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case-control study in Finland. Lancet Psychiatry. 2024;11(6):443-450. 60 citations
   Finnish national cohort of 61,769. Agranulocytosis risk with clozapine fell steeply after the first six months.
3. Verdoux H et al. The time has come for revising the rules of clozapine blood monitoring in Europe. A joint expert statement from the European Clozapine Task Force. Eur Psychiatry. 2025;68(1):e17. 59 citations
4. Partanen JJ et al. High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study. Am J Psychiatry. 2024;181(10):879-892. 53 citations
   FinnGen follow-up of 2,659 clozapine users. Ileus in 5.3% and pneumonia in 29.5% at 20 years, both tied to higher mortality.
5. Siskind D et al. Absolute neutrophil count and adverse drug reaction monitoring during clozapine treatment: consensus guidelines from a global Delphi panel. Lancet Psychiatry. 2026;13(1):77-86. 47 citations
   Global Delphi consensus recommending lower neutrophil thresholds and an end to routine blood count monitoring after two years.
6. Faden J et al. A systematic review of clozapine for aggression and violence in patients with schizophrenia or schizoaffective disorder. Schizophr Res. 2024;268:265-281. 45 citations
7. Schneider-Thoma J et al. Efficacy of clozapine versus second-generation antipsychotics in people with treatment-resistant schizophrenia: a systematic review and individual patient data meta-analysis. Lancet Psychiatry. 2025;12(4):254-265. 44 citations
   A meta-analysis of 19 blinded trials, with individual patient data from 12, found no clear advantage for clozapine over other second-generation antipsychotics in short trials. Confidence graded very low.
8. Agid O et al. Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice. Eur Neuropsychopharmacol. 2024;84:35-47. 44 citations
9. Murray RM et al. Why Is Clozapine Uniquely Effective in Treatment-Resistant Schizophrenia? A Review and Proposal. Biol Psychiatry. 2026;99(7):517-526. 32 citations
10. De Las Cuevas C et al. Clozapine may consistently protect from suicidal behaviors while other antipsychotics may lack a specific protective effect: a comprehensive VigiBase study interpreted in the context of the prior literature. Expert Opin Drug Saf. 2025;24(11):1301-1311. 28 citations
11. Wagner E et al. Multidisciplinary consensus on prevention, screening and monitoring of clozapine-associated myocarditis and clozapine rechallenge after myocarditis. Br J Psychiatry. 2026;228(4):348-356. 27 citations
    An international consensus on screening for clozapine-associated myocarditis. Recommends slower titration.
12. De Las Cuevas C et al. Pharmacovigilance in Action: Utilizing VigiBase Data to Improve Clozapine Safety. Patient Prefer Adherence. 2024;18:2261-2280. 27 citations
13. Tiihonen J et al. Effectiveness of clozapine augmentation with specific doses of other antipsychotics in schizophrenia: a meta-analysis from two nationwide cohorts. World Psychiatry. 2025;24(2):250-259. 24 citations
    Finnish and Swedish registers. Medium-dose aripiprazole added to high-dose clozapine was associated with fewer psychosis hospitalizations.
14. Smessaert S et al. Evaluating Monitoring Guidelines of Clozapine-Induced Adverse Effects: a Systematic Review. CNS Drugs. 2024;38(2):105-123. 24 citations
15. Luykx JJ et al. Transdiagnostic effectiveness and safety of clozapine in individuals with psychotic, affective, and personality disorders: nationwide and meta-analytic comparisons with other antipsychotics. Lancet Psychiatry. 2025;12(12):921-931. 22 citations
16. Qubad M et al. When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis. CNS Drugs. 2024;38(9):671-696. 20 citations
17. Tanzer T et al. Overcoming clozapine's adverse events: a narrative review of systematic reviews and meta-analyses. Expert Opin Drug Saf. 2024;23(7):811-831. 20 citations
18. Kikuchi Y et al. Effects of titration speed, gender, obesity and concomitant medications on the risk and onset time of clozapine-associated fever among Japanese patients with schizophrenia: retrospective review of charts from 21 hospitals. Br J Psychiatry. 2024;225(5):492-498. 19 citations
    512 patients in 21 Japanese hospitals. Faster titration and concurrent valproate or quetiapine were associated with a higher risk of fever during initiation.
19. Lind PA et al. Clozapine Efficacy and Adverse Drug Reactions Among a Nationwide Study of 1021 Australians Prescribed Clozapine: The ClozaGene Study. Schizophr Bull. 2025;51(2):458-469. 19 citations
20. Dell'Osso L et al. Rethinking Clozapine: Lights and Shadows of a Revolutionary Drug. Brain Sci. 2024;14(1). 19 citations
21. Torrey EF et al. The Underuse of Clozapine and Long-Acting Injectable Antipsychotics. Psychiatr Serv. 2025;76(1):90-92. 18 citations
    A call for federal agencies and professional bodies to take responsibility for the underuse of clozapine and long-acting injectables.
22. Kane JM et al. Clozapine in treatment-resistant schizophrenia: Reflections from the Hallmark US clinical trial and beyond. Schizophr Res. 2024;268:9-13. 16 citations
23. Fitzgerald I et al. Global trends in clozapine utilisation between 2014 and 2024: a longitudinal epidemiological study with data from 75 countries. Lancet Reg Health Eur. 2026;63:101602. 15 citations
    Clozapine use across 75 countries, 2014 to 2024. Use tracked the number of psychiatrists and was unrelated to how strict blood monitoring was.
24. Onodera B et al. Elevated neutrophil-to-lymphocyte ratios correlate with increased clozapine concentration-to-dose ratios during titration. Schizophrenia (Heidelb). 2025;11(1):96. 15 citations
25. Waszak PM et al. Anti-Suicidal Effects of Lithium, Ketamine, and Clozapine-A 10-Year Systematic Review. Pharmaceuticals (Basel). 2025;18(5). 15 citations

My own work in this area

With Mark Olfson, Christoph Correll, and Erica Duncan, I evaluated the FDA's 2015 change to clozapine blood count thresholds in a Veterans Affairs cohort. Among 160 patients starting clozapine, 3.1% met criteria for treatment interruption in the first year under the former rules and 0.6% under the revised ones. Of 14,620 patients with schizophrenia in the cohort, 1.7% received clozapine.³ The paper is summarized on the page about clozapine blood tests after the REMS ended.

How to read this literature

Citation counts measure influence and age, and some heavily cited findings have been revised since. Several of the most-cited trials compared clozapine with first-generation antipsychotics such as chlorpromazine and haloperidol, and a 2025 individual patient data meta-analysis found no clear advantage over other second-generation antipsychotics in short blinded trials. Real-world cohort studies continue to favor clozapine on hospitalization and treatment continuation. The pages on when to start clozapine, side effects, and suicide risk go through that evidence.

In a crisis: call or text 988, or go to the nearest emergency department. A first episode of psychosis belongs in a hospital-based or coordinated specialty care program.

I start and manage clozapine in an outpatient practice in Chelsea, Manhattan. Details are on the schizophrenia care in NYC page. Clozapine should not be stopped, skipped, or restarted without the prescriber. This page is general information and does not replace an evaluation.

Related: Schizophrenia and psychosis treatment guide · When to start clozapine · Clozapine blood tests after the REMS ended · Clozapine side effects · Missed clozapine doses · Clozapine and suicide risk · Cannabis and psychosis · Cobenfy vs clozapine · Injections vs pills · Stimulants and psychosis · Drug-induced psychosis · Clozapine levels · Clozapine myocarditis · Clozapine constipation · Clozapine drooling · Clozapine weight gain · Who can prescribe clozapine · Clozapine in teenagers · When clozapine isn't enough · Benign ethnic neutropenia · Starting clozapine · Clozapine and pneumonia · Clozapine seizures · Clozapine in pregnancy · Clozapine rechallenge