End the FDA’s Regulatory Barriers to Clozapine for Serious Mental Illness

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ATTN:

United States Food and Drug Administration (FDA)

Department of Health and Human Services

RE: Request for Comments--Clozapine REMS

We represent thousands of patients, family members, caregivers, and advocates for individuals with Serious Mental Illnesses (SMI).[1] Our loved ones face risks of decompensation, self-harm, homelessness, incarceration, and death. We are seeking to eliminate the FDA’s Risk Evaluation and Mitigation Strategy (REMS) for clozapine and to correct certain flaws we find in the clozapine product label.[2,3] The clozapine REMS has created insurmountable treatment barriers, especially in underfunded, rural, and incarcerated settings.[4,5] The clozapine package insert reflects treatment parameters from the 1980s clinical trials, which were based on primarily White male populations.[6,7] This has disadvantaged Blacks, Asians, certain ethnic minorities, and female patients.[8,9,10]

Clozapine’s FDA approval in 1989 was contingent on weekly monitoring of patient White Blood Cell count (WBC) and/or Absolute Neutrophil Count (ANC) to detect severe neutropenia, a potentially fatal condition relating to the body’s ability to fight infection.[11] These federal mandates were initially helpful in understanding the risks of this new medication. However, much has been learned about the risks, risk management, and broad benefits of clozapine since its FDA approval in 1989. The “NO BLOOD, NO DRUG” policy, whether formally mandated or embedded in clinical and pharmacy culture, has long outlived its usefulness. It is time to remove the government from the day-to-day practice of psychiatry and allow physicians to apply the lessons of the past 35 years.

CLOZAPINE IS THE MOST EFFECTIVE ANTIPSYCHOTIC EVER DEVELOPED [12,13]

CLOZAPINE IS THE SAFEST ANTIPSYCHOTIC MEDICINE AVAILABLE [14,15,16,17]

PATIENTS ARE SUFFERING AND DYING DUE TO LACK OF ACCESS TO CLOZAPINE

The rate of clozapine-induced neutropenia is much lower than originally thought. Eight years after clozapine’s FDA approval, research revealed neutropenia to be one of the lowest causes of death for clozapine patients.[18] The incidence is less than 1%, with most studies estimating severe clozapine-induced neutropenia to affect only 1 in 250 patients. Of these cases, mortality rates are 3% or less, with total fatalities only around 2 in 10,000 clozapine-treated patients.[7,19,20,21,22,23,24] These extremely rare events are now readily treatable with granulocyte colony-stimulating factors and newer agents,[25] thus minimizing fatal risk. Most severe neutropenia cases occur during the first 18 weeks of clozapine treatment, rendering frequent mandatory long-term monitoring unnecessary.[19,22,24,26,27]

The FDA has suggested these low mortality rates are simply a positive outcome of the frequent mandatory ANC monitoring. In response to a 2020 citizens petition,[28] the FDA cited a single study from 1977 that implied frequent ANC blood tests prevent about 35 deaths per 10,000 patients.[29] This was a smaller-scale retrospective study that captured the cluster of eight neutropenia deaths in Finnish patients that led to the suspension of clozapine’s clinical trials in 1975. During the 50 years since that notorious event, neutropenia-related fatalities in clozapine patients have remained far lower, even in countries with significantly reduced testing requirements compared to the U.S.[30,31,32,33]

This rare incidence of severe neutropenia is critical to understand in context. In 2002, thirteen years after its FDA approval with stringent ANC monitoring, clozapine became the only medication in history to receive an FDA indication for reducing suicide risks.[34] In 2009, clozapine was confirmed to significantly reduce all causes of mortality compared to other antipsychotics or no treatment at all.[35] A longitudinal follow-up in 2020 reinforced this finding.[14] Based on these studies, for every 10,000 patients with Treatment-Resistant Schizophrenia (TRS) or recurrent suicidal behavior, clozapine will prevent 300 to 400 suicides or around 1,000 premature deaths. These profound benefits of clozapine would far eclipse any risks associated with severe neutropenia, even if patients were to waive ANC testing altogether.

Clozapine remains severely underutilized in the US, with over 85% of indicated patients unable to access treatment.[36] Three decades of reluctance to initiate clozapine due to the overwhelming burden of mandatory ANC monitoring has resulted in thousands of suicides and premature deaths that could have been prevented with clozapine intervention.[37,38] Combining prescribing habits with prevalence statistics, for every life allegedly saved by frequent ANC monitoring, hundreds of SMI patients may die from lack of access to clozapine.[39]

Dangerous Treatment Interruptions and Discontinuations

Frequent ANC testing also contributes to dangerous surveillance bias. Families report doctors engaging in “panic stops” for mild or moderate neutropenia rather than temporarily increasing the testing frequency per the prescribing guidelines. High rates of “false positives,” unrelated conditions and misinterpreted test results are likely causing far more deaths from wrongful discontinuation of clozapine than the number of fatalities prevented for neutropenia.[40,41,42] The FDA does not monitor regulation-induced adverse events, but the experience of The Angry Moms suggests these occurrences are unacceptably high.

Furthermore, there is no evidence that restricting dispensing and distribution of clozapine improves patient safety. The clozapine REMS blocks refills of lifesaving medication and limits dose quantities. Prescriptions are often dispensed in weekly or bi-weekly quantities to match the mandatory testing frequency with no accommodations for emergency doses. Families call this “clozapine rationing,” which has caused serious treatment interruptions when patients face any logistical delay in obtaining and reporting laboratory results. These instances are frequent. Clozapine REMS-related interruptions have caused clinical decompensation, psychosis relapse, injury, hospitalization, violence, and death.[43,44,45,46,47]

This unfair patient experience is exacerbated by clinical policies requiring patients to wait for laboratory results and data entry. Each ANC testing period usually means two trips to the clinic: one trip for the blood draw and another two days later to pick up the next ration of clozapine. Even though the REMS rules don’t technically require this, most community clozapine programs are unwilling to dispense any clozapine until the ANC value is recorded in the REMS. Comparatively, cancer medications with 10- to 100-times higher risks of severe neutropenia do not impose this extreme level of rigid patient monitoring.[48,49] Is it acceptable to derail treatment and inconvenience a psychiatric patient, but not a cancer patient?

Previous FDA efforts to “simplify” the clozapine REMS requirements and reduce patient burden have failed. The monitoring flexibility granted by the 2021 REMS changes and the “enforcement discretion” notices have only increased confusion.[50,51] Patient obstacles go far beyond the package insert, REMS literature, and public notices. Doctors are broadly unwilling to prescribe clozapine, and pharmacies hesitate to dispense it, often expressing great pride in upholding even stricter policies than the REMS requires. The existence of a REMS program has contributed to the widespread misperception that clozapine is a “very dangerous drug,” rather than the safest medicine based on longevity data.[52] Clinicians repeat the tragically misinformed mantra that clozapine is only prescribed as a “last resort,” even though this classification is not found in any official treatment guidelines.[53]

The barriers to clozapine treatment are profound: prescriber reluctance, transportation, laboratory mix-ups, fear of needles, denied blood draws for unpaid balances, data entry delays, REMS program confusion, non-participating pharmacies, and even mistaking clozapine for a controlled substance with addiction risks. Beyond these “technical” issues are the patients themselves. Cognitive impairment, poor insight, and uncooperative and paranoid behaviors can completely preclude all hopes of participation in the clozapine REMS. For those afflicted and for those who love and care for them, this represents the utter loss of hope in accessing this lifesaving medication.

Clozapine patients and families already face agonizing stigma, discrimination, and mistreatment. The inability to strictly comply with the clozapine REMS requirements often means unbearable torment, suffering, and death. These hardships exist because of an outdated policy that overstated the risks of clozapine’s adverse effects and the decades-long failure to modify strict monitoring procedures.

Clozapine Saves Lives and Remains the “Gold Standard”

• Psychosis disorders are deadly and dangerous illnesses with high risks of suicide and violence, especially toward caregivers.[54,55,56,57,58,59]

• Clozapine is the only medication effective for TRS; it is the only broad-spectrum antipsychotic that works for patients who have responded sub-optimally to prior medications.[60,61,62]

• Clozapine is unique among all available therapies as the only medication FDA-approved for reducing risks of recurrent suicidal behaviors in psychosis disorders.

• Clozapine reduces violence, aggression and prevents incarceration.[63,64,65,66]

• Clozapine significantly reduces hospitalization and healthcare costs.[67,68,69]

• Clozapine improves the quality of life for patients with Serious Mental Illness (SMI).[70,71]

• With its two totally unique indications, treatment-resistant schizophrenia and recurrent suicidal behavior, there is no substitute for clozapine.

For these reasons alone, REMS mandates should be promptly removed from clozapine product labeling since these regulations interfere with smooth access to an irreplaceable medicine. Regulators must intelligently weigh the crucial balance between benefits and risks. With 35 years of well-established effectiveness, clozapine’s benefits dramatically outweigh the risks. This would be true without rigid ANC monitoring and without a REMS program. The clozapine REMS, though well-intended, has become counter-productive. The REMS program itself creates far more hazards than it prevents.

All antipsychotic medications have adverse effects, some potentially fatal. Several other medications have similar or higher hematological risks compared to clozapine, including other neuropsychiatric medications (e.g., carbamazepine[72,73,74]). Yet clozapine remains the only medication with a product label requiring strict mandatory blood testing and participation in a rigid REMS program as a condition for treatment. This reflects deep discrimination against psychosis disorders and those who treat them.

The clozapine REMS is outright cruel. Imagine a diabetic being denied a weekly ration of insulin if they could not produce a timely lab report for the pharmacists. Yet this is exactly what is happening with lifesaving clozapine treatment for vulnerable psychiatric patients. Few within this population have the resources, support, or cognitive ability to navigate the complex protocol required to obtain clozapine prescription refills.

The Angry Moms offers the perspective of the individual patient and family. There is a broader perspective in the interest of protecting public welfare and the public budget. Nationally, suicide rates have reached an 80-year high,[75] and completed suicide is a major cost to society. Poor access to clozapine also means society is experiencing more unnecessary violence, homelessness, and disability.[76,77] Increasing clozapine utilization has significant public health implications. As protectors of US health and government funds, the FDA has an obligation to remove barriers to this vital medication.

Our formal requests:

• Eliminate the clozapine Risk Evaluation and Mitigation Strategy (REMS).

• Discontinue all pharmacy dispense authorizations contingent on hematological test results and authorize all pharmacies to dispense any lawful and active clozapine prescription.

• Discontinue all prescriber and pharmacy pre-certification requirements necessary to prescribe and dispense clozapine.

• Adopt the attached proposed revisions to the clozapine product label to improve patient safety and access to treatment.

Thank you for your time and attention to this matter of great concern to us and our loved ones.

Sincerely,

The Angry Moms

---------

Flaws in the Current Clozapine Label:

The Angry Moms has reviewed numerous studies and cataloged the clozapine patient experience within our community. We have identified the following problems and inaccuracies.

• Overly ominous boxed warnings and extreme language surrounding severe neutropenia compared to product label warnings for other medications with similar or higher hematological risks.[78,79]

• The separate and sequential wording of the two FDA-approved indications has contributed to the false impression that treatment resistance must be established before using clozapine to treat recurrent suicidal behavior.

• The use of the phrase “severely ill” in the indication for Treatment-Resistant Schizophrenia (TRS) is not a medically accurate term and incorrectly implies that clozapine should only be used “as a last resort.”

• The indication for TRS incorrectly uses the word “only” for use in patients who have failed standard antipsychotic treatment and fails to properly define treatment resistance per the American Psychiatric Association (APA) guidelines.[80]

• Exclusion of White Blood Cell count (WBC) as a preliminary testing option, removed in 2005, eliminating the possibility of a finger stick alternative to full venous blood draws.

• Lack of emphasis on the need for antipsychotic substitution and mitigations of cholinergic rebound in the event of an abrupt interruption.[81,82]

• Missing essential guidance that minor variations in hematological parameters, including mild and moderate neutropenia, may be unrelated to clozapine.[40,41,42]

• Lack of explicit instruction that it is NOT appropriate to abruptly interrupt or discontinue clozapine treatment solely due to the absence of a routine blood test result.

• No reference to the importance of maintaining access to medication without limits on dispensed quantities or emergency doses.

• Content does not reflect recent research regarding age and genetic risk factors linked to developing severe neutropenia associated with clozapine.[22,83,84,85,86]

• Threshold-based guidance for ANC monitoring promotes abrupt interruption in treatment for mild or moderate neutropenia without considering the possibility of concurrent medications or other conditions.[42]

• Initial dosing and titrations are based on the original six-week clinical trials with parameters appropriate for White male populations that do not reflect a newer understanding of clozapine metabolism in vulnerable and diverse populations and the dangerous effects of rapid titration.7,10,[87,88]

• Implications that Benign Ethnic Neutropenia (BEN) affecting many African Americans and other ethnicities must be verified by a geneticist or hematologist before modified ANC thresholds are applied, rather than based on observation.[89]

• Failure to address vital and necessary means of removing barriers to clozapine treatment, including less invasive methods for patient monitoring.

Our proposed edits to the product label reflect corrections based on decades of clinical experience, research, best practices for patient safety, and common sense. Above all, implementing our recommendations will offer long-overdue respect for patients, families, clinicians, and all those affected by serious psychiatric illnesses.

Click to download PDF of The Angry Moms proposed clozapine product label: 

Proposed Clozapine Label Changes (TAM) FDA-2024-N-3617

.pdf

Download PDF • 123KB

Sources:

[1] The Angry Moms Advocacy Group www.theangrymoms.com

[2] The Clozapine REMS www.newclozapinerems.com

[3] Example of current generic clozapine product label: https://www.accordhealthcare.us/wp-content/uploads/2022/07/Clozapine_PIL.pdf

[4] Stroup, T. S., Gerhard, T., Crystal, S., Huang, C., & Olfson, M. (2014). Geographic and Clinical Variation in Clozapine Use in the United States. Psychiatric Services, 65(2), 186–192. https://doi.org/10.1176/appi.ps.201300180

[5] Sheitman, B. B., Catlett, T. L., & Zarzar, T. R. (2019). Limited Availability and Use of Clozapine in State Prisons. Psychiatric Services, 70(3), 256–256. https://doi.org/10.1176/appi.ps.201800470

[6] de Leon J. (2022). The history of clozapine in clinical practice: From its introduction to a guideline proposing personalized titrations. Journal of psychopharmacology (Oxford, England), 36(6), 657–660. https://doi.org/10.1177/02698811221101059

[7] Brandt, A. S., Nucifora, F. C., Jr, Zandi, P. P., & Margolis, R. L. (2024). The timing and severity of clozapine-associated neutropenia in the US: Is the risk overstated?. Schizophrenia research, 272, 104–109. https://doi.org/10.1016/j.schres.2024.08.018

[8] Kelly, D. L., Kreyenbuhl, J., Dixon, L., Love, R. C., Medoff, D., & Conley, R. R. (2007). Clozapine underutilization and discontinuation in African Americans due to leucopenia. Schizophrenia bulletin, 33(5), 1221–1224. https://doi.org/10.1093/schbul/sbl068

[9] Ventura, A. M. B., Hayes, R. D., & Fonseca de Freitas, D. (2022). Ethnic disparities in clozapine prescription for service-users with schizophrenia-spectrum disorders: a systematic review. Psychological medicine, 52(12), 2212–2223. https://doi.org/10.1017/S0033291722001878

[10] de Leon, J., Ruan, C. J., Schoretsanitis, G., & De Las Cuevas, C. (2020). A Rational Use of Clozapine Based on Adverse Drug Reactions, Pharmacokinetics, and Clinical Pharmacopsychology. Psychotherapy and psychosomatics, 89(4), 200–214. https://doi.org/10.1159/000507638

[11] Clozapine FDA approval September 26th, 1989: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019758  

[12] Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., Arndt, T., Bäckers, L., Rothe, P., Cipriani, A., Davis, J., Salanti, G., & Leucht, S. (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet (London, England), 394(10202), 939–951. https://doi.org/10.1016/S0140-6736(19)31135-3

[13] Stroup, T. S., Gerhard, T., Crystal, S., Huang, C., & Olfson, M. (2016). Comparative Effectiveness of Clozapine and Standard Antipsychotic Treatment in Adults With Schizophrenia. The American journal of psychiatry, 173(2), 166–173. https://doi.org/10.1176/appi.ajp.2015.15030332

[14] Taipale, H., Tanskanen, A., Mehtälä, J., Vattulainen, P., Correll, C.U. and Tiihonen, J. (2020), 20-year follow-up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry, 19: 61-68. https://doi.org/10.1002/wps.20699

[15] Vermeulen, J. M., van Rooijen, G., van de Kerkhof, M. P. J., Sutterland, A. L., Correll, C. U., & de Haan, L. (2019). Clozapine and Long-Term Mortality Risk in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years. Schizophrenia bulletin, 45(2), 315–329. https://doi.org/10.1093/schbul/sby052

[16] Hayes, R., Johnny Downs, Chin-Kuo Chang, Richard G. Jackson, Hitesh Shetty, Matthew Broadbent, Matthew Hotopf, Robert Stewart, The Effect of Clozapine on Premature Mortality: An Assessment of Clinical Monitoring and Other Potential Confounders, Schizophrenia Bulletin, Volume 41, Issue 3, May 2015, Pages 644–655, https://doi.org/10.1093/schbul/sbu120

[17] Wimberley, T., MacCabe, J. H., Laursen, T. M., Sørensen, H. J., Astrup, A., Horsdal, H. T., Gasse, C., & Støvring, H. (2017). Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia. The American journal of psychiatry, 174(10), 990–998. https://doi.org/10.1176/appi.ajp.2017.16091097

[18] Walker, A. M., Lanza, L. L., Arellano, F., & Rothman, K. J. (1997). Mortality in current and former users of clozapine. Epidemiology (Cambridge, Mass.), 8(6), 671–677. https://doi.org/10.1097/00001648-199710000-00010

[19] Alvir, J. M., Lieberman, J. A., Safferman, A. Z., Schwimmer, J. L., & Schaaf, J. A. (1993). Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. The New England journal of medicine, 329(3), 162–167. https://doi.org/10.1056/NEJM199307153290303

[20] Honigfeld, G., Arellano, F., Sethi, J., Bianchini, A., & Schein, J. (1998). Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. The Journal of clinical psychiatry, 59 Suppl 3, 3–7. https://pubmed.ncbi.nlm.nih.gov/9541331/

[21] Rubio, J. M., Kane, J. M., Tanskanen, A., Tiihonen, J., & Taipale, H. (2024). Long-term persistence of the risk of agranulocytosis with clozapine compared with other antipsychotics: a nationwide cohort and case-control study in Finland. The lancet. Psychiatry, S2215-0366(24)00097-X. Advance online publication. https://doi.org/10.1016/S2215-0366(24)00097-X

[22] Taylor, D., Vallianatou, K., Whiskey, E., Dzahini, O., & MacCabe, J. (2022). Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis. Schizophrenia (Heidelberg, Germany), 8(1), 21. https://doi.org/10.1038/s41537-022-00232-0

[23] Magistri, C., & Mellini, C. (2023). Clozapine-Associated Agranulocytosis: A Systematic Review. Is It Really So Frighteningly Common?. Journal of clinical psychopharmacology, 43(6), 527–533. https://doi.org/10.1097/JCP.0000000000001765

[24] Myles, N., Myles, H., Xia, S., Large, M., Kisely, S., Galletly, C., Bird, R., & Siskind, D. (2018). Meta-analysis examining the epidemiology of clozapine-associated neutropenia. Acta psychiatrica Scandinavica, 138(2), 101–109. https://doi.org/10.1111/acps.12898

[25] Khan, A. A., Harvey, J., & Sengupta, S. (2013). Continuing clozapine with granulocyte colony-stimulating factor in patients with neutropenia. Therapeutic advances in psychopharmacology, 3(5), 266–271. https://doi.org/10.1177/2045125313476877

[26] Schulte P. (2006). Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. The Annals of pharmacotherapy, 40(4), 683–688. https://doi.org/10.1345/aph.1G396

[27] Krupp, P., & Barnes, P. (1992). Clozapine-associated agranulocytosis: risk and aetiology. The British journal of psychiatry. Supplement, (17), 38–40. https://pubmed.ncbi.nlm.nih.gov/1418887/

[28] Douglas C. Throckmorton, M.D. and Patrizia Cavazzoni, M.D., U.S. Food and Drug Administration response to Docket No. FDA 2020-P-1073, citizen petition dated March 9, 2020 by Dr. David Behar.

[29] de la Chapelle, A., Kari, C., Nurminen, M., & Hernberg, S. (1977). Clozapine-induced agranulocytosis. A genetic and epidemiologic study. Human genetics, 37(2), 183–194. https://doi.org/10.1007/BF00393581

[30] Ingimarsson, O., MacCabe, J. H., Haraldsson, M., Jónsdóttir, H., & Sigurdsson, E. (2016). Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland. BMC psychiatry, 16(1), 441. https://doi.org/10.1186/s12888-016-1167-0

[31] Oloyede, E., Dzahini, O., Abolou, Z., Gee, S., Whiskey, E., Malhotra, D., Hussain, M., Osborne, I., Casetta, C., McGuire, P., MacCabe, J. H., & Taylor, D. (2023). Clinical impact of reducing the frequency of clozapine monitoring: controlled mirror-image cohort study. The British journal of psychiatry : the journal of mental science, 223(2), 382–388. https://doi.org/10.1192/bjp.2023.44

[32] Li, X. H., Zhong, X. M., Lu, L., Zheng, W., Wang, S. B., Rao, W. W., Wang, S., Ng, C. H., Ungvari, G. S., Wang, G., & Xiang, Y. T. (2020). The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies. Psychological medicine, 50(4), 583–594. https://doi.org/10.1017/S0033291719000369

[33] Sing, C. W., Wong, I. C., Cheung, B. M., Chan, J. C., Chu, J. K., & Cheung, C. L. (2017). Incidence and risk estimate of drug-induced agranulocytosis in Hong Kong Chinese. A population-based case-control study. Pharmacoepidemiology and drug safety, 26(3), 248–255. https://doi.org/10.1002/pds.4156

[34] Meltzer, H. Y., Alphs, L., Green, A. I., Altamura, A. C., Anand, R., Bertoldi, A., Bourgeois, M., Chouinard, G., Islam, M. Z., Kane, J., Krishnan, R., Lindenmayer, J. P., Potkin, S., & International Suicide Prevention Trial Study Group (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Archives of general psychiatry, 60(1), 82–91. https://doi.org/10.1001/archpsyc.60.1.82

[35] Tiihonen, J., Lönnqvist, J., Wahlbeck, K., Klaukka, T., Niskanen, L., Tanskanen, A., & Haukka, J. (2009). 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet (London, England), 374(9690), 620–627. https://doi.org/10.1016/S0140-6736(09)60742-X

[36] Torrey EF, Knable MB, Quanbeck C, et al.: Clozapine for Treating Schizophrenia: A Comparison of the States. Arlington, VA, Treatment Advocacy Center, November 2015, https://www.tac.org/wp-content/uploads/2023/11/Clozapine-for-Treating-Schizophrenia.pdf

[37] Messamore, E. (2021, November 2) This One Fix Could Prevent 50,000 Suicide Deaths. Erik Messamore blog. https://erikmessamore.com/this-one-fix-could-prevent-50000-suicide-deaths/

[38] Warnez, S., & Alessi-Severini, S. (2014). Clozapine: a review of clinical practice guidelines and prescribing trends. BMC psychiatry, 14, 102. https://doi.org/10.1186/1471-244X-14-102

[39] Meltzer H. Y. (1997). Treatment-resistant schizophrenia--the role of clozapine. Current medical research and opinion, 14(1), 1–20. https://doi.org/10.1185/03007999709113338

[40] Gee, S., & Taylor, D. (2021). COVID-19 infection causes a reduction in neutrophil counts in patients taking clozapine. Journal of psychiatry & neuroscience : JPN, 46(2), E232–E237. https://doi.org/10.1503/jpn.200208

[41] Taylor, D., Vallianatou, K., Gandhi, S., Casetta, C., Howes, O., & MacCabe, J. (2024). Severe neutropenia unrelated to clozapine in patients receiving clozapine. Journal of psychopharmacology (Oxford, England), 38(7), 624–635. https://doi.org/10.1177/02698811241262767

[42] Demler, T. L., & Trigoboff, E. (2011). Are clozapine blood dyscrasias associated with concomitant medications?. Innovations in clinical neuroscience, 8(4), 35–41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105838/

[43] Young, K.D., (2022, March 3) Clozapine Interrupted: APA, Others Seek FDA Forum on REMS. Medscape Family Medicine. https://www.medscape.com/viewarticle/969634

[44] Frysh, P. (2023, May 24) Schizophrenia: Is the FDA Hindering the Most Effective Med? WebMD, https://www.webmd.com/schizophrenia/features/schizophrenia-fda-hindering-clozapine

[45] The Angry Moms, (2023, April 3) The FDA Has Blood on Their Hands. The Angry Moms blog. https://www.theangrymoms.com/post/the-fda-has-blood-on-their-hands

[46] Schizophrenia & Psychosis Action Alliance. (2022, November 2), Schizophrenia Externally-Led Patient Focused Drug Development Meeting [Video]. YouTube. https://youtu.be/F9F3BiFsrhk

[47] National Alliance on Mental Illness (2023). New Clozapine REMS Update: Impact Survey. https://www.nami.org/NAMI/media/NAMI-Media/Research/NAMI-Clozapine-REMS-Survey-Summary-5-22_1.pdf

[48] Highlights of prescribing information IBRANCE® (palbociclib) capsules, for oral use Initial U.S. Approval: 2015 https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207103s002lbl.pdf

[49] Highlights of prescribing information KISQALI® (ribociclib) tablets, for oral use. Initial U.S. Approval: 2017 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209092s003lbl.pdf)

[50] Moran, M. (2022). APA Joins in Negotiations Over New Problematic Clozapine REMS. Psychiatric News, 57(01). https://doi.org/10.1176/appi.pn.2022.2.21

[51] Moran, M. (2022). APA Files FOIA Request With FDA Seeking Resolution to Clozapine REMS Problems. Psychiatric News, 57(4). https://doi.org/10.1176/appi.pn.2022.04.4.53

[52] Oloyede, E., Blackman, G., Mantell, B., Harris, E., Williams, J., Taylor, D., MacCabe, J., & McGuire, P. (2023). What are the barriers and facilitators of clozapine use in early psychosis? A survey of UK early intervention clinicians. Schizophrenia (Heidelberg, Germany), 9(1), 26. https://doi.org/10.1038/s41537-023-00353-0

[53] Jakobsen, M. I., Austin, S. F., Storebø, O. J., Nielsen, J., & Simonsen, E. (2023). Non-prescribing of clozapine for outpatients with schizophrenia in real-world settings: The clinicians' perspectives. Schizophrenia (Heidelberg, Germany), 9(1), 91. https://doi.org/10.1038/s41537-023-00423-3

[54] Sher, L., & Kahn, R. S. (2019). Suicide in Schizophrenia: An Educational Overview. Medicina (Kaunas, Lithuania), 55(7), 361. https://doi.org/10.3390/medicina55070361

[55] Palmer, B. A., Pankratz, V. S., & Bostwick, J. M. (2005). The lifetime risk of suicide in schizophrenia: a reexamination. Archives of general psychiatry, 62(3), 247–253. https://doi.org/10.1001/archpsyc.62.3.247

[56] Bertelsen, M., Jeppesen, P., Petersen, L., Thorup, A., Øhlenschlaeger, J., le Quach, P., Christensen, T. Ø., Krarup, G., Jørgensen, P., & Nordentoft, M. (2007). Suicidal behaviour and mortality in first-episode psychosis: the OPUS trial. The British journal of psychiatry. Supplement, 51, s140–s146. https://doi.org/10.1192/bjp.191.51.s140

[57] Walsh, E., Buchanan, A., & Fahy, T. (2002). Violence and schizophrenia: examining the evidence. The British journal of psychiatry : the journal of mental science, 180, 490–495. https://doi.org/10.1192/bjp.180.6.490

[58] Glick, I. D., Cerfolio, N. E., Kamis, D., & Laurence, M. (2021). Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. Journal of clinical psychopharmacology, 41(4), 366–369. https://doi.org/10.1097/JCP.0000000000001417

[59] Onwumere, J., Grice, S., Garety, P., Bebbington, P., Dunn, G., Freeman, D., Fowler, D., & Kuipers, E. (2014). Caregiver reports of patient-initiated violence in psychosis. Canadian journal of psychiatry. Revue canadienne de psychiatrie, 59(7), 376–384. https://doi.org/10.1177/070674371405900705

[60] Masuda, T., Misawa, F., Takase, M., Kane, J. M., & Correll, C. U. (2019). Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics: A Systematic Review and Meta-analysis of Cohort Studies. JAMA psychiatry, 76(10), 1052–1062. https://doi.org/10.1001/jamapsychiatry.2019.1702

[61] Mizuno, Y., McCutcheon, R. A., Brugger, S. P., & Howes, O. D. (2020). Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 45(4), 622–631. https://doi.org/10.1038/s41386-019-0577-3

[62] Wagner, E., Siafis, S., Fernando, P. et al. Efficacy and safety of clozapine in psychotic disorders—a systematic quantitative meta-review. Transl Psychiatry 11, 487 (2021). https://doi.org/10.1038/s41398-021-01613-2

[63] Frogley, C., Taylor, D., Dickens, G., & Picchioni, M. A systematic review of the evidence of clozapine's anti-aggressive effects, International Journal of Neuropsychopharmacology, Volume 15, Issue 9, October 2012, Pages 1351–1371, https://doi.org/10.1017/S146114571100201X

[64] Buckley, P., Bartell, J., Donenwirth, K., Lee, S., Torigoe, F., & Schulz, S. C. (1995). Violence and schizophrenia: clozapine as a specific antiaggressive agent. The Bulletin of the American Academy of Psychiatry and the Law, 23(4), 607–611. https://pubmed.ncbi.nlm.nih.gov/8639988/

[65] Andreea, T., Petru, I., Miron, A. A., Paula-Simina, P., & Lorena, D. (2021). Clozapine for Treatment-Refractory Aggressive Behavior. The Psychiatric quarterly, 92(2), 721–733. https://doi.org/10.1007/s11126-020-09839-x

[66] Mela, M., & Depiang, G. (2016). Clozapine's Effect on Recidivism Among Offenders with Mental Disorders. The journal of the American Academy of Psychiatry and the Law, 44(1), 82–90. https://pubmed.ncbi.nlm.nih.gov/26944747/

[67] Tiihonen, J., Haukka, J., Taylor, M., Haddad, P. M., Patel, M. X., & Korhonen, P. (2011). A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. The American journal of psychiatry, 168(6), 603–609. https://doi.org/10.1176/appi.ajp.2011.10081224

[68] Kesserwani, J., Kadra, G., Downs, J., Shetty, H., MacCabe, J. H., Taylor, D., Stewart, R., Chang, C. K., & Hayes, R. D. (2019). Risk of readmission in patients with schizophrenia and schizoaffective disorder newly prescribed clozapine. Journal of psychopharmacology (Oxford, England), 33(4), 449–458. https://doi.org/10.1177/0269881118817387

[69] Gören, J. L., Rose, A. J., Smith, E. G., & Ney, J. P. (2016). The Business Case for Expanded Clozapine Utilization. Psychiatric services (Washington, D.C.), 67(11), 1197–1205. https://doi.org/10.1176/appi.ps.201500507

[70] Verma, M., Grover, S., & Chakrabarti, S. (2021). Effectiveness of clozapine on quality of life and functioning in patients with treatment-resistant schizophrenia. Nordic journal of psychiatry, 75(2), 135–144. https://doi.org/10.1080/08039488.2020.1811374

[71] Kim, S., Kim, S., Choe, A. Y., & Kim, E. (2021). Associations of Clozapine Use With Psychosocial Functioning and Quality of Life in Patients With Schizophrenia: A Community-Based Cross-Sectional Study. Psychiatry investigation, 18(10), 968–976. https://doi.org/10.30773/pi.2021.0190

[72] Maan JS, Duong T vi H, Saadabadi A. Carbamazepine. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK482455/

[73] Daughton, J. M., Padala, P. R., & Gabel, T. L. (2006). Careful monitoring for agranulocytosis during carbamazepine treatment. Primary care companion to the Journal of clinical psychiatry, 8(5), 310–311. https://doi.org/10.4088/pcc.v08n0510a

[74] Ibáñez, L., Vidal, X., Ballarín, E., & Laporte, J. R. (2005). Population-based drug-induced agranulocytosis. Archives of internal medicine, 165(8), 869–874. https://doi.org/10.1001/archinte.165.8.869

[75] Curtin, S.C., Garnett, M.F., & Ahmad, F.B. Vital Statistics Rapid Release, Provisional Estimates of Suicide by Demographic Characteristics, United States, 2022. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics National Vital Statistics System Vital Statistics Surveillance Report, No. 34, November 2023 https://www.cdc.gov/nchs/data/vsrr/vsrr034.pdf

[76] Shangraw, K., Schmutz, C., Dowdle, T., Kelley, R., Porter, C., Reynolds, M., … Kious, B. (2024). Medical, Psychiatric, and Sociodemographic Predictors of Clozapine Initiation at an Academic Medical Center. Psychiatric Research and Clinical Practice, 6(3), 104–111. https://doi.org/10.1176/appi.prcp.20240056

[77] Kaneda, Y., Jayathilak, K., & Meltzer, H. (2010). Determinants of work outcome in neuroleptic-resistant schizophrenia and schizoaffective disorder: cognitive impairment and clozapine treatment. Psychiatry research, 178(1), 57–62.

https://doi.org/10.1016/j.psychres.2009.04.001

[78] Highlights of prescribing information TEGRETOL (carbamazepine) tablets, for oral use Novartis Rev. February 2009 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016608s101,018281s048lbl.pdf)

[79] Highlights of prescribing information AZULFIDINE (sulfasalazine) tablets, for oral administration Pfizer Rev. 2009 https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/007073s133lbl.pdf

[80] American Psychiatric Association, The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia, Third Edition September 01, 2020. Page 66.  https://doi/book/10.1176/appi.books.9780890424841

[81] Blackman, G., Oloyede, E., Horowitz, M., Harland, R., Taylor, D., MacCabe, J., & McGuire, P. (2022). Reducing the Risk of Withdrawal Symptoms and Relapse Following Clozapine Discontinuation-Is It Feasible to Develop Evidence-Based Guidelines?. Schizophrenia bulletin, 48(1), 176–189. https://doi.org/10.1093/schbul/sbab103

[82] Meyer, J. M., & Stahl, S. M. (2020). The Clozapine Handbook: Stahl's Handbooks (Stahl's Essential Psychopharmacology Handbooks) (pp. 78-89). Cambridge University Press. https://doi.org/10.1017/9781108553575

[83] Goldstein, J. I., Jarskog, L. F., Hilliard, C., Alfirevic, A., Duncan, L., Fourches, D., Huang, H., Lek, M., Neale, B. M., Ripke, S., Shianna, K., Szatkiewicz, J. P., Tropsha, A., van den Oord, E. J., Cascorbi, I., Dettling, M., Gazit, E., Goff, D. C., Holden, A. L., Kelly, D. L., … Sullivan, P. F. (2014). Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nature communications, 5, 4757. https://doi.org/10.1038/ncomms5757

[84] Valevski, A., Klein, T., Gazit, E., Meged, S., Stein, D., Elizur, A., Narinsky, E. R., Kutzuk, D., & Weizman, A. (1998). HLA-B38 and clozapine-induced agranulocytosis in Israeli Jewish schizophrenic patients. European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics, 25(1), 11–13. https://doi.org/10.1046/j.1365-2370.1998.00091.x

[85] Saito, T., Ikeda, M., Mushiroda, T., Ozeki, T., Kondo, K., Shimasaki, A., Kawase, K., Hashimoto, S., Yamamori, H., Yasuda, Y., Fujimoto, M., Ohi, K., Takeda, M., Kamatani, Y., Numata, S., Ohmori, T., Ueno, S., Makinodan, M., Nishihata, Y., Kubota, M., … Iwata, N. (2016). Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population. Biological psychiatry, 80(8), 636–642. https://doi.org/10.1016/j.biopsych.2015.12.006

[86] Legge, S. E., & Walters, J. T. (2019). Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Pharmacogenomics, 20(4), 279–290. https://doi.org/10.2217/pgs-2018-0188

[87] Correll, C. U., Agid, O., Crespo-Facorro, B., de Bartolomeis, A., Fagiolini, A., Seppälä, N., & Howes, O. D. (2022). A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia. CNS drugs, 36(7), 659–679. https://doi.org/10.1007/s40263-022-00932-2

[88] de Leon, J., Ruan, C. J., Schoretsanitis, G., Rohde, C., Yağcıoğlu, E. A., Baptista, T., Kirilochev, O. O., De Las Cuevas, C., & Correll, C. U. (2022). An international guideline with six personalised titration schedules for preventing myocarditis and pneumonia associated with clozapine. General psychiatry, 35(3), e100773. https://doi.org/10.1136/gpsych-2022-100773

[89] Kelly, D. L., Freudenreich, O., Sayer, M. A., & Love, R. C. (2018). Addressing Barriers to Clozapine Underutilization: A National Effort. Psychiatric services (Washington, D.C.), 69(2), 224–227. https://doi.org/10.1176/appi.ps.201700162

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