We’re in a Mental Health Crisis. Why Do We Refuse to Help People with Treatment-Resistant Schizophrenia?

90% of our country believes we are facing a mental health crisis.1 And whenever there is a tragic incident in New York City, our City and State say that yet another person with schizophrenia has fallen through the cracks.2 We have a solution staring us in the face which can help alleviate suffering, improve quality of life, and reduce the burden of disease for many who are suffering with persisting psychosis due to schizophrenia. We largely refuse to use it, leaving our city’s most vulnerable at risk and in an endless cycle of psychiatric hospitalizations, homelessness, and incarceration.

Abstract illustration concept of schizophrenia

According to a recent report, schizophrenia costs the US an estimated $281.6 billion annually.3 Costs for patients with persisting psychosis, often referred to as treatment-resistant schizophrenia (TRS), are 3 to 11-fold higher.4 Left untreated, psychosis – a collection of symptoms that affect the mind, where there has been some loss of contact with reality – poses severe debilitation.5 However, with proper care, many individuals will thrive, with a significantly reduced risk of tragic premature death,6 and go on to lead healthy, productive, and fulfilling lives.

At the forefront of treatment for persisting psychosis (TRS) stands clozapine, a medication renowned for its efficacy. It is the gold standard therapy, outperforming all other antipsychotics in symptom management, proven reduction in suicide, and quality of life improvement.7,8 Despite its proven effectiveness, only a fraction of individuals who could potentially benefit from clozapine receive it – roughly 2-4% of all cases – a travesty that underscores systemic failures in mental health care.9

The history of clozapine dates to its initial use in the 1960s, when it emerged as a highly effective treatment option for all psychotic disorders. However, in 1975, sixteen elderly women in a small Finnish village on multiple medications, including clozapine, developed severe neutropenia. This resulted in clozapine’s temporary withdrawal from the market. Clozapine was reintroduced in the US in 1989 after Gil Honigfeld and John Kane’s study demonstrated clozapine’s superiority to other antipsychotics in treatment-resistant schizophrenia.10 It came back on the market with cumbersome strict monitoring protocols in place. Despite its remarkable efficacy, clozapine remained vastly underutilized.11

As it stands now, clozapine, the gold standard treatment for persisting psychosis, is offered as a last resort, often after years of multiple antipsychotics being tried and failed and frequently at the urging of desperate families and loved ones. The delay in offering clozapine is inexcusable. If symptoms persist after two adequate antipsychotic drug trials, there is an insignificant chance of a meaningful recovery with any other medication except clozapine.12,13 Inadequate and delayed treatment of psychosis narrows the window of recovery. This is a huge risk to take, to put someone’s life on the line. To put this in perspective, imagine if the gold standard treatment for cancer was withheld for such a duration. No surgery to remove malignant tumors, no chemotherapy. The outrage would be palpable. So, why is it acceptable for people with serious mental illness?

Various barriers hinder access to clozapine. Physicians, Psychiatrists, and Nurse Practitioners are reluctant to prescribe clozapine for several reasons. These include special monitoring requirements, administrative burden, a lack of prescriber knowledge and confidence, negative prescriber attitudes, unprepared health systems, and inadequate appreciation of clozapine’s unique efficacy by policymakers and payers.14

The primary barrier is the FDA Risk Evaluation and Mitigation Strategies (REMS) for clozapine. Clozapine’s REMS program places a tremendous administrative burden on patients and providers. The program for clozapine is the most restrictive of any other FDA-mandated REMS. The clozapine REMS mandates weekly blood draws for 26 weeks, followed by a mandatory blood draw every two weeks for an additional 26 weeks, after which blood draws are required every four weeks for life. This leads to tragic outcomes as patients face no drug because of no blood scenarios.

The weekly blood monitoring aims to detect the risk of severe neutropenia (agranulocytosis: absolute neutrophil count less than 500). The true risk of severe agranulocytosis in this population is less than 0.5%, and the mortality rate is 2.7-3.1%.15 In this same population, the risk of suicide is 5-10%, and clozapine, compared to other antipsychotics, reduces this risk by greater than 70%.16 Suicidal behavior in patients with psychotic disorders represents a seriously undertreated, life-threatening condition – and clozapine is the only FDA-approved medication for TRS and for suicidal behavior.17

There are numerous tragedies resulting from the inadequate treatment of psychosis, highlighting the devastating impact of clozapine underutilization and abrupt withdrawal. After years of meaningful recovery, a Texas man’s clozapine was discontinued because of a REMS snafu. His rebound psychosis led him to draw a wooden gun on a police officer, resulting in his fatal shooting. One young man’s clozapine ran out on a Friday after the laboratory failed to report his test results, and his clinic was closed all weekend. By Monday morning, his rebound psychosis was so severe he drove disoriented on a freeway and crashed into a wall. While hospitalized for internal bleeding, his psychosis caused him to assault a nurse, and he was arrested shortly after discharge. Why do we allow needless suffering for people with schizophrenia, particularly young adults and their loved ones?

Even the road to recovery can be an almost impossible journey. The torturous five-and-a-half-year struggle of one young man from New York and his family included attempted suicide, nine hospitalizations, and 13 antipsychotics. Once on clozapine, his psychosis resolved. He graduated with honors from a prestigious university and is working at a high level in a career of his choosing. Another young man was subjected to five antipsychotics and, at one point, three simultaneously. He remained paranoid, delusional, and, at times, suicidal. After clozapine, he was able to thrive. He finished college with honors and is now a successful standup comedian in New York City.

There needs to be an investment in educating physicians on the timely, safe, and effective use of clozapine and compensation for diligent patient care and monitoring. And it’s more than time to ease the clozapine REMS requirements to ensure that people with treatment-resistant schizophrenia have access to life-saving treatment. It is inhumane to deny a cancer patient chemotherapy, a diabetes patient insulin, and patients with TRS clozapine.

Not another person should be subjected to these draconian requirements. We urge you to contact the FDA to ease the REMS requirements and invest in physician education. Visit www.naminyc.org/clozapine.

Matt Kudish is CEO of NAMI-NYC, a non-profit helping individuals and families affected by mental illness for over 40 years. Robert Laitman, MD and Ann Mandel-Laitman, MD, are Mental Illness Psychiatric Internists with special expertise in clozapine; Team Daniel: Running for Recovery from Mental Illness. Donna Taylor MSN, RN, Team Daniel Running for Recovery from Mental Illness; Advocate for Caregivers and their loved ones with SMI.

Footnotes

  1. McPhillips, D. 5 October 2022. 90% of US adults say the United States is experiencing a mental health crisis, CNN/KFF poll finds. CNN. https://www.cnn.com/2022/10/05/health/cnn-kff-mental-health-poll-wellness/
  2. Iscoe, A. 10 May 2023. The System That Failed Jordan Neely. The New Yorker. https://www.newyorker.com/magazine/2023/05/22/the-system-that-failed-jordan-neely.
  3. Societal & Caregiver Costs of Schizophrenia & Related Disorders. SCZ Action. https://sczaction.org/insight-initiative/societal-costs/.
  4. Kennedy, J. (2014 March). The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. International Clinical Psychopharmacology. https://pubmed.ncbi.nlm.nih.gov/23995856/.
  5. Understanding psychosis. National Institute of Mental Health. https://www.nimh.nih.gov/health/publications/understanding-psychosis.
  6. Lee, B. et al (3 April 2023). The Protective Effect of Clozapine on Suicide. Journal of Clinical Psychiatry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069951/.
  7. Alphs, L. et. al. (2004). The international suicide prevention trial (interSePT): rationale and design of a trial comparing the relative ability of clozapine and olanzapine to reduce suicidal behavior in schizophrenia and schizoaffective patients. Schizophrenia Bulletin. https://pubmed.ncbi.nlm.nih.gov/15631247/.
  8. Gammon, D. et al (July 2021) Clozapine: Why Is It So Uniquely Effective in the Treatment of a Range of Neuropsychiatric Disorders? Biomolecules. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301879/.
  9. Kelly, D. et al. (2018 February). Addressing Barriers to Clozapine Underutilization: A National Effort. Psychiatric Services. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581998/.
  10. Kane, J. et. al. (1988 September). Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Archives of General Psychiatry. https://pubmed.ncbi.nlm.nih.gov/3046553/.
  11. Sharma, S. et. al. (Jan 2021). Cluster Analysis of Clozapine Consumer Perspectives and Comparison to Consumers on Other Antipsychotics. Schizophrenia Bulletin Open. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521287/.
  12. ‘Last resort’ antipsychotic remains the gold standard for treatment-resistant schizophrenia. (10 February 2019). National Institute for Health and Care Research. https://evidence.nihr.ac.uk/alert/last-resort-antipsychotic-remains-the-gold-standard-for-treatment-resistant-schizophrenia/.
  13. Weiden, P. (2016 May). How Many Treatments Before Clozapine? Medication Choices Across the Spectrum of Treatment Resistance in Schizophrenia. Psychiatrist.com. https://www.psychiatrist.com/jcp/many-treatments-before-clozapine-medication-choices/#:~:text=Clozapine%20was%20approved%20in%201990,criterion%20for%20starting%20clozapine%20treatment.
  14. Kelly, D. (February 2018). Addressing Barriers to Clozapine Underutilization: A National Effort. Psychiatric Services. https://pubmed.ncbi.nlm.nih.gov/29032704/.
  15. Mijovic, A. (August 2020). Clozapine-induced agranulocytosis. Annals of Hematology. https://link.springer.com/article/10.1007/s00277-020-04215-y.
  16. Masdrakis, V. (April 2023). Prevention of suicide by clozapine in mental disorders: systematic review. European Neuropsychopharmacology. https://www.sciencedirect.com/science/article/pii/S0924977X22009300.
  17. Lee, B. et al. (April 2023). The Protective Effect of Clozapine on Suicide: A Population Mortality Study of Statewide Autopsy Records in Maryland. Journal of Clinical Psychiatry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10069951.

One Response

  1. Laura Craciun says:
    August 15, 2024 at 8:45 am

    This was an informative and eye opening article. I’m one of the caregivers for a son with SMI and an advocate in Massachusetts. I am told of so many families unable to find prescribers of Clozapine, or increase their loved one’s dose. One woman had to take her perscriber to court in order to get her to increase her adult son’s dosage. Eventually, she won but for families who are already overburdened with the care of this cruel condition to have to go through this added struggle to access treatment is inhumane.

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