Skip to main content
Full access
Open Forum
Published Online: 9 October 2024

The Underuse of Clozapine and Long-Acting Injectable Antipsychotics

Publication: Psychiatric Services

Abstract

Schizophrenia is among the most devastating and costly human diseases. The public face of the failure to appropriately treat schizophrenia includes approximately 100,000 homeless individuals with schizophrenia and related psychoses and 200,000 incarcerated individuals with similar diagnoses. Clozapine and long-acting injectable antipsychotics are among the most effective treatments, but both are markedly underused. The following organizations should take responsibility for fixing this problem: National Institute of Mental Health, Patient-Centered Outcomes Research Institute, Substance Abuse and Mental Health Services Administration, Centers for Medicare and Medicaid Services, U.S. Food and Drug Administration, American Psychiatric Association, and patient and family advocacy groups.
Schizophrenia places an enormous burden of suffering and cost on individuals, families, and society. The authors of a recent report estimated that in the United States in 2019, the excess economic burden of schizophrenia, a disease affecting approximately 3.9 million individuals, was $343.2 billion (1). The authors noted that this huge cost “highlights the importance of effective strategies and treatment options to improve the management of this difficult-to-treat patient population” (1). Some patients do not have access to treatment; others do not respond to the treatments they receive. Still others do not adhere to treatment; for many, nonadherence is due to a lack of insight into their illness and because the individuals do not believe that they are sick—that is, they have a cognitive deficit called anosognosia.
The most glaring public manifestations of schizophrenia treatment failures are the approximately 100,000 homeless individuals with schizophrenia and related psychoses (2) and the 200,000 people with similar diagnoses who are incarcerated—17% of the 514,000 inmates in local jails and 10% of the 1.2 million in state and federal prisons (3, 4). In addition, although only 4% of violent crime involves persons with mental illness, 20%–30% of mass violence incidents are committed mostly by males with untreated psychotic disorders (5). Given the need for better treatments for schizophrenia, it is puzzling why two of the best treatments—clozapine and long-acting injectable antipsychotics (LAIs)—are markedly underused.

Clozapine

Clozapine became available in the United States in 1989 and is the gold standard among antipsychotics. A meta-analysis reported that it is almost twice as effective as other antipsychotics (6). Clozapine is the only antipsychotic approved by the U.S. Food and Drug Administration (FDA) for decreasing suicidal ideation, has the lowest mortality rate among antipsychotics, and was reported to be more effective than other antipsychotics in decreasing hostility and aggression among patients with schizophrenia (7, 8). Despite its superior properties, only 4% of individuals treated with antipsychotic medication in the United States receive clozapine, compared with rates of 20%–38% in countries such as Germany, Australia, Taiwan, and China (9). What percentage of people with schizophrenia should be treated with clozapine? Dr. John Kane, an expert on the treatment of schizophrenia, suggested that “10% is a bare minimum and 20% would be more appropriate” (10).
The major reasons for the low use of clozapine are side effects. Of primary concern is agranulocytosis, which requires monitoring with periodic blood testing. Myocarditis, seizures, and weight gain are other potential issues that contribute to patients’ reluctance to use the drug. The possible side effects may also contribute to clinicians’ overestimation of patients’ reluctance to use clozapine and clinicians’ fears of legal liability (9, 10).

LAIs

Similarly, LAIs have been available in the United States since 1972. Currently in the United States, 11 formulations of seven antipsychotics with dosing intervals ranging from 2 to 24 weeks are approved for use (see the online supplement to this Open Forum). Studies comparing the efficacy of LAIs with the efficacy of oral antipsychotics have consistently shown the superiority of the former for medication adherence, rate and duration of hospitalizations, and emergency department visits, especially for patients who are typically medication nonadherent (11). Some LAIs may decrease hostility and aggression among individuals with schizophrenia (8).
Despite these useful properties, a 2018 survey of Medicaid beneficiaries with schizophrenia reported that only 15% were receiving an LAI (12). This contrasts with LAI use rates in other developed countries, such as 30% in the United Kingdom (13). A survey of 9,433 U.S. psychiatric outpatient clinics reported that 70% of them did not prescribe LAIs at all, including 40% of clinics that had treatment programs specifically for patients with severe mental illness (14).

Who Is Responsible for Fixing the Problem?

Given the clear rationale for using the best treatments available for schizophrenia and related psychotic disorders, we are surprised that clozapine and LAIs are underused. If the most effective drugs were being underused for other medical conditions such as diabetes, hypertension, or cancer, a great outcry would arise among those affected. For schizophrenia, several stakeholders, noted next, should have some responsibility for correcting the current underuse of clozapine and LAIs.

National Institute of Mental Health (NIMH)

NIMH supports and promotes research to improve the treatment of psychiatric disorders. In 2015, it funded a study that attempted but failed to identify genetic predictors of clozapine-related agranulocytosis. NIMH should now undertake extensive research to determine the reasons for clozapine’s side effects and superior efficacy. Most existing research was conducted 30 years ago and focused on clozapine’s metabolites, its broad spectrum of affinities for multiple neuroreceptors, and its unusual binding to the D2 receptor. Improvements in imaging and other research techniques may allow for a better understanding of clozapine’s side effects and efficacy at this time. Because clozapine is generic, drug companies have little economic incentive to undertake such research, and thus the work is unlikely to get done without NIMH support.

Patient-Centered Outcomes Research Institute (PCORI)

PCORI is an independent organization created by Congress to fund comparative clinical effectiveness research to help patients make better informed decisions. It should fund studies of the various LAIs to identify the superior drugs. The LAIs, like other psychiatric drugs, obtained FDA approval by showing merely that they were superior to placebos, not that they were superior or even equipotent to other LAIs. With rare exceptions, the LAIs have never been compared with each other (15). Such head-to-head treatment trials—the types of studies PCORI is supposed to support—would provide clinicians with more evidence-based data for choosing LAIs and thus promote their greater use.

Substance Abuse and Mental Health Services Administration (SAMHSA)

SAMHSA’s purview includes improving mental health services. It recently initiated the SMI Adviser, a clinical support system for severe mental illness. The program provides free education and consultations for clinicians treating people with severe mental illness, especially on the topic of the use of clozapine. SMI Adviser should also emphasize the use of LAIs. SAMHSA could use financial incentives to promote the use of clozapine and LAIs.

Centers for Medicare and Medicaid Services

The Centers for Medicare and Medicaid Services fund much of the treatment that patients with schizophrenia receive. The centers could use their authority to structure formularies that include incentives for states to promote the use of clozapine and LAIs for patients with schizophrenia. Such approaches would necessarily affect the autonomy of physicians but for justifiable and good purposes, and the results could be empirically evaluated.

FDA

The approval authority the FDA wields over all pharmaceuticals, medical devices, over-the-counter medications, and nutritional supplements could be used to enhance the use of neglected treatments like clozapine and LAIs. One example of a valuable application of this authority would be to mandate phase 4 studies of comparative effectiveness, which would demonstrate the value of treatments like clozapine and LAIs and their cost-effectiveness.

American Psychiatric Association (APA)

APA is the major professional organization for psychiatrists, and it administered the SAMHSA SMI Adviser program. It has a legitimate role in stewarding the practice patterns of psychiatry to ensure that they adhere to the highest standards of care and that its practitioners are fulfilling their professional responsibilities. In addition to its education work, APA should offer educational programs on the use of clozapine and LAIs at its scientific meetings. A psychiatrist with knowledge of APA’s educational programs reports that such education has not occurred very often.

Patient and Family Advocacy Groups

These groups should play an important role in promoting the use of clozapine and LAIs; some already do. For example, the group The Angry Moms has been lobbying to minimize the FDA’s blood-testing requirements for patients taking clozapine so that it may become more widely used (www.theangrymoms.com). As another example, the Treatment Advocacy Center published a report in 2015 titled Clozapine for Treating Schizophrenia: A Comparison of the States (10). In addition, such groups should do direct outreach to patients and their families with appropriately balanced educational materials that help them make better informed treatment decisions.

Conclusions

Schizophrenia is among the most devastating and costly human diseases, and patients need better treatment options. Clozapine and LAIs are among the most effective treatments for this disease but are markedly underused. All government and nongovernment stakeholders are responsible for correcting this situation.

Supplementary Material

File (appi.ps.20240110.ds001.pdf)

References

1.
Kadakia A, Catillon M, Fan Q, et al: The economic burden of schizophrenia in the United States. J Clin Psychiatry 2022; 83:22m14458
2.
Ayano G, Tesfaw G, Shumet S: The prevalence of schizophrenia and other psychotic disorders among homeless people: a systematic review and meta-analysis. BMC Psychiatry 2019; 19:370
3.
Steadman HJ, Osher FC, Robbins PC, et al: Prevalence of serious mental illness among jail inmates. Psychiatr Serv 2009; 60:761–765
4.
James DJ, Beatty LG: Mental Health Problems of Prison and Jail Inmates. Bureau of Justice Statistics Special Report NCJ 213600. Washington, DC, Bureau of Justice Statistics, 2006. https://bjs.ojp.gov/library/publications/mental-health-problems-prison-and-jail-inmates. Accessed Sept 13, 2024
5.
Mass Violence in America: Causes, Impacts and Solutions. Washington DC, National Council for Mental Wellbeing, Medical Director Institute, 2019. https://www.thenationalcouncil.org/resources/mass-violence-in-america-causes-impacts-and-solutions. Accessed Sept 13, 2024
6.
Leucht S, Cipriani A, Spineli L, et al: Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382:951–962
7.
Tiihonen J, Lönnqvist J, Wahlbeck K, et al: 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet 2009; 374:620–627
8.
Victoroff J, Coburn K, Reeve A, et al: Pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders: a systematic review. J Neuropsychiatry Clin Neurosci 2014; 26:283–312
9.
Love RC, Kelly DL, Freudenreich O, et al: Clozapine Underutilization: Addressing the Barriers. Alexandria, VA, National Association of State Mental Health Program Directors, 2016. https://nasmhpd.org/sites/default/files/Assessment%201_Clozapine%20Underutilization.pdf
10.
Torrey EF, Knable MB, Quanbeck C, et al: Clozapine for Treating Schizophrenia: A Comparison of the States. Arlington, VA, Treatment Advocacy Center, 2015. https://www.treatmentadvocacycenter.org/reports_publications/clozapine-for-treating-schizophrenia-a-comparison-of-the-states. Accessed Sept 13, 2024
11.
Kishimoto T, Hagi K, Kurokawa S, et al: Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry 2021; 8:387–404
12.
Patel C, Pilon D, Gupta D, et al: National and regional description of healthcare measures among adult Medicaid beneficiaries with schizophrenia within the United States. J Med Econ 2022; 25:792–807
13.
Bosanac P, Castle DJ: Why are long-acting injectable antipsychotics still underused? BJPsych Adv 2015; 21:98–105
14.
Bunting SR, Chalmers K, Yohanna D, et al: Prescription of long-acting injectable antipsychotic medications among outpatient mental health care service providers. Psychiatr Serv 2023; 74:1146–1153
15.
McEvoy JP, Byerly M, Hamer RM, et al: Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA 2014; 31:1978–1987

Information & Authors

Information

Published In

Go to Psychiatric Services
Go to Psychiatric Services
Psychiatric Services

History

Received: 6 March 2024
Revision received: 30 May 2024
Accepted: 5 August 2024
Published online: 9 October 2024

Keywords

  1. Schizophrenia
  2. Treatment guidelines
  3. Violence/aggression
  4. Jails and prisons/mental health services
  5. Homelessness

Authors

Details

E. Fuller Torrey, M.D. [email protected]
The Stanley Medical Research Institute, Rockville, Maryland (Torrey); Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York City (Lieberman).
Jeffrey Lieberman, M.D.
The Stanley Medical Research Institute, Rockville, Maryland (Torrey); Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York City (Lieberman).

Notes

Send correspondence to Dr. Torrey ([email protected]).

Competing Interests

The authors report no financial relationships with commercial interests. Marvin S. Swartz, M.D., served as action editor for this Open Forum.

Funding Information

These views represent the opinions of the authors and not necessarily those of the Stanley Medical Research Institute or Columbia University Vagelos College of Physicians and Surgeons.

Metrics & Citations

Metrics

Citations

Export Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format
Citation style
Style
Copy to clipboard

View Options

View options

PDF/EPUB

View PDF/EPUB

Get Access

Login options

Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.

Personal login Institutional Login Open Athens login

Not a subscriber?

Subscribe Now / Learn More

PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

Media

Figures

Other

Tables

Share

Share

Share article link

Share