Studies Clear Up Confusion Surrounding Clozapine

by Denis Storey
June 17, 2024 at 6:59 AM UTC

A growing contingent has called for fewer clozapine restrictions, while concerns about side effects and treatment disparities persist.

Clinical relevance: A growing contingent has called for fewer clozapine restrictions, while concerns about side effects and treatment disparities persist.

  • Clozapine’s benefits in managing treatment-resistant schizophrenia continue to surpass its risks.
  • Clozapine, recognized as the optimal treatment for severe or treatment-resistant psychotic disorders, remains underused despite its effectiveness.
  • A recent case report highlights a rare adverse effect of clozapine on a 65-year-old male patient with intellectual disability, autism spectrum disorder, and schizophrenia.

As clozapine, the atypical, antipsychotic known for treating schizophrenia, earns enough widespread use, some are calling for fewer regulations.

Multiple studies have shown that the risk of adverse events drops after even a few months. And as recently as April, the U.S. Food and Drug Administration (FDA) announced it would “discuss the reevaluation of the Clozapine Risk Evaluation and Mitigation Strategy (REMS).”

The Journal of Clinical Psychiatry and The Primary Care Companion for CNS Disorders has published multiple papers and even a case study that examines the latest research on the antipsychotic. We’ve compiled the relevant summaries and links for further review.

Research Ties Clozapine to Increased Risk of Hematologic Malignancies

The medical community has long restricted clozapine to treatment-resistant cases due to its adverse effect profile. Now recent studies have raised concerns over a potential link between the drug and hematologic malignancies such as lymphomas, leukemias, and myeloma.

A Finnish study – working with a national cohort of schizophrenia patients – spotted a link between clozapine use and hematologic cancers. In this study, users had more than double the odds of developing these malignancies. A separate World Health Organization analysis supported these findings. That report found a 9.1-fold increase in lymphoma reports and a 3.5-fold increase in leukemia reports among clozapine users.

Further bolstering these results, a new study replicated the Finnish findings using data from the US Veterans Health Administration. This research identified 2,306 schizophrenia patients with hematologic malignancies and matched them with 23,043 controls. The analysis revealed that clozapine users had a 31% higher risk of these cancers.

Despite the compelling association, experts emphasize the context. Researchers linked the drug to a 10% reduction in overall mortality for schizophrenia patients.a benefit that outweighs the small absolute increase in cancer risk. Regular monitoring, including monthly blood tests, can help detect malignancies early without deterring clozapine use in suitable patients.

While vigilance is necessary, clozapine’s benefits in managing treatment-resistant schizophrenia continue to surpass its risks.

Study Exposes Racial Disparities in Clozapine Treatment for Severe Psychotic Disorders

Clozapine, recognized as the optimal treatment for severe or treatment-resistant psychotic disorders, is significantly underused despite its proven effectiveness.

However, a new study examining data from 11 large U.S. health systems reveals a troubling gap between recommendations and actual usage. Despite evidence supporting clozapine’s superiority in reducing hospitalizations and suicidal behavior, only about 5% of eligible patients receive it. Among Medicaid recipients with multiple hospitalizations, caregivers prescribed clozapine in 5% of new trials. Only 9% of veterans with a history of suicide attempts had ever received clozapine treatment.

The study highlights several barriers to clozapine use, including frequent lab monitoring, side effect concerns, and clinicians’ lack of experience with the drug. Geographic variation suggests local practices influence clozapine use more than the prevalence of treatment-resistant cases.

Racial disparities are also evident. In the United States, non-Hispanic White patients are more than twice as likely to receive clozapine as Black or Hispanic patients, a trend mirrored in UK studies. These disparities persist despite no significant clinical effectiveness or safety differences across racial groups. Historically, monitoring guidelines did not account for benign ethnic neutropenia, affecting patients of African and Middle Eastern descent. But revisions in 2016 addressed this.

Using data from 11 health systems, the study analyzed clozapine use among patients with severe psychotic disorders experiencing specific indicators for the drug. The findings reveal that fewer than 2% of these patients start clozapine within a year, with even lower rates among Black and Hispanic patients.

This underutilization and racial disparity call for systematic, multicomponent interventions to increase clozapine uptake where clinically indicated and ensure equitable treatment across all racial and ethnic groups.

Case Study Reveals Urinary Retention as a Rare Clozapine Adverse Effect

A recent case report in PCC highlights a rare adverse effect of clozapine on a 65-year-old male patient with intellectual disability, autism spectrum disorder, and schizophrenia. This patient experienced significant urinary retention and required emergency medical intervention.

The patient, who was nonverbal and had a history of noncompliance with medications like risperidone and topiramate, was admitted to the emergency department from his group home due to severe agitation and aggressive behavior. After risperidone failed to improve his condition, they switched his treatment to clozapine. They then gradually increased the dosage to 200 mg twice daily.

Despite the medication adjustments, including the addition of valproate and topiramate for mood stabilization, the patient’s condition did not improve. Three days after starting clozapine, he developed severe lower abdominal pain and decreased urinary output. Doctors also added clonazepam to his regimen for anxiety. Given his intellectual disability, doctors monitored the patient constantly to prevent falls and aggressive outbursts.

As the patient’s oral intake worsened, leading to ketonuria, a medical evaluation revealed trace pleural effusion at his left lung base. He was transferred to a medical floor and required nasogastric tube feeding, and straight catheterization for worsening urinary retention. The psychiatric team then reduced the clozapine dose, resulting in improved urinary function and behavior after 4-5 days. Ultimately, the patient stabilized on a reduced clozapine dose of 25 mg twice daily. Doctors also prescribed valproate, topiramate, and tamsulosin for urinary retention.

This case underscores the importance of recognizing clozapine’s anticholinergic side effects, which can lead to severe bladder control issues. The patient’s improvement upon dose reduction highlights the necessity of careful medication monitoring in managing such adverse effects.

Further Reading

Clozapine Use and Specific Indications

Why Clozapine is Still an Essential Antipsychotic

Managing Clozapine in Primary Care Settings

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