Clozapine for Schizophrenia

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Ohio State University

Must be taking: Antipsychotics

Must not be taking: Lithium, Immunomodulatory, Anti-inflammatory

Disqualifiers: Cardiovascular, Pulmonary, Endocrine, Renal, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The specific aim of this protocol is to compare Clozapine treatment vs Non-Clozapine antipsychotic treatment in a population of treatment-refractory individuals with schizophrenia. Specifically, it is to test if Clozapine leads to a decrease in levels of inflammatory markers, namely interleukin-6 but with an exploratory view of other markers. Clozapine has superior efficacy and is the only medication approved for treatment-refractory schizophrenia in addition to decreasing the risk of suicidal behavior as well. It is unclear why Clozapine has increased efficacy from a mechanistic viewpoint. We will look at the role of inflammatory markers and assess them 1x along with rating scales for psychosis and suicidality, the other entities which Clozapine has been shown to improve.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are currently taking lithium, immunomodulatory, or anti-inflammatory therapy, you cannot participate in the trial.

What data supports the effectiveness of the drug clozapine for treating schizophrenia?

Research shows that clozapine is more effective than some other antipsychotic drugs in improving symptoms in people with schizophrenia who have not responded well to other treatments. It also has fewer side effects related to movement disorders compared to older drugs like chlorpromazine. ^{1 2 3 4 5}

Is clozapine safe for humans?

Clozapine has several safety concerns, including serious risks like blood disorders (neutropenia and agranulocytosis), seizures, heart problems (myocarditis and cardiomyopathy), and metabolic issues (diabetes). It requires careful monitoring to manage these risks and maximize its benefits. ^{6 7 8 9 10}

How is the drug clozapine different from other treatments for schizophrenia?

Clozapine is unique because it is the only antipsychotic specifically approved for treatment-resistant schizophrenia, meaning it is used when other medications have not worked. It is known for its effectiveness in reducing both positive symptoms (like hallucinations) and negative symptoms (like lack of emotion) in patients who do not respond to other treatments, but it requires careful monitoring due to potential serious side effects. ^{11 12 13 14 15}

Research Team

Eligibility Criteria

This trial is for individuals aged 18-40 with treatment-refractory schizophrenia, who are physically healthy and can consent to the study. Participants will either start Clozapine or continue non-Clozapine antipsychotics. Exclusions include significant medical conditions, recent infections, chronic viral infections, autoimmune diseases, past Clozapine use within 6 months, immunomodulatory therapy use, recent vaccinations, substance abuse disorders, pregnancy or intellectual disability.

Inclusion Criteria

I am physically healthy with no major unstable health conditions.

Participants must be able to give informed consent

I am between 18 and 65 years old.

Exclusion Criteria

Unwilling or unable to sign informed consent document

I am currently taking lithium.

I have a history of autoimmune or chronic inflammatory conditions.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive either Clozapine or non-Clozapine antipsychotic treatment for at least 6 months

6 months

1 visit (in-person)

Follow-up

Participants are monitored for changes in inflammatory markers and symptom rating scales

Up to 1 year

Treatment Details

Interventions

• Antipsychotics,Other (non-Clozapine) (Other)
• Clozapine (Other)

Trial Overview The trial aims to compare the effects of Clozapine versus other antipsychotics on inflammatory markers in people with hard-to-treat schizophrenia. It explores whether starting Clozapine reduces levels of interleukin-6 among other markers and assesses its impact on psychosis and suicidality.

Participant Groups

Group I: Clozapine Arm Experimental Treatment 1 Intervention

Patients will be on Clozapine for at least 6 months

Group II: Non-Clozapine arm Active Control 1 Intervention

Patients will be on non-Clozapine antipsychotic for at least 6 months

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Dr. John J. Warner

Ohio State University

Chief Executive Officer since 2023

MD, MBA

Dr. Peter Mohler

Ohio State University

Chief Medical Officer since 2023

PhD in Molecular Biology

Findings from Research

Clozapine was found to be more effective than chlorpromazine in treating newly admitted, acutely psychotic schizophrenic patients, showing better overall improvement and higher discharge rates.

Unlike chlorpromazine, clozapine did not cause extrapyramidal side effects, making it a safer option for patients, although it did have side effects like sedation and hypotension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. Shopsin, B., Klein, H., Aaronsom, M., et al.[2019]

Clozapine is more effective than other second-generation antipsychotic drugs in improving symptoms for patients with schizophrenia who have not responded to two or more previous treatments, as shown by a significant reduction in the PANSS total score in a study of 136 participants over one year.

While clozapine did not show a significant advantage in Quality of Life scores compared to other SGAs, it was associated with fewer extrapyramidal side effects and reported better mental health by participants at 12 weeks, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Lewis, SW., Barnes, TR., Davies, L., et al.[2022]

Olanzapine has been authorized for treating schizophrenia, but its specific effects on positive or negative symptoms have not been proven due to a lack of relevant trials.

While olanzapine shows similar overall efficacy to haloperidol and does not outperform risperidone, it has fewer neurological side effects than haloperidol; however, it can cause weight gain and other adverse effects, necessitating ongoing monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine. Keep an eye on this neuroleptic. [2022]

Clozapine is a significant advancement in treating schizophrenia, showing superior efficacy in managing symptoms and cognitive function compared to typical neuroleptic drugs, and it does not cause tardive dyskinesia.

Other novel antipsychotic medications, such as risperidone and olanzapine, show promise but require further research to confirm their effectiveness compared to clozapine and traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the pharmacotherapy of schizophrenia. Meltzer, HY., Lee, MA., Ranjan, R.[2019]

Clozapine is effective for many treatment-resistant patients, but about 60% of these patients in Denmark also take additional medications, often classical neuroleptics, to enhance treatment outcomes.

The paper presents two case studies suggesting that combining risperidone with clozapine may improve treatment efficacy, although this combination has not been rigorously studied before.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risperidone augmentation of clozapine. McCarthy, RH., Terkelsen, KG.[2013]

Clozapine is an effective antipsychotic with a unique clinical profile, but it carries significant safety risks, including potentially life-threatening conditions like neutropenia, seizures, and myocarditis.

A thorough understanding of clozapine's safety profile is essential for maximizing its benefits while minimizing risks, making careful monitoring crucial during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of clozapine safety. Fitzsimons, J., Berk, M., Lambert, T., et al.[2013]

Risperidone and olanzapine, two novel antipsychotics, show improved efficacy and safety compared to conventional antipsychotic medications in treating schizophrenia, based on a synthesis of randomized clinical trials.

Risperidone demonstrated clearer benefits in symptom control compared to olanzapine, and patients on these novel medications were less likely to need additional treatment for extrapyramidal symptoms, indicating a better overall safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The clinical value of risperidone and olanzapine: A meta-analysis of efficacy and safety. Peuskens Marc De Hert Michael Jones, J.[2014]

The review highlights the cardiovascular side effects associated with novel antipsychotic medications, including clozapine, risperidone, olanzapine, quetiapine, and ziprasidone, emphasizing the importance of understanding these risks as they are used as first-line treatments.

The manuscript provides clinical guidelines for the safe use of these antipsychotics, aiming to improve patient management and minimize cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular side effects of novel antipsychotics. Gupta, S., Masand, PS., Gupta, S.[2022]

A study of 104 patients prescribed clozapine revealed that the most common reasons for hospitalization were pulmonary (32.2%) and gastrointestinal (19.8%) illnesses, with pneumonia being the leading cause of pulmonary admissions.

While clozapine is known for serious side effects like agranulocytosis and seizures, this study found that gastrointestinal and pulmonary issues were more prevalent in hospitalizations, highlighting the need for further research on these adverse events and better management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of Admission Types in Medically Hospitalized Patients Prescribed Clozapine. Leung, JG., Hasassri, ME., Barreto, JN., et al.[2018]

Clozapine is an effective treatment for severe resistant schizophrenia, but its safety profile during pregnancy and labor is not well understood, highlighting the need for awareness among healthcare providers.

The case presented demonstrates the successful management of an emergency caesarean section in a patient on clozapine, suggesting that with proper care, it is possible to safely perform surgical procedures in patients taking this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications for anaesthesia in a patient established on clozapine treatment. Doherty, J., Bell, PF., King, DJ.[2013]

Patients with treatment-resistant schizophrenia experienced a significant average delay of 47.7 months before starting clozapine, highlighting a gap in timely treatment despite its effectiveness.

Before initiating clozapine, a notable percentage of patients (36.2%) were on multiple antipsychotics and 34.2% were receiving high doses, indicating that current treatment practices often do not align with established guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Howes, OD., Vergunst, F., Gee, S., et al.[2021]

A new nomogram was developed to predict the need for ICU admission in patients with acute clozapine intoxication, showing a high accuracy of 80.8% and an area under the curve (AUC) of 83.9% based on factors like age, respiratory rate, O2 saturation, and blood glucose levels.

External validation of the nomogram demonstrated even higher accuracy (96.2%) and AUC (99.2%), making it a valuable tool for clinicians, especially in low-resource settings, to quickly assess the severity of clozapine intoxication and determine the need for intensive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a risk prediction nomogram for disposition of acute clozapine intoxicated patients to intensive care unit. Sharif, AF., Aouissi, HA., Kasemy, ZA., et al.[2023]

Lurasidone, an atypical antipsychotic, showed significant improvement in treatment-resistant schizophrenia (TRS) patients, with 41.8% of participants experiencing at least a 20% reduction in symptoms over a 6-month trial.

The study found that lurasidone was effective at both 80 mg and 240 mg doses, with improvements comparable to other antipsychotics like clozapine, but required a longer treatment duration to see significant results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lurasidone Improves Psychopathology and Cognition in Treatment-Resistant Schizophrenia. Meltzer, HY., Share, DB., Jayathilake, K., et al.[2022]

Clozapine is effective for treating psychotic symptoms in patients with nonschizophrenic disorders, such as bipolar disorder and schizoaffective disorder, and is particularly beneficial for those who have not responded to other treatments.

While clozapine has a lower risk of causing extrapyramidal side effects, making it suitable for patients with Parkinson's disease and those experiencing tardive dyskinesia, its potential risk of agranulocytosis means it is not a first-choice treatment for psychotic symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Uses of clozapine in nonschizophrenic patients. Frankenburg, FR., Zanarini, MC.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Clozapine, chlorpromazine, and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. [2022]

3. Canada pubmed.ncbi.nlm.nih.gov

Olanzapine. Keep an eye on this neuroleptic. [2022]

4. Denmark pubmed.ncbi.nlm.nih.gov

Recent advances in the pharmacotherapy of schizophrenia. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Risperidone augmentation of clozapine. [2013]

6. England pubmed.ncbi.nlm.nih.gov

A review of clozapine safety. [2013]

7. England pubmed.ncbi.nlm.nih.gov

The clinical value of risperidone and olanzapine: A meta-analysis of efficacy and safety. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Cardiovascular side effects of novel antipsychotics. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Characterization of Admission Types in Medically Hospitalized Patients Prescribed Clozapine. [2018]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Implications for anaesthesia in a patient established on clozapine treatment. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Development and validation of a risk prediction nomogram for disposition of acute clozapine intoxicated patients to intensive care unit. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. [2019]

14. United States pubmed.ncbi.nlm.nih.gov

Lurasidone Improves Psychopathology and Cognition in Treatment-Resistant Schizophrenia. [2022]

15. United States pubmed.ncbi.nlm.nih.gov

Uses of clozapine in nonschizophrenic patients. [2019]