Clozapine for Schizophrenia

Overseen By Craig J Parris, MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 6 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether Clozapine, a medication for schizophrenia, is more effective than other antipsychotics in reducing inflammation and improving symptoms. Researchers aim to determine if Clozapine lowers inflammatory markers, such as interleukin-6, which might explain its effectiveness. The trial includes individuals with schizophrenia that hasn't improved with other treatments and who have been on their current medication for at least six months. Participants may already be on Clozapine or another antipsychotic but eligible for Clozapine. As a Phase 4 trial, Clozapine is already FDA-approved and proven effective, and this research seeks to understand how it benefits more patients.

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 is the safety track record for these treatments?

Research shows that clozapine effectively treats schizophrenia, especially for those who haven't improved with other treatments. Studies have found that clozapine reduces symptoms better than many other antipsychotic drugs. However, awareness of possible side effects is important.

Clozapine can cause serious but rare side effects, such as lowering white blood cell counts, which weakens the immune system. Regular blood tests often monitor this. Some people may also experience weight gain, drowsiness, or increased saliva.

The other antipsychotic drugs in the study are generally well-tolerated but can have different side effects. Common issues include weight gain, dizziness, or restlessness.

Overall, while both treatment options have risks, they are well-established and widely used. Participants should discuss any concerns with their healthcare provider. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Clozapine is unique because it's often used when other antipsychotic medications don't work for schizophrenia. Unlike most antipsychotic drugs that primarily target dopamine receptors, Clozapine also affects several other neurotransmitter systems, which can help manage symptoms that are resistant to treatment. Researchers are excited about Clozapine because it has shown potential in reducing suicidal behavior in patients and improving overall treatment outcomes. This makes it a valuable option for those who haven't found success with typical antipsychotics.

What is the effectiveness track record for Clozapine in treating schizophrenia?

Research shows that Clozapine, which participants in this trial may receive, outperforms other antipsychotic medications for treating schizophrenia, particularly in individuals unresponsive to other treatments. Studies have found that Clozapine reduces schizophrenia symptoms, measured by the Positive and Negative Syndrome Scale (PANSS). It remains the only medication approved for cases where other treatments have failed. Additionally, Clozapine helps reduce the risk of suicidal behavior in these patients. Although the reasons for Clozapine's superior effectiveness are not fully understood, its better results are well-documented. Participants in the non-Clozapine arm will receive other antipsychotic medications for comparison in this trial. ^{4 5 6 7 8}

Are You a Good Fit for This Trial?

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've been on a non-Clozapine antipsychotic for 6+ months and haven't tried Clozapine for specific reasons.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Antipsychotics,Other (non-Clozapine)
• Clozapine

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.

How Is the Trial Designed?

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

Antipsychotics,Other (non-Clozapine) is already approved in United States, European Union for the following indications:

Approved in United States as Zyprexa for:

• Schizophrenia
• Bipolar Disorder

Approved in European Union as Zyprexa for:

• Schizophrenia
• Bipolar Disorder
• Major Depressive Disorder

Who Is Running the Clinical Trial?

Ohio State University

Lead Sponsor

Trials

891

Recruited

2,659,000+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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 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]

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]

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]

Clozapine demonstrated superior efficacy compared to haloperidol in treating positive symptoms of schizophrenia in outpatients who had previously shown partial response to other treatments, with 8 out of 19 clozapine patients meeting clinical responder criteria.

While clozapine also showed some effectiveness in reducing negative symptoms, this was more pronounced in patients with nondeficit schizophrenia, indicating its potential utility across a broader range of schizophrenia patients beyond just the severely ill.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Breier, A., Buchanan, RW., Kirkpatrick, B., et al.[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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40023172/

a systematic review and individual patient data meta-analysis The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) between clozapine and other ...

2. thelancet.com thelancet.com/journals/lanpsy/article/PIIS2215-0366(25)00001-X/fulltext

a systematic review and individual patient data meta-analysis IPD were requested from trial investigators. The primary outcome was change in overall schizophrenia symptoms as measured by the Positive and ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2215036625001634

Real-world effectiveness of clozapine augmentation with ... Only 40% of people with treatment-resistant schizophrenia will have an adequate response to clozapine. Data on the effect of antidepressant augmentation on ...

4. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2824666

Comparative Effectiveness of Antipsychotics in Patients ... Our results also suggest that clozapine, which is the criterion standard for treatment-resistant schizophrenia, performed better on relapse ...

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/ajp.156.7.990

Evidence of Clozapine's Effectiveness in Schizophrenia This meta-analysis confirms that clozapine is more effective than conventional neuroleptics in reducing symptoms of patients with both treatment-resistant and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8458455/

Efficacy and safety of clozapine in psychotic disorders—a ... Clozapine appears to have superior effects on positive, negative, and overall symptoms and relapse rates in schizophrenia.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2215036625002974

Transdiagnostic effectiveness and safety of clozapine in ... Our results show that clozapine is more effective than other oral antipsychotics in reducing psychiatric hospitalisations and several secondary ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31365048/

A Systematic Review and Meta-analysis of Cohort Studies In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes.