Clozapine vs Risperidone for Psychosis

Recruiting at4 trial locations

Overseen by Carol A Tamminga, MD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Antipsychotics

Must not be taking: Lithium, Anticonvulsants, Benzodiazepines, others

Disqualifiers: Substance abuse, Neurological conditions, others

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The CLOZAPINE study is designed as a multisite study across 5 sites and is a clinical trial, involving human participants who are prospectively assigned to an intervention. The study will utilize a stringent randomized, double-blinded, parallel group clinical trial design. B2 group will serve as psychosis control with risperidone as medication control. The study is designed to evaluate effect of clozapine on the B1 participants, and the effect that will be evaluated is a biomedical outcome. The study sample will be comprised of individuals with psychosis, including 1) schizophrenia, 2) schizoaffective disorder and 3) psychotic bipolar I disorder. The investigators plan to initially screen and recruit n=524 (from both the existing B-SNIP library and newly-identified psychosis cases, \~50% each) in order to enroll n=320 (B1 and B2) into the RCT.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that affect EEG properties or interact with the study drugs, such as lithium, anticonvulsants, benzodiazepines, and some antibiotics and seizure medications. If you are on these, you may need to discontinue them safely before participating.

What data supports the effectiveness of the drugs clozapine and risperidone for treating psychosis?

Clozapine has been shown to be effective in up to 60% of patients with treatment-resistant schizophrenia, and it provides significant symptom improvement over other second-generation antipsychotic drugs. Risperidone may be equally effective as clozapine in some cases, but more research is needed to confirm this. ^{1 2 3 4 5}

What safety data exists for Clozapine and Risperidone?

Clozapine can cause serious blood disorders, seizures, heart problems, and weight gain, and requires regular blood monitoring to manage risks. Risperidone is generally considered safer but may still have side effects like weight gain and metabolic changes. ^{6 7 8 9 10}

How does the drug clozapine differ from other treatments for psychosis?

Clozapine is unique because it is specifically effective for treatment-resistant schizophrenia, meaning it works for patients who do not respond to other antipsychotic drugs. Unlike many other antipsychotics, clozapine has a low D2-blocking effect, which can make it necessary to combine it with other medications to fully manage symptoms. ^{1 5 9 11 12}

Research Team

Carol A Tamminga, MD

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for adults aged 18-60 with schizophrenia, schizoaffective disorder, or bipolar I with psychotic features. Participants must be medically stable, have a certain level of symptom severity, and not belong to vulnerable groups like pregnant women. They shouldn't have used clozapine before or certain long-acting antipsychotics recently.

Inclusion Criteria

Able to provide written informed consent

I am between 18 and 60 years old.

Able to read, speak, and understand English

Exclusion Criteria

You have had a severe allergic reaction called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or Drug-Induced Hypersensitivity Syndrome (DIHS) in the past.

I do not have severe neurological or medical conditions affecting my brain.

You are currently having thoughts about hurting someone and have a detailed plan on how to do it, which means you cannot receive treatment as an outpatient.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive clozapine or risperidone treatment, with concomitant medications for symptomatic management

14 weeks

Regular visits for monitoring and dose adjustments

Stable Treatment

Participants continue on a stable dose of clozapine or risperidone

8 weeks

Regular visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Clozapine (Atypical Antipsychotic)
• Risperidone (Atypical Antipsychotic)

Trial Overview The study compares the effects of clozapine versus risperidone on individuals with specific types of psychosis. It's a rigorous test where participants are randomly assigned to one of the drugs in a controlled environment across multiple sites to see which drug works better for their condition.

Participant Groups

Group I: Biotype 1 - Clozapine (B1C) Experimental Treatment 1 Intervention

Target doses will be up to clozapine 500mg po qd. In addition, several concomitant (open label) medications for symptomatic management will be available via the study protocol \[non-benzodiazepine sleep aid (melatonin, hydroxyzine); motor side effect treatments (benztropine, propranolol)\]. The doses for these medications will be consistent with those routinely used in a clinical practice: melatonin \[up to 10mg at bedtime\], hydroxyzine \[up to 100mg at bedtime\]; benztropine \[up to 4mg/day (2mg twice/day)\], propranolol \[up to 40mg/day (20mg twice/day)\].

Group II: Biotype 2 - Clozapine (B2C) Active Control 1 Intervention

Target doses will be up to clozapine 500mg po qd. In addition, several concomitant (open label) medications for symptomatic management will be available via the study protocol \[non-benzodiazepine sleep aid (melatonin, hydroxyzine); motor side effect treatments (benztropine, propranolol)\]. The doses for these medications will be consistent with those routinely used in a clinical practice: melatonin \[up to 10mg at bedtime\], hydroxyzine \[up to 100mg at bedtime\]; benztropine \[up to 4mg/day (2mg twice/day)\], propranolol \[up to 40mg/day (20mg twice/day)\].

Group III: Biotype 1 - Risperidone (B1R) Placebo Group 1 Intervention

Target doses will be up to risperidone 6mg po qd. In addition, several concomitant (open label) medications for symptomatic management will be available via the study protocol \[non-benzodiazepine sleep aid (melatonin, hydroxyzine); motor side effect treatments (benztropine, propranolol)\]. The doses for these medications will be consistent with those routinely used in a clinical practice: melatonin \[up to 10mg at bedtime\], hydroxyzine \[up to 100mg at bedtime\]; benztropine \[up to 4mg/day (2mg twice/day)\], propranolol \[up to 40mg/day (20mg twice/day)\].

Group IV: Biotype 2 - Risperidone (B2R) Placebo Group 1 Intervention

Target doses will be up to risperidone 6mg po qd. In addition, several concomitant (open label) medications for symptomatic management will be available via the study protocol \[non-benzodiazepine sleep aid (melatonin, hydroxyzine); motor side effect treatments (benztropine, propranolol)\]. The doses for these medications will be consistent with those routinely used in a clinical practice: melatonin \[up to 10mg at bedtime\], hydroxyzine \[up to 100mg at bedtime\]; benztropine \[up to 4mg/day (2mg twice/day)\], propranolol \[up to 40mg/day (20mg twice/day

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Daniel K. Podolsky

University of Texas Southwestern Medical Center

Chief Executive Officer since 2008

MD from Harvard Medical School

Robert L. Bass

University of Texas Southwestern Medical Center

Chief Medical Officer since 2019

MD from University of Texas Southwestern Medical School

University of Georgia

Collaborator

Trials

109

Recruited

43,500+

Dr. Biao He

University of Georgia

Chief Executive Officer

PhD in Veterinary Medicine

Dr. Hank Radziewicz

University of Georgia

Chief Medical Officer

MD from Duke University, MSCR from Emory University

Hartford Hospital

Collaborator

Trials

140

Recruited

19,700+

Dr. Ajay Kumar

Hartford Hospital

Chief Medical Officer since 2016

MD, University of Connecticut School of Medicine

Jeffrey A. Flaks

Hartford Hospital

Chief Executive Officer since 2019

Master's in Health Administration, George Washington University

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Dr. Joshua A. Gordon

National Institute of Mental Health (NIMH)

Chief Executive Officer since 2016

MD, PhD

Dr. Shelli Avenevoli

National Institute of Mental Health (NIMH)

Chief Medical Officer

PhD

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

Dr. Kevin Tabb

Beth Israel Deaconess Medical Center

Chief Executive Officer since 2021

MD from Hebrew University Hadassah Medical School

Dr. Chi Chang Daniel Siao

Beth Israel Deaconess Medical Center

Chief Medical Officer since 2023

MD from King George’s Medical University

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Pete Salzmann

University of Chicago

Chief Executive Officer since 2018

MD from University of Chicago’s Pritzker School of Medicine, MBA from Stanford University’s Graduate School of Business

Anh Nguyen

University of Chicago

Chief Medical Officer

MD from Rutgers New Jersey Medical School, MBA from University of Chicago

Findings from Research

In a study of 24 chronically institutionalized patients with refractory schizophrenia, clozapine was found to be more effective than risperidone, with 58% of patients responding to clozapine compared to only 25% responding to risperidone.

Clozapine showed significant improvements in managing aggressive behavior (71% response) and positive symptoms (38% response), while risperidone had lower response rates across all symptom domains, suggesting that clozapine remains the gold standard for treatment despite the better risk/benefit profile of risperidone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative efficacy of risperidone and clozapine in the treatment of patients with refractory schizophrenia or schizoaffective disorder: a retrospective analysis. Sharif, ZA., Raza, A., Ratakonda, SS.[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]

Risperidone may serve as an effective alternative to clozapine for treating refractory schizophrenia, as shown in a study with 19 participants over 10 weeks, where both medications led to clinical improvements without significant differences in outcomes.

The study found that both treatments resulted in similar levels of symptom reduction and patient satisfaction, suggesting that further larger-scale trials are needed to confirm these findings and explore the potential of risperidone as a standard treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study. Wahlbeck, K., Cheine, M., Tuisku, K., et al.[2022]

Clozapine was found to be more effective than risperidone in reducing positive symptoms of schizophrenia and parkinsonian side effects in a study of 29 patients over 6 weeks.

Both medications showed similar efficacy for negative symptoms and depression, but clozapine had fewer effects on plasma prolactin levels compared to risperidone, suggesting a potentially safer profile regarding hormonal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Breier, AF., Malhotra, AK., Su, TP., et al.[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]

Clozapine is effective for treating schizophrenia but carries a significant risk of serious blood disorders, while newer atypical antipsychotics may offer similar efficacy with potentially fewer severe side effects.

The review of eight studies suggests that newer atypical antipsychotics may improve social functioning compared to clozapine, but the evidence is limited and requires further research with larger, longer trials to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newer atypical antipsychotic medication versus clozapine for schizophrenia. Tuunainen, A., Wahlbeck, K., Gilbody, SM.[2018]

Clozapine has been shown to be more effective than other antipsychotics for treating refractory positive symptoms of schizophrenia, with a systematic review of 14 clinical trials indicating superiority in most cases.

Clozapine has a low risk of extrapyramidal symptoms (EPS) compared to other neuroleptics, but careful monitoring is necessary due to potential serious side effects like agranulocytosis and myocarditis, especially in young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Leponex, 10 years after -- a clinical review]. Llorca, PM., Pere, JJ.[2020]

Risperidone (RIS) has been shown to significantly improve symptoms in 43% of clozapine-resistant schizophrenic or schizoaffective patients, based on a review of 15 studies involving 86 patients.

While RIS is generally effective as an adjunct treatment, it can cause side effects such as extrapyramidal symptoms (9.3%) and sedation (7%), highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risperidone augmentation of clozapine: a critical review. Kontaxakis, VP., Ferentinos, PP., Havaki-Kontaxaki, BJ., et al.[2022]

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]

Clozapine remains the only antipsychotic specifically approved for treatment-refractory schizophrenia, having undergone extensive testing in patients who did not respond to other medications.

Recent studies have begun to compare clozapine with newer atypical antipsychotics like risperidone and olanzapine, which are better tolerated but have shown varying success in patients with poor responses to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing treatment-resistant schizophrenia: evidence from randomized clinical trials. Citrome, L., Bilder, RM., Volavka, J.[2019]

In a 28-day randomized double-blind trial involving 59 patients with paranoid hallucinatory psychoses, risperidone (both 4 mg and 8 mg) was found to be better tolerated than clozapine (400 mg), with fewer drop-outs due to side effects.

Both risperidone and clozapine demonstrated significant and clinically relevant antipsychotic effects, suggesting that risperidone could be a viable alternative to clozapine for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double blind, randomized trial. Heinrich, K., Klieser, E., Lehmann, E., et al.[2022]

References

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

Comparative efficacy of risperidone and clozapine in the treatment of patients with refractory schizophrenia or schizoaffective disorder: a retrospective analysis. [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. England pubmed.ncbi.nlm.nih.gov

Risperidone versus clozapine in treatment-resistant schizophrenia: a randomized pilot study. [2022]

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

Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. [2013]

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

Newer atypical antipsychotic medication versus clozapine for schizophrenia. [2018]

8. France pubmed.ncbi.nlm.nih.gov

[Leponex, 10 years after -- a clinical review]. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Risperidone augmentation of clozapine: a critical review. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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

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

Managing treatment-resistant schizophrenia: evidence from randomized clinical trials. [2019]

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

Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double blind, randomized trial. [2022]