Clozapine vs Risperidone for Psychosis

Recruiting at 4 trial locations

Overseen By Emily McNeil

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

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 This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 weeks

524 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two medications, clozapine and risperidone, to determine which is more effective for treating psychosis. It targets individuals with schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Participants will be randomly assigned to receive either clozapine or risperidone to understand how each medication affects symptoms. This study suits those diagnosed with one of these conditions who experience significant symptoms impacting daily life. As a Phase 4 trial, the treatment has already received FDA approval and proven effective, and this research aims to understand how it benefits more patients.

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 is the safety track record for these treatments?

Research has shown that clozapine is generally well-tolerated for treating psychotic disorders like schizophrenia. It reduces symptoms and lowers the risk of relapses. However, clozapine can cause a rare but serious side effect called agranulocytosis, where the body doesn't produce enough white blood cells, weakening the immune system. Fortunately, this risk is low, affecting only 0.8% of people over a year, and it becomes even less common after the first six months of treatment.

Clozapine is often recommended for individuals who do not respond to other treatments. It has been shown to reduce suicidal behavior in patients, even those not considered treatment-resistant. This makes it a trusted option for many doctors when other medications fail. While clozapine is generally safe, patients are usually monitored closely to detect any side effects early. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because clozapine and risperidone offer different approaches to managing psychosis. Clozapine is unique as it is often considered a last-resort medication due to its effectiveness in treatment-resistant cases, offering hope for patients who haven't responded to other antipsychotics like aripiprazole or quetiapine. Meanwhile, risperidone is known for its ability to address both positive symptoms of psychosis, like hallucinations and delusions, and negative symptoms, such as withdrawal and lack of motivation. The combination of these treatments in the trial could provide insights into more tailored approaches for individuals with distinct biotypes of psychosis, potentially improving outcomes by matching patients to the most effective treatment for their specific needs.

What evidence suggests that this trial's treatments could be effective for psychosis?

Research has shown that clozapine, one of the treatments under study in this trial, effectively treats psychosis, particularly in conditions like schizophrenia and schizoaffective disorder. Studies have found that clozapine outperforms other medications in reducing symptoms and preventing relapses. It addresses both positive symptoms, such as hallucinations, and negative symptoms, like lack of motivation. Clozapine can also reduce substance abuse and suicidal thoughts in individuals with psychosis. Overall, clozapine is considered the best option when other treatments have failed. Participants in this trial may receive either clozapine or risperidone, another treatment option being evaluated for its effectiveness in managing psychosis. ^{3 4 5 6 7}

Who Is on the Research Team?

Carol A Tamminga, MD

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

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

Able to read, speak, and understand English

My health condition is currently stable.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Clozapine
• Risperidone

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.

How Is the Trial Designed?

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

Clozapine is already approved in United States, European Union for the following indications:

Approved in United States as Clozaril for:

• Schizophrenia
• Borderline Personality Disorder
• Paranoid Disorder

Approved in European Union as Clozapine for:

• Schizophrenia
• Treatment-resistant schizophrenia

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

University of Georgia

Collaborator

Trials

109

Recruited

43,500+

Hartford Hospital

Collaborator

Trials

140

Recruited

19,700+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Published Research Related to This Trial

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]

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]

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]

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 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 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]

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]

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]

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]

Citations

1. 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.

2. 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 ...

3. 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 ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006322325012703

Review Why Is Clozapine Uniquely Effective in Treatment ... As shown in Table 1, clozapine decreases substance abuse (115), violence (116), and suicidal ideation (111) in patients with psychosis. While ...

5. psychiatryonline.org psychiatryonline.org/doi/10.1176/ps.49.6.829

Cost-Effectiveness of Clozapine Therapy for Severe ... Based on a sample of 20 patients, use of clozapine resulted in estimated cost savings of between $3,000 and $9,000 per patient per year, including the costs of ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK535399/

Clozapine - StatPearls - NCBI Bookshelf Regarding suicide risk, clozapine has been demonstrated to reduce suicidal behavior even in non-treatment-resistant schizophrenia and patients ...

7. movementdisorders.onlinelibrary.wiley.com movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.30295

The FDA Has Ended Required Blood Monitoring for Clozapine ... The cumulative incidence was 0.8% at 12 months, but with very few incident cases after 6 months. Risk of agranulocytosis was independent of dose ...