Once-Daily vs Twice-Daily Clozapine for Schizophrenia

Overseen By Carol Borlido, BSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Centre for Addiction and Mental Health

Must be taking: Clozapine

Disqualifiers: Significant medical, neurological illnesses, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Plasma half-life has routinely been used to establish the dosing schedule of antipsychotics; for example, it is recommended that agents with a short plasma half-life be administered multiple times per day. However, to date, several randomized controlled trials (RCTs) have shown no differences in clinical outcomes between once- and twice-daily dosing of various antipsychotics, suggesting that once-daily dosing of antipsychotics is a viable option regardless of plasma half-life. This would apply to clozapine as well; however, there have been no studies comparing once-daily vs. twice-daily dosing regimens of clozapine in terms of efficacy and tolerability. To address this gap in the literature, the investigators shall conduct a pilot, double-blind, RCT to examine efficacy and tolerability following a switch to once-daily dosing regimen of clozapine in patients with schizophrenia receiving clozapine twice a day.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that you have been taking clozapine twice a day for at least 3 months. It seems you will continue with clozapine, but the dosing schedule might change.

Is once-daily clozapine dosing safe compared to twice-daily dosing?

Research shows that once-daily clozapine dosing has a similar safety profile to twice-daily dosing, with no significant differences in adverse reactions (unwanted side effects) between the two methods. ^{1 2 3 4 5}

How does once-daily clozapine dosing differ from other schizophrenia treatments?

Once-daily clozapine dosing is unique because it simplifies the medication regimen, potentially improving adherence, despite the drug's short half-life which typically suggests twice-daily dosing. This approach is often used to manage side effects like sedation by administering the dose at bedtime. ^{2 3 4 6 7}

What data supports the effectiveness of once-daily versus twice-daily clozapine dosing for schizophrenia?

Research shows that clozapine, a drug for treatment-resistant schizophrenia, is often prescribed once daily to simplify medication regimens and improve adherence, despite the lack of clear evidence favoring once-daily over twice-daily dosing in terms of effectiveness or side effects. ^{1 2 3 4 7}

Who Is on the Research Team?

Gary Remington, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Are You a Good Fit for This Trial?

This trial is for adults over 18 with schizophrenia or schizoaffective disorder, currently taking clozapine twice daily. They must be outpatients, fluent in English, and able to consent. It's not for those with serious medical conditions or women who are pregnant or breastfeeding.

Inclusion Criteria

I have been taking clozapine twice daily, including bedtime, at the same dose for 3 months.

I have been diagnosed with schizophrenia or schizoaffective disorder.

I am not currently admitted to a hospital.

Exclusion Criteria

Having significant medical or neurological illnesses

Pregnant or lactating

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are switched from twice-daily to once-daily clozapine dosing or continue with twice-daily dosing

12 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Switching From Twice-Daily to Once-Daily Clozapine Dosing

Trial Overview The study tests if taking clozapine once a day is as effective and tolerable as the standard twice-daily dose for schizophrenia treatment. Participants will be randomly assigned to one of the dosing schedules in a controlled environment.

How Is the Trial Designed?

Group I: Switch group Experimental Treatment 1 Intervention

Participants will receive clozapine once daily at evening or bedtime throughout the study period. If a participant takes ≥200 mg of clozapine at a time other than evening/bedtime, half of this dose will be switched to an evening/bedtime regimen on day 0 (baseline), then another half dose will be switched on day 7 (week 1). Participants will receive placebo in place of the clozapine dose that was switched to evening/bedtime.

Group II: Maintenance group Active Control 1 Intervention

Participants will continue to take clozapine twice daily throughout the study period.

Switching From Twice-Daily to Once-Daily Clozapine Dosing is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Approved in European Union as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Approved in Canada as Clozaril for:

• Schizophrenia
• Recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Published Research Related to This Trial

In a study of 108 participants, there were no significant differences in the plasma concentrations of clozapine between once-daily and divided dosing regimens, suggesting that once-daily dosing may be just as effective.

Psychiatric symptoms and subjective adverse effects were similar for both dosing strategies, indicating that once-daily dosing could be a feasible alternative in clinical practice for patients on clozapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan. Kitagawa, K., So, R., Nomura, N., et al.[2022]

Clozapine is the most effective treatment for resistant schizophrenia, but its pharmacokinetic properties suggest it should ideally be administered twice daily due to its short half-life and quick dissociation from the dopamine D2 receptor.

Current practices often prescribe clozapine once daily to manage side effects and simplify regimens, but this may not provide optimal therapeutic outcomes, indicating a need for reevaluation of dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine administered once versus twice daily: does it make a difference? Procyshyn, RM., Vila-Rodriguez, F., Honer, WG., et al.[2014]

A study involving 118 patients with treatment-resistant schizophrenia found no significant difference in all-cause discontinuation rates between once-daily and divided dosing of clozapine, suggesting both methods are equally effective.

The safety profiles were also similar for both dosing regimens, indicating that patients can be prescribed either method without increased risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the Effectiveness and Safety of Clozapine Between Once-Daily and Divided Dosing Regimen in Patients With Treatment-Resistant Schizophrenia. Sathienluckana, T., Jansing, T., Srisuriyakamon, S., et al.[2023]

In a study of 159 participants with treatment-resistant schizophrenia, once-daily dosing of clozapine was linked to younger age, better cognitive performance, and lower clinical symptom severity compared to divided dosing regimens.

The once-daily dosing group also had lower trough plasma concentrations of clozapine and norclozapine, suggesting that this regimen may be effective without increasing the risk of severe symptoms or side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily versus divided dosing regimens of clozapine: A cross-sectional study in Singapore. Yang, Z., Takeuchi, H., Yee, JY., et al.[2023]

In a study involving 2810 clozapine-treated individuals, patients on multiple-daily dosing exhibited more severe clinical symptoms and a higher risk of adverse drug reactions (ADRs) compared to those on once-daily dosing, suggesting that multiple dosing may be linked to worse outcomes.

The analysis indicated that patients on multiple-daily dosing were often prescribed higher doses and more co-medications, which could contribute to the increased severity of symptoms and ADRs, highlighting the importance of considering patient preferences and adherence when choosing a dosing regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis. Kuzo, N., Haen, E., Ho, DM., et al.[2023]

In an 18-week study involving 147 patients with treatment-resistant schizophrenia, olanzapine showed similar efficacy to clozapine, with no significant differences in key measures of schizophrenia symptoms or response rates.

Both olanzapine and clozapine were well tolerated, with no significant safety concerns, making olanzapine a viable and safer alternative for patients who cannot tolerate clozapine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. Bitter, I., Dossenbach, MR., Brook, S., et al.[2018]

In a study of 55 treatment-resistant schizophrenia patients, 85% continued clozapine treatment, with significant improvements in BPRS scores observed after 1 month, indicating its efficacy as a long-term treatment option.

Clozapine should be administered as a monotherapy with a gradual dosage increase to minimize side effects, as it was discontinued in a few cases due to adverse effects like leukopenia and neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical experience with clozapine in 55 cases of treatment-resistant schizophrenia]. Enomoto, T., Ito, T., Sekine, K., et al.[2013]

Citations

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

Clozapine Once-Daily Versus Divided Dosing Regimen: A Cross-sectional Study in Japan. [2022]

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

Clozapine administered once versus twice daily: does it make a difference? [2014]

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

Comparison of the Effectiveness and Safety of Clozapine Between Once-Daily and Divided Dosing Regimen in Patients With Treatment-Resistant Schizophrenia. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Once-daily versus divided dosing regimens of clozapine: A cross-sectional study in Singapore. [2023]

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

Clozapine once- versus multiple-daily dosing: a two-center cross-sectional study, systematic review and meta-analysis. [2023]

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

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia. [2018]

7. Japan pubmed.ncbi.nlm.nih.gov

[Clinical experience with clozapine in 55 cases of treatment-resistant schizophrenia]. [2013]