Extended Antipsychotic Dosing for Schizophrenia

Overseen by Gary Remington, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Centre for Addiction and Mental Health

Must be taking: Antipsychotics

Must not be taking: Depot antipsychotics

Disqualifiers: Substance use disorder, Neurological condition, Pregnancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The study wishes to examine whether "extended" antipsychotic treatment, in this case, antipsychotic treatment every other day, is as effective as daily treatment. It is also evaluating whether there may be differences in terms of side effects. Participants will be randomly assigned to either the treatment as usual group (i.e., taking antipsychotic daily) or the extended dosing group (i.e., taking antipsychotic one day on, one day off). That means, like flipping a coin, there is a 50/50 chance that participants will continue on daily dosing of your antipsychotic or have it switched to every other day dosing. This study will last for 1 year. Participants will be evaluated at the beginning and every two weeks during the first 6 months, with visits once every 4 weeks for the final 6 months. In total, participants will make 22 visits over 52 weeks to the investigator's office. The investigators hypothesize that with ED, there will be no change in symptom severity but improvement in the frequency and severity of side effects, wellbeing, and functioning.

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 seems you will continue with your current antipsychotic medication, either daily or every other day. You should discuss your specific situation with the trial team.

What data supports the effectiveness of the drugs Olanzapine and Risperidone for treating schizophrenia?

Research shows that Olanzapine and Risperidone are effective in treating schizophrenia, with Olanzapine being more effective than some older drugs for both positive and negative symptoms. Risperidone is considered a first-choice treatment due to its effectiveness and safety, while higher doses of Olanzapine may help patients who don't respond to standard doses. ^{1 2 3 4 5}

Is extended antipsychotic dosing with olanzapine or risperidone generally safe for humans?

Olanzapine and risperidone have been studied for safety in treating schizophrenia and related conditions. Olanzapine is associated with some side effects like sleepiness and weight gain, but serious side effects are rare. Risperidone, especially in long-acting form, is generally well-tolerated, though some patients may experience side effects like movement disorders and weight gain. ^{6 7 8 9 10}

How is the drug combination of Olanzapine and Risperidone unique for treating schizophrenia?

The combination of Olanzapine and Risperidone for treating schizophrenia is unique because it explores extended dosing strategies, potentially using higher doses of Olanzapine (up to 60 mg/day) for patients who do not respond to standard treatments, while Risperidone is known for its good safety profile. This approach may offer benefits for treatment-resistant patients who have not found success with typical antipsychotics. ^{1 2 4 11 12}

Research Team

Gary Remington, MD, PhD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

This trial is for adults over 18 with schizophrenia or related disorders, stabilized on oral risperidone (1-6mg) or olanzapine (5-20mg). Participants must be able to communicate in English and provide consent. Women of childbearing age need a negative pregnancy test and reliable contraception; men cannot father a child during the study.

Inclusion Criteria

I have been diagnosed with a schizophrenia spectrum or other psychotic disorder.

(iv) ability to communicate in English

(vii) evidence of adherence with current AP treatment

Exclusion Criteria

Current diagnosis of substance use disorder according to DSM-5 criteria (verified through the MINI for Psychotic Disorders (Version 7.0.2) and a positive drug screen for street and /or prescription drugs not prescribed to the participant by treating physicians

I haven't had a depot antipsychotic injection in the last year.

Pregnancy or lactation

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomly assigned to either daily or alternate day antipsychotic dosing for 1 year

52 weeks

22 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Olanzapine (Antipsychotic)
• Risperidone (Antipsychotic)

Trial Overview The study tests if taking antipsychotics every other day ('extended' dosing) is as effective as daily dosing for schizophrenia treatment. It compares side effects, wellbeing, and functioning between usual daily medication intake and alternate-day dosing over one year.

Participant Groups

Group I: Extended Dosing Group Experimental Treatment 2 Interventions

Participants taking olanzapine or risperidone will be switched to an alternate day dosing schedule.

Group II: Treatment as Usual group Active Control 1 Intervention

Participants will continue to take their olanzapine or risperidone following the same prescribed daily schedule.

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Dr. Catherine Zahn

Centre for Addiction and Mental Health

Chief Executive Officer since 2009

MD, University of Toronto

Dr. James Graham

Centre for Addiction and Mental Health

Chief Medical Officer since 2024

PhD in Functional Neuroimaging

Findings from Research

In a report involving three treatment-resistant schizophrenic patients, high dosages of olanzapine (35, 40, and 60 mg/day) were successfully administered without any side effects, suggesting that higher doses may be effective and well-tolerated.

The findings indicate that some patients who do not respond to standard doses of olanzapine (up to 20 mg/day) may benefit from increased dosages, highlighting the need for further clinical studies to explore this treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose olanzapine for treatment-refractory schizophrenia. Lerner, V.[2019]

Antipsychotic medications are essential for treating schizophrenia, but high doses often do not provide additional benefits for most patients, with effective doses typically being lower than 15-20 mg of haloperidol or 500-800 mg of chlorpromazine.

Clozapine remains the preferred treatment for patients who do not respond well to other medications, while risperidone is noted for its effectiveness and safety, although further research is needed to fully understand its advantages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antipsychotic medication in the treatment of schizophrenia. Kane, JM.[2013]

In a study of 78 acute schizophrenia patients, augmenting risperidone with olanzapine did not show a significant advantage over simply increasing the risperidone dose for improving symptoms after 2 weeks.

Patients who had their risperidone dose increased had a shorter time to treatment discontinuation compared to early responders, suggesting that while both strategies were similar in efficacy, the increased dose may lead to quicker treatment changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone. Hatta, K., Otachi, T., Sudo, Y., et al.[2018]

The optimal daily doses for treating schizophrenia are established at 4-6 mg for risperidone and around 15 mg for olanzapine, which can guide more effective clinical practice.

Economic and efficacy analyses suggest that risperidone should be the first choice for treating schizophrenia, while olanzapine and clozapine are recommended as second-line therapies, highlighting the need to reassess current treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The economic value of atypical antipsychotics: A comparison of risperidone and olanzapine revisited. Lecompte, D., Cookson, RF.[2014]

Atypical antipsychotics, like clozapine, show dose-related efficacy in treating schizophrenia, with clozapine being effective up to 600 mg/day, but higher doses may increase the risk of seizures.

Olanzapine's efficacy is dose-related within the 10-20 mg/day range, and higher doses may improve efficacy without significantly increasing adverse events, indicating a need for further research on optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose response and atypical antipsychotics in schizophrenia. Kinon, BJ., Ahl, J., Stauffer, VL., et al.[2018]

Olanzapine demonstrated statistically significant improvements in both efficacy and safety compared to risperidone in treating schizophrenia, based on a meta-analysis of randomized, double-blind studies.

The analysis showed that olanzapine was associated with fewer anticholinergic side effects and lower dropout rates, indicating it may enhance patient quality of life and treatment adherence over both short (≤12 weeks) and longer-term (>12 weeks) periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of olanzapine versus risperidone for the treatment of schizophrenia: a meta-analysis of randomised clinical trials. Mudge, MA., Davey, PJ., Coleman, DK., et al.[2014]

In a clinical safety review involving 2500 patients treated with olanzapine for acute schizophrenia, the overall discontinuation rate was low, indicating good tolerability of the medication.

While olanzapine was associated with some significant adverse effects such as somnolence, weight gain, and elevated liver enzymes, it showed minimal risk for parkinsonism, akathisia, and no cases of hematotoxicity, making it a relatively safe option compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of olanzapine. Beasley, CM., Tollefson, GD., Tran, PV.[2018]

In a study of 151 hospitalized elderly patients with psychosis, both risperidone and olanzapine demonstrated similar efficacy, with around 78% of risperidone patients and 75% of olanzapine patients responding positively to treatment.

Both medications were found to be relatively safe, with adverse events reported in 16-17% of patients in each group, suggesting they can be effective options for treating psychosis in elderly patients with other medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with the atypical antipsychotics--risperidone and olanzapine in the elderly. Madhusoodanan, S., Suresh, P., Brenner, R., et al.[2019]

In a study of 34 patients with schizophrenia who were nonresponsive or intolerant to risperidone, olanzapine treatment led to a significant reduction in symptoms, with an average 25% decrease in PANSS scores after 14 weeks.

Olanzapine was well tolerated, with no patients discontinuing due to intolerable side effects, suggesting it is a safe alternative for those who did not respond to risperidone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for the effectiveness of olanzapine among patients nonresponsive and/or intolerant to risperidone. Dossenbach, MR., Kratky, P., Schneidman, M., et al.[2018]

In a 6-month study involving 5134 patients with paranoid schizophrenia, risperidone long-acting injectable (RLAI) demonstrated significant improvements in both clinical severity and patient functioning, indicating its efficacy in routine clinical practice.

The treatment was generally well-tolerated, with 20% of patients experiencing treatment-emergent adverse events, the most common being akathisia and weight gain, but overall, the study confirmed RLAI's good safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of long-acting injectable risperidone in daily practice: an open-label, noninterventional, prospective study in schizophrenia and related disorders. Parellada, E., Kouniakis, F., Siurkute, A., et al.[2019]

In a 1-year study involving 431 patients with schizophrenia, higher doses of olanzapine (up to 15 mg/day) significantly improved overall psychopathology and positive psychotic symptoms compared to a low dose of 1 mg/day and haloperidol.

Olanzapine was associated with fewer extrapyramidal symptoms than haloperidol, although it did lead to some weight gain and transient increases in prolactin levels, which were less severe than those caused by haloperidol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. Beasley, CM., Hamilton, SH., Crawford, AM., et al.[2022]

In a 14-week trial involving 43 patients with treatment-resistant schizophrenia, olanzapine showed modest effectiveness, with 16.7% of participants meeting response criteria, particularly at doses higher than 20 mg.

While olanzapine treatment led to improvements in cognitive and depression/anxiety symptoms, it also resulted in a significant decrease in extrapyramidal side effects, suggesting it may be a viable option before considering more complex treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial. Lindenmayer, JP., Volavka, J., Lieberman, J., et al.[2019]

References

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

High-dose olanzapine for treatment-refractory schizophrenia. [2019]

2. Israel pubmed.ncbi.nlm.nih.gov

Antipsychotic medication in the treatment of schizophrenia. [2013]

3. Ireland pubmed.ncbi.nlm.nih.gov

A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone. [2018]

4. England pubmed.ncbi.nlm.nih.gov

The economic value of atypical antipsychotics: A comparison of risperidone and olanzapine revisited. [2014]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Dose response and atypical antipsychotics in schizophrenia. [2018]

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

A comparison of olanzapine versus risperidone for the treatment of schizophrenia: a meta-analysis of randomised clinical trials. [2014]

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

Safety of olanzapine. [2018]

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

Experience with the atypical antipsychotics--risperidone and olanzapine in the elderly. [2019]

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

Evidence for the effectiveness of olanzapine among patients nonresponsive and/or intolerant to risperidone. [2018]

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

Safety and efficacy of long-acting injectable risperidone in daily practice: an open-label, noninterventional, prospective study in schizophrenia and related disorders. [2019]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial. [2022]

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

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial. [2019]