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Greetings from Boston, Massachusetts. I am Oliver Freudenreich, also known as Dr. F, for the Psychopharmacology Institute. In this Quick Take, I will discuss a systematic review on the efficacy of high-dose olanzapine for treating schizophrenia. This review was published by my colleagues from Dublin and London in the Journal Therapeutic Advances in Psychopharmacology.
The clinical problem this article addresses is about a patient with schizophrenia who, after several antipsychotic trials, ends up on olanzapine at a dose of 20 mg—the maximum dose in the United States, according to the package insert. The patient’s condition is mediocre; he still has symptoms despite taking olanzapine. Ideally, clozapine would be used next for treatment-resistant schizophrenia (TRS). However, both the patient and his family are against it. They propose increasing the dose of olanzapine instead.
Increasing medication dosage, particularly antipsychotics, is not always beneficial. Most antipsychotics lead to more side effects but no added therapeutic benefits beyond a certain point. However, in the case of olanzapine, it is not unreasonable to consider this option; the FDA-approved highest dose of 20 mg may not represent the optimal highest dose on its dose–response curve. We simply do not know what that curve looks like.
In past decades, there have been clinical trials examining high-dose olanzapine for TRS. This publication provides a summary of these older clinical trials that people may have forgotten or never learned about, depending on when they entered the field. It is important to note that olanzapine is structurally similar to clozapine and was developed hoping it would be a safer replacement, especially regarding agranulocytosis and eliminating regular blood monitoring needs. So, clinically, it is crucial to determine if high-dose olanzapine can be used instead of clozapine with equal efficacy.
The authors of the selected article identified 10 studies that explored the use of high-dose olanzapine for TRS. Half of these studies were randomized clinical trials; 1 was a double-blind crossover trial, and the others were not randomized. Some were even open-label. Most trials defined high-dose olanzapine as above 20 mg, but the maximum allowed dose varied across trials—1 trial even permitting up to 60 mg per day. In 3 of these randomized trials, clozapine was used as the comparator.
A noteworthy finding from this article is that high-dose olanzapine was not inferior to clozapine, using noninferiority statistical language. However, in 1 clozapine crossover trial, clozapine was still more effective than high-dose olanzapine. Other trials found better tolerability compared with clozapine, perhaps unsurprisingly, and possibly better efficacy compared with antipsychotics other than clozapine—also unsurprising given that olanzapine is a highly effective medication.
The authors rightly conclude that the data are too weak to claim that high-dose olanzapine is equivalent to clozapine. Each trial individually was either too small or had significant design weaknesses, such as suboptimal clozapine dose. Thus, I believe that although clozapine remains the gold standard for TRS, high-dose olanzapine may be a good second-best option in selected patients—for instance, if a patient rejects a clozapine trial or if monitoring it is not feasible.
In their abstract, the authors note, and I quote, ”high-dose olanzapine was well tolerated with no serious side effects.” This statement could be misleading because both olanzapine and clozapine are metabolically high-risk antipsychotics; hence, they definitely have serious long-term side effects. In their defense, they thoroughly discuss this matter in the article itself, which probably means there were no additional acute serious side effects during the trial.
Lastly, after using olanzapine for many years, I cannot confidently say whether weight gain with olanzapine is dose related. If it were, we would want to keep the olanzapine dose as low as possible. However, I do not believe that adjusting the dose can manage weight gain from olanzapine. Most people will gain weight with any dose, and managing it medically is necessary under all circumstances. Therefore, a higher dose should be used if better clinical efficacy is needed.
As a clinician, my verdict regarding high-dose olanzapine is that I use it—a strategy supported by the literature, like this review helpfully summarizes. I define high dose as over 20 mg/day, such as 30 mg or 40 mg. Using much higher doses could lead to diminishing returns; you may even get pushback from payers. High-dose olanzapine is not a substitute for clozapine, which remains the first-line treatment for TRS, and obviously, you need to manage olanzapine’s metabolic side effects proactively.
Lastly, for those listening in the United States, ensure you have a risk–benefit discussion with your patient and their family about using high-dose olanzapine off-label—specifically that you’re using olanzapine at a higher than FDA-approved dose of 20 mg/day—and document this discussion.
Abstract
High-Dose Olanzapine in Treatment-Resistant Schizophrenia: A Systematic Review
Louisa Gannon, John Reynolds, Martin Mahon, Fiona Gaughran, John Lally
Background: Treatment-resistant schizophrenia (TRS) affects approximately 30% of people with schizophrenia. Clozapine is the gold standard treatment for TRS but is not always suitable, with a proportion of individuals intolerant of side effects or unable to engage in necessary blood monitoring. Given the profound impact TRS can have on those affected, alternative pharmacological approaches to care are needed.
Objectives: To review the literature on the efficacy and tolerability of high-dose olanzapine (>20 mg daily) in adults with TRS.
Design: This is a systematic review.
Data sources and methods: We searched for eligible trials published prior to April 2022 in PubMed/MEDLINE, Scopus and Google Scholar. Ten studies met the inclusion criteria [five randomised controlled trials (RCTs), one randomised crossover trial and four open label studies]. Data were extracted for predefined primary outcomes (efficacy, tolerability).
Results: Compared with standard treatment, high-dose olanzapine was non-inferior in four RCTs, three of which used clozapine as the comparator. Clozapine was superior to high-dose olanzapine in a double-blind crossover trial. Open-label studies demonstrated tentative evidence in support of high-dose olanzapine use. It was better tolerated than clozapine and chlorpromazine in two respective RCTs, and was generally well tolerated in open-label studies.
Conclusion: This evidence suggests high-dose olanzapine is superior for TRS when compared with other commonly used first- and second-generation antipsychotics, including haloperidol and risperidone. In comparison with clozapine, the data are encouraging for the use of high-dose olanzapine where clozapine use is problematic, but larger, better designed trials are needed to assess the comparative efficacy of both treatments. There is insufficient evidence to consider high-dose olanzapine equivalent to clozapine when clozapine is not contraindicated. Overall, high-dose olanzapine was well tolerated, with no serious side effects.
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Reference
Gannon, L., Reynolds, J., Mahon, M., Gaughran, F., & Lally, J. (2023). High-dose olanzapine in treatment-resistant schizophrenia: A systematic review. Therapeutic Advances in Psychopharmacology, 13, 204512532311687.
