High-dose olanzapine in treatment-resistant schizophrenia: a systematic review

BackgroundRecent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is unclear due to the absence of cohort studies.MethodsWe extracted data from a territory-wide public healthcare database in Hong Kong to build a retrospective cohort of anonymized patients aged 18+ with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least two prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated.ResultsIn total, 9,965 patients were included, with 834 clozapine users, who had a significant IRR of 2.22 (95% CI 1.52, 3.34) for HM compared to olanzapine users. Absolute rate difference was estimated to be 57.40 (95% CI 33.24, 81.55) per 100,000 person-years. Findings were consistent across sub-groups by age and sex in terms of effect size, although the IRR was non-significant for those aged 65 or older. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers.ConclusionAbsolute rate difference in HM incidence was very small although there is a twofold elevated rate. Pharmacotherapies with clozapine may consider this potential rare risk in addition to known side effects.

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A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose–response literature

O’Neill,

Jameson,

McLean

et al. 2024

J Psychopharmacol

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Background: Presently, there is limited guidance on the maximal dosing of psychosis drugs that is based on effectiveness rather than safety or toxicity. Current maximum dosing recommendations may far exceed the necessary degree of dopamine D2 receptor blockade required to treat psychosis. This may lead to excess harm through cognitive impairment and side effects. Aims: This analysis aimed to establish guidance for prescribers by optimally dosing drugs for psychosis based on efficacy and benefit. Methods: We used data from two dose–response meta-analyses and reviewed seven of the most prescribed drugs for psychosis in the UK. Where data were not available, we used appropriate comparison techniques based on D2 receptor occupancy to extrapolate our recommendations. Results: We found that the likely threshold dose for achieving remission of psychotic symptoms was often significantly below the currently licensed dose for these drugs. We therefore recommend that clinicians are cautious about exceeding our recommended doses. Individual factors, however, should be accounted for. We outline potentially relevant factors including age, ethnicity, sex, smoking status and pharmacogenetics. Additionally, we recommend therapeutic drug monitoring as a tool to determine individual pharmacokinetic variation. Conclusions: In summary, we propose a new set of maximum target doses for psychosis drugs based on efficacy. Further research through randomised controlled trials should be undertaken to evaluate the effect of reducing doses from current licensing maximums or from doses that are above our recommendations. However, dose reductions should be implemented in a manner that accounts for and reduces the effects of drug withdrawal.

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High-dose olanzapine in treatment-resistant schizophrenia: a systematic review

Cited by 6 publications

References 55 publications

Iron Dyshomeostasis in Schizophrenia and Potential Treatments to Mitigate Its Effects

Iron Dyshomeostasis in Schizophrenia and Potential Treatments to Mitigate Its Effects

Rare but elevated incidence of hematological malignancy after clozapine use in schizophrenia: a population cohort study

A proposal for reducing maximum target doses of drugs for psychosis: Reviewing dose–response literature

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