Dose Equivalents for Antipsychotic Treatment for Acute Bipolar Mania: A Classical Mean Dose Method
Creators: name: Liang, Chih-Sung
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Medicine and Health Sciences

description: Review question To examine the dose equivalence of different antipsychotics for acute bipolar mania by applying a classical mean dose approach. Searches The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and PsycINFO will be searched from their inception to March 15, 2022. A search algorithm was developed and adapted for each database, with no restrictions on age, setting, sex, ethnicity, language, and publication year. The electronic search will be supplemented by a hand search of reference lists of relevant studies and reviews. Corresponding authors and companies will be contacted to provide missing information and unpublished data. The PICO (population, intervention, comparison, outcome) settings of the current meta-analysis are (1) P: patients with bipolar I disorder experiencing an acute manic episode; (2) I: monotherapy with an antipsychotic drug; (3) C: a placebo; and (4) O: changes in manic symptoms. We will only include double-blind randomized controlled trials (RCTs) of oral monotherapy with an antipsychotic drug versus placebo in adult patients with acute bipolar mania. We will exclude: (1) trials with fixed-dose design (i.e., no dose titration); (2) trials showing no efficacy of the investigated antipsychotic drugs; (3) trials with special population (e.g., children, elderly, bipolar II disorder, schizoaffective disorder); (4) trials using add-on or combination treatments; (5) head-to-head trials without a placebo group; and (6) relapse prevention studies. We will include only studies which allowed for prescribing of the lower and the upper doses as determined by each drug’s target dose range.1 The rationale is that if not even target doses can be prescribed within the trials, then these trials will not be appropriate to identify the optimum dose. For example, the mean dose of quetiapine in a study with a predefined dose range of 25–50 mg/d will necessarily be too low and distort the analysis. The search, selection of the literature, and data extraction will be conducted independently by ≥2 reviewers. Disagreements will be resolved by consensus. Condition or domain being studied Acute bipolar mania (i.e., bipolar I disorder) Intervention(s), exposure(s) We will include all antipsychotic drugs that are available in at least one country, including first-generation (“typical”, “conventional”) antipsychotics as well as second-generation (“atypical”) antipsychotics and placebo. We will include all these compounds at any dose and in any oral forms of administration (for example tablets, liquid). We will not include long-acting injectable antipsychotic drugs (i.e., intramuscular depot formulations) because this form of administration is seldom used in patients with acute bipolar mania. Comparator(s)/control Placebo will be used as reference for presentation. Context There are no restrictions in terms of setting, for example, we will include in- and outpatients. Outcome The main outcome is weighted means, and the secondary outcomes are direct ratios, and combined direct and indirect ratios. Selection of trials Two reviewers will independently inspect all abstracts identified in the searches. Disagreement will be resolved by discussion, and where doubt still remains, we will acquire the full article for further inspection. Once the full articles are obtained, at least two reviewers will independently decide whether the studies meet the review criteria. If disagreement cannot be resolved by discussion, we will resolve it with a third reviewer or seek further information from the study authors. Data extraction At least two reviewers will independently extract data from all selected trials on specifically customized digital forms in the Microsoft Access database. Disagreement will be resolved by discussion with a third reviewer. In double-blind RCTs, physicians adjusted the dose to obtain the maximum clinical response. Therefore, we will extract the mean dose of at week 3. If this was not available, we will extract the closet approximation from the data (median or mode). Data analyses We assume that the different studies were sufficiently similar such that if all the drugs had been used in one very large study, the same mean doses would have been found. We will calculate the sample size weighted mean dose of each antipsychotic drugs and then divided by the weighted mean dose of olanzapine. Therefore, we can obtain each antipsychotic drug equivalent dose of olanzapine. Besides, the direct ratios of mean doses in all individual studies will be calculated and then the sample size weighted ratios will be averaged which allows for some variability in methods of the single studies to be reduced. This analysis can only use studies in which a drug was directly compared with our chosen comparator drug olanzapine. In addition to direct ratios, we will calculate the indirect ratios. For example, if we have direct ratios of olanzapine/haloperidol and risperidone/haloperidol, we can calculate the ratio of risperidone/olanzapine. Sensitivity analysis We will exclude studies using dose out of the range recommended by the International Consensus Study of Antipsychotic Dosing.1 Reference 1. Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsy- chotic dosing. Am J Psychiatry. 2010;167:686–693.