Cotherpay vs Monotherapy of Antimanic Treatment in Adult Patients with Acute Manic or Mixed Episode: A Systematic Review and Meta-Analysis of Variation

Rationale Bipolar disorder is a complex and severe mental disorder affecting approximately 2.4% of the general population.1-3 Acute bipolar mania is a psychiatric emergency. Patients in acute manic states often present with elevated mood, impulsivity, agitation, aggression, risky behaviors, and psychotic features.2,4 These symptoms may be severe, leading to marked functional impairment, hospitalization, burden, and societal costs.4,5 Rapid resolution of acute bipolar mania is important, which ensures patient safety and prevent serious consequences. Pharmacological treatment is a cornerstone strategy for the management of acute mania.6 Both the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology (BAP) guidelines suggest antipsychotic monotherapy as a first-line treatment for acute mania,7,8 while the most recent version of the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines6 recommends different first-line treatment options for acute mania, namely (i) monotherapy with lithium, valproate, or atypical antipsychotics or (ii) a combination with two antimanic drugs (cTWOAM) (e.g., an atypical antipsychotic with a mood stabilizer). A multicenter, double-blind, randomized controlled trial (RCT) found that adding lithium to extended-release quetiapine was more efficacious than adding placebo to extended-release quetiapine in adult patients with acute manic episode.9 Another RCT found that adding olanzapine to divalproex was more efficacious than adding placebo to divalproex in adult patients with acute mixed episode.10 Another RCT reported that adding olanzapine to valproate was more efficacious than either olanzapine or valproate monotherapy after 4 weeks of treatment.11 However, another study found that adding ziprasidone to mood stabilizer was not more efficacious than adding placebo to mood stabilizer.12 Therefore, it remains inconclusive that cTWOAM is more efficacious than either monotherapy of a mood stabilizer or monotherapy of an antipsychotic drug. On the other hand, it is common experience that individuals with acute manic episode varied considerably in their response to the same antimanic drug or the same cTWOAM, although the evidence seems to point to uniform efficacy for every patient. However, whether cTWOAM has more or less variation than antimanic monotherapy is still understudied. If cTWOAM compared with monotherapy has better efficacy and lower variability in treatment response, this suggests that sTWOAM could produce a more stable therapeutic response and thus be favored for managing acute bipolar mania. Aims The aim of the current study is to examine the variability in treatment response of cTWOAM vs antimanic monotherapy in adult participants experiencing an acute manic or mixed episode. We will also examine the efficacy and tolerability. Methods Search strategy The MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, PsycINFO, and Clinical trials.gov will be systematically searched to identify RCTs testing different antimanic agents without language restriction. The specific search terms are to be determined and will be adapted to each database. PICO The PICO (population, intervention, comparison, outcome) settings of the current meta-analysis are: P: Adults patients with bipolar I disorder experiencing an acute manic or mixed episode. I: Combined antimanic drugs (combination of any two of the following antimanic drugs: lithium, valproate, anticonvulsants, and antipsychotics) C: Antimanic monotherapy (i.e., one of the following antimanic drugs: lithium, valproate, anticonvulsants, and antipsychotics) O: Heterogeneity in antimanic response Inclusion and exclusion criteria We will only include blind RCTs of cTWOAM versus cTWOAM or antimanic monotherapy and reported the necessary information (i.e., standard deviations, means, and sample sizes). Although the ultimate goal of this review was to compare cTWOAM with antimanic monotherapy, we also included studies comparing cTWOAM or antimanic monotherapy with placebo to develop a more informative network of comparisons. We will exclude: (1). Nonblind RCT. (2). Non-RCT. (3). RCT that enrolled participants with pure bipolar II disorder or schizoaffective disorder. (4). Relapse prevention studies (i.e., RCT addressing on maintenance treatment). (5). Studies without available data on standard deviations and mean changes in manic symptoms. Screening and selection of studies will be performed independently by four of the authors, with each study assessed by a minimum of two authors. Disagreements will be resolved by consulting with the corresponding author. Data extraction For each study, we will extract the following data: (1). Trial characteristics (e.g., sample size, authors, publication years). (2). Treatment medications. (3). Standard deviation (or variance, standard error) and means of changes in manic symptoms at week 3 from each study, as measured with the Young Mania Rating Scale or the Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia, Change Version, or other validated rating scales for manic or mixed episdoe. Intention-to-treat datasets will be used when available. For RCTs that compared different dosages of antimanic drugs versus placebo, we will calculate the aggregated SDs and means across all active arms, leaving only one standard deviation and one mean per study. At least two authors will double-check the data-transfer accuracy and calculations. The quality of the included studies will be rated using the Cochrane Risk of Bias Assessment Tool. Any discrepancies will be resolved by consensus. Data analysis Data management and analysis will be carried out using Stata (version 16) and R-Project (V.4.0.3, R Foundation). Meta-analysis will be performed using a random-effects model under a frequentist framework. An intention-to-treat approach will be used. The I² statistic will be used to evaluate heterogeneity. The meta-analysis of variation will follow the validated methodology.13 A p value of <0.05 is considered significant (two-tailed). Subgroup analysis, meta-regression, and assessment of possible publication bias (Egger’s test and visual inspection of funnel plots) analyses will be conducted if feasible. Sensitivity analyses will include: (1). Excluding studies with a high risk of bias. (2). Excluding studies that enrolled mixed populations (e.g., mixed bipolar I disorder and bipolar II disorder). (3). Excluding studies with patients who partially responded or failed to respond to one of the drugs of their cTWOAM. References 1. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. Mar 2011;68(3):241-51. doi:10.1001/archgenpsychiatry.2011.12 2. Vieta E, Berk M, Schulze TG, et al. Bipolar disorders. Nat Rev Dis Primers. Mar 8 2018;4:18008. doi:10.1038/nrdp.2018.8 3. Carvalho AF, Firth J, Vieta E. Bipolar Disorder. N Engl J Med. Jul 2 2020;383(1):58-66. doi:10.1056/NEJMra1906193 4. McIntyre RS, Berk M, Brietzke E, et al. Bipolar disorders. Lancet. Dec 5 2020;396(10265):1841-1856. doi:10.1016/S0140-6736(20)31544-0 5. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. Feb 2016;3(2):171-8. doi:10.1016/S2215-0366(15)00505-2 6. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. Mar 2018;20(2):97-170. doi:10.1111/bdi.12609 7. Bipolar Disorder: The NICE Guideline on the Assessment and Management of Bipolar Disorder in Adults, Children and Young People in Primary and Secondary Care. 2014. National Institute for Health and Care Excellence: Clinical Guidelines. 8. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. Jun 2016;30(6):495-553. doi:10.1177/0269881116636545 9. Bourin MS, Severus E, Schronen JP, et al. Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study. Int J Bipolar Disord. 2014;2:14. doi:10.1186/s40345-014-0014-9 10. Houston JP, Tohen M, Degenhardt EK, Jamal HH, Liu LL, Ketter TA. Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry. Nov 2009;70(11):1540-7. doi:10.4088/JCP.08m04895yel 11. Xu L, Lu Y, Yang Y, Zheng Y, Chen F, Lin Z. Olanzapine-valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar I mania: a randomized controlled study in a Chinese population group. Neuropsychiatr Dis Treat. 2015;11:1265-71. doi:10.2147/NDT.S81146 12. Sachs GS, Vanderburg DG, Karayal ON, Kolluri S, Bachinsky M, Cavus I. Adjunctive oral ziprasidone in patients with acute mania treated with lithium or divalproex, part 1: results of a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. Nov 2012;73(11):1412-9. doi:10.4088/JCP.11m07388 13. Senior AM, Viechtbauer W, Nakagawa S. Revisiting and expanding the meta-analysis of variation: The log coefficient of variation ratio. Res Synth Methods. Jul 2020;11(4):553-567. doi:10.1002/jrsm.1423

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