Ethnic differences in efficacy of drug treatment in patients with an acute manic episode: an individual patient data meta-analysis of randomized placebo-controlled trials

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Storosum, Sem . E. Cohen, Cedrine Steinz, Taina Mattila, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4875496/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Feb, 2025 Read the published version in International Journal of Bipolar Disorders → Version 1 posted 12 You are reading this latest preprint version Abstract Background Little is known about the effect of ethnicity on drug treatment in patients with an acute manic episode. The aim of this study is to determine whether ethnicity moderates the response to drug treatment in patients with an acute manic episode, and whether this moderation is independent of potential confounders. Methods We analysed ten short-term placebo-controlled registration trials of atypical antipsychotics and anticonvulsive mood stabilizers in patients with an acute manic episode (n = 2199). A one-step random effects individual patient data meta-analysis (IPD) was applied to establish the moderating effect of ethnicity on symptom improvement on the Young Mania Rating Scale (Y)MRS and on response defined as 50% (Y)MRS symptom reduction. These analyses were corrected for baseline severity, age, and gender. A two-step IPD comparing these outcomes between White, Black and Asian patients. Additionally, a conventional meta-analysis was performed to determine the effect size of drug treatment separately for these ethnic groups. Results In the complete dataset, 60.4% of the patients was White, 8.0% was Black, 12.7% was Asian, 33.7% was of other ethnicities. Ethnicity did not significantly moderate the efficacy of drug treatment: pooled beta-coefficient (β) for the interaction between treatment and the ethnicities White, Black and Asian, varying from 0.889 to 0.899 with overlapping confidence-intervals ranging from 2.356–2.430 in the main analysis. The drug treatment effects were significant in all three analysable ethnicity groups compared to placebo. Discussion In White,Black, and Asian patients with an acute manic episode drug treatment is equally effective. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Bipolar Disorder (BD) is characterized by mania, hypomania, depressive, and mixed episodes. Although, the prevalence rates of BD are similar in the White and the Black population (1–3), ranging from 2–4% (3–5), Black patients with BD often are misdiagnosed with schizophrenia (6–10). Mania, is characterised by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and is the hallmark of a bipolar I disorder(11). Besides mood stabilizers and lithium, antipsychotic medications are an important mainstay in the treatment of patients with an acute manic episode. Black patients with BD are receiving antipsychotics more often than White BD patients (12) with no ethnic differences in the use of atypical vs. typical antipsychotics (13). Different clinical and demographic factors as well as trial characteristics have been associated with the effect sizes of drug treatment in an acute manic episode: a larger number of collaborating study sites is associated with a smaller treatment effect and the presence of higher baseline mania symptom ratings predicts greater improvement in the active medication arm but not in the placebo arm of studies (14). In an individual patient data (IPD) meta-analysis, we investigated the effect of gender on drug treatment response in patients with an acute manic episode and found a significant difference in effect size between men and women(15), with a higher response in men relative to women. In a recent IPD meta-analysis we have shown that atypical antipsychotic medication is equally effective in White andBlack patients with schizophrenia (16). To the best of our knowledge, so far only two studies investigated the moderating effect of ethnicity on response to antipsychotic drug treatment in patients with an acute manic episode. One study compared Black patients (n = 41) to White patients (n = 190) treated with olanzapine. Post-hoc analysis showed similar symptom improvement for both ethnic groups(17). In the second study, treatment with olanzapine was compared between Latin American patients and White patients. Latin American patients treated with olanzapine (n = 51) or haloperidol (n = 48) had similar remission rates (64.7% vs. 68.8%) at week 6, whereas White patients treated with olanzapine (n = 120) had higher remission rates than White patients treated with haloperidol (n = 113): 49.2% vs. 32.7% (p = 0.012) (18) The relative paucity of research on ethnic differences in the response to drug treatment in acute mania is in contrast to other fields in medicine. For instance, regarding antihypertensives in which Black patients respond less to beta-blockers and ACE-inhibitors than White patients (19). The aim of the current individual patient data (IPD) meta-analysis is the first meta-analysis to test whether ethnicity moderates the response to drug treatment in patients with acute mania, and whether a potential moderating effect is independent on baseline severity, age, or gender. Definitions In the literature, the terms ‘race’ and ‘ethnicity’ are often used interchangeably. Due to the negative connotations to the term ‘race’, we will use the term ‘ethnicity’, even though ‘race’ was used in some of the quoted literature and in the databases. Current guidelines of describing specific ethnic groups are followed (e.g., capitalizing and using adjectival forms instead of nouns): ‘White’ and ‘Black’ are used instead of ‘Caucasian’ and ‘African-American’. Methods Selection of studies We included all studies (n = 10) submitted to the Dutch Medicines Evaluation Board during an 11-year period (1991–2004) as part of market authorization applications in Europe for the indication acute manic episode of BD. All studies were short-term double-blind randomized, placebo-controlled trials involving patients diagnosed with an acute manic episode of BD (DSM IV criteria). Pharmaceutical companies provided data to enable an IPD meta-analysis. All studies were approved by the ethic committees of their respective research-centers, and all participants gave informed consent.Restrictions apply to the availability of these data, especially regarding the specific compounds that were investigated. Data were available from the authors with the permission of the pharmaceutical companies. The drugs investigated were antipsychotics and anticonvulsant mood stabilizers. Active comparators were included and analyzed as treatment. Availability of data on ethnicity was a prerequisite for inclusion. In the database, the following predefined ethnic groups were available: Caucasian, Black, Asian, Oriental, Hispanic, Native American, and Other. The original studies were identified for the purpose of collecting manuscripts and corresponding authors were contacted in case of unclarities or missing information (e.g., on the definition of ethnic subgroups). In addition, the ethnic subgroups were examined and redefined according to the current JAMA Network guidelines as: American Indian or Alaska Native, Asian, ‘Black’, Native Hawaiian or Other Pacific Islander, ‘White’ and ‘Some Other Race’ (20). In the original studies, the term ‘race’ was used, or may have been used interchangeably with ‘ethnicity’. We further restricted the analyses to subjects that were given a potential effective dose of the medication, as indicated in the Summary of Product Characteristics (SmPC). Risk of bias was assessed using the Cochrane Risk of Bias tool (21). The guideline for the preferred reporting items for systematic reviews and meta-analyses (PRISMA) was followed except for items pertaining specifically to systematic reviews (20). We pre-specified our methods and analysis plan in the PROSPERO database for systematic reviews (ID: CRD42024543671). Instruments Severity of manic episode The severity of the acute manic episode of BD at baseline and at study endpoint was assessed with two instruments. The Young Mania Rating Scale (YMRS) comprises 11 items: seven items are scored on a 0–4 scale and four items are scored on a 0–8 scale. The total score thus ranges from 0 (no symptoms) to 60 (severe symptoms) (22). The Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia – Change Version (MRS from SADS-C) also comprises 11 items: one item is scored on a 0–2 scale and ten items are scored on a 0–5 scale (higher score indicates higher severity). The total score thus ranges from 0 (no symptoms) to 52 (severe symptoms) (23) . Outcome We used two efficacy outcomes: the standardised difference in mean change score on the (Y)MRS from baseline to follow-up and the difference in percentage of responders. Patients were considered a responder if their score on the YMRS or MRS decreased by 50% or more from baseline to follow-up (23). Since two different rating scales were used in the studies, we decided to use mean percent improvement as primary outcome measure. The endpoint was defined as the three-week post-baseline assessment, since this is the time point recommended for establishing short-term efficacy in the EMA Committee for Proprietary Medicinal Products (CPMP) guideline on the clinical investigation of medicinal products for the treatment of mania (24). For any missing individual (Y)MRS item, we imputed the average of the other (Y)MRS items for that patient for that visit. For patients who dropped out before week three, the last observation was carried forward (LOCF) to week three. The difference in mean improvement and the difference in percent responders between active treatment and placebo at endpoint (LOCF) were considered as the main outcome measures. To examine possible confounding effects, baseline severity, age, and gender were used as covariates in the various statistical models. To provide an impression of the possible influence of the publication date of the individual studies on the results, the studies were ranked in chronological order. Statistical analysis We used a one-stage, random effects IPD meta-analysis (Borenstein, 2009). Traditional methods for meta-analysis synthesis use aggregate study level data that are generally obtained from publications. Meta-analysis synthesis of individual patient data uses the crude data from individual patients from each study. To explore participant-level variations and to control for potential confounders and between-study heterogeneity, IPD meta-analysis was chosen over pooled linear regression analysis or study aggregate meta-analysis Because of existing heterogeneity between studies (e.g., different patient populations, different types of medications, and different companies), random effect rather than fixed effect models were used. The one-stage approach was chosen over the two-stage for primary analysis, as it can analyse predictors at the subject-level, has more power to detect treatment-covariate interactions and leads to less bias when few studies or studies with small sample sizes are included (Panayidou et al., 2016). In case of missing data for some subjects in one or more studies, the last observation will be carried forward (LOCF). Forest plots for each primary outcome will be visualized as it provides an overview in which combined estimates, inconsistency across studies and the precision of individual studies can be examined (Brignardello-Petersen et al., 2020). Between-study heterogeneity was in part be mitigated by the study-specific fixed intercept and random treatment effect, and was further be corrected by adjusting for confounders such as baseline severity, age, and gender in order to determine the effect of a treatment*ethnicity interactionterm in addition to an ethnicity variable. As a sensitivity analysis for the one-stage IPD, a two stage approach was used. The two-stage IPD analysed studies that included at least 5 patients from each ethnicity group in each study arm in order to ensure adequately powered analysis.. In the two stage analysis ethnicity was defined as a dichotomous variable, alternating two ethnicity subgroups so every effect between them can be compared. For the first step, we calculated the total scores on the respective questionnaires at baseline and week three. We also calculated response rate, defined as at least 50% reduction of (Y)MRS score between baseline and week three. Subsequently, for each study, multivariate linear regression analyses were performed with mean percentual (Y)MRS change from baseline as the dependent variable and treatment condition, ethnicity, and treatment condition*ethnicity as the independent variables Similarly, for each study, a multivariate logistic regression analysis was performed with response as dependent variable. Thus, in both analyses (symptom change from and response as the dependent variable), for each study, the interaction of ethnicity*treatment condition (active medication vs placebo) was added to the main effects (ethnicity and treatment condition) as an independent variable for a modifier effect of ethnicity on treatment effect. Subsequently, to examine the effect of baseline severity, age, and gender these variables were cumulatively added as independent variables to the main effects and the interaction of ethnicity by treatment. For these analyses, the Statistical Package for the Social Sciences (SPSS) version 26 was used. As the second step, a random effect meta-analysis was performed with the regression-coefficients and odds ratios (ORs) for the treatment condition*ethnicity interactions in the different studiesa. In these analyses, the 95% confidence interval (CI) indicates the scope of uncertainty in the effect estimate of the treatment condition*ethnicity interactions considering heterogeneity between studies. For these analyses, the Comprehensive Meta-Analysis (CMA) version 2 software was used. Finally, the treatment effect in the different ethnic subgroups (White, Black and Asian) was examined separately. A conventional IPD meta-analysis for each ethnic group was performed, yielding ethnicity-specific pooled mean differences in outcomes (symptom change and response) between participants receiving active medication and participants receiving placebo. Results Study selection and baseline characteristics The original database consisted of 10 studies with a total of 2199 patients. Of these, 1281 (58.3%) were White patients, 175 (8.0%) were Black patients 269 (12.2%)were Asian, 41 (1.8%), were Oriental,, 45(1.8%) were Hispanic, and 384 (17.5)were described as having “ Other” ethnicity. All patients could be included in the one-stage IPD. Six of these studies, with a total of 874 patients, had enough participants per study arm (n > 5) to perform adequately powered comparisons between White and Black patients: 700 White patients (80.1%) and 174 Black patients (19.9%). Four of the studies had enough participants per study arm to perform adequately powered coomparisons between Asian and white patients: 662 (72.5) white patients and 251 (27.5%) asian patients. Two studies had enough participants per study arm to compare Black and Asian patients: 79 (51.6%) black and 74 Asian (48.4%). Nkone of the studies had enough patients included of ethnicities other than White, Black, or Asian to perform adequately powered analyses. The ‘Other’ group had patients with mixed ethnicities, rendering them unsuitable to be subdivided into the existing groups. Based on the Cochrane Risk of Bias Tool, all studies were determined as low risk (Table S1 ). Table 1 presents demographic and clinical baseline characteristics per ethnic group. There were no relevant baseline differences between ethnic groups. For a list of demographic charactersitics per study, please see appendix 1. Table 1 Baseline characteristics White Black Asian Active compound Placebo Active compound Placebo Active compound Placebo N (%) 1281 (60.4) 175 (8.0) 269 (12.7) N (%) 763 (59.6) 518 (40.4) 102 (58.3) 73 (41.7) 159 (59.1) 110 (40.9) N using mood stabiliser 118 15 71 Age in years, mean (SD) 41.9 (12.769) 40.54 (12.20) 38.79 (11.00) 39.9 (9.470) 33.50 (10.708) 34.5 (11.63) Gender f % 415 (54.4) 257 (49.6) 40 (39.2) 32 (43.8) 23 (74.2) 11 (78.2) MRS N (%) 171 32 63 N (%) 68 103 15 17 23 40 MRS score at baseline, mean (SD) 27.35 (6.8) 26.31 (6.52) 29.5 (8.749) 32.8 (7.248) 28.43 (4.143) 28.1 (4.971) YMRS N (%) 795 143 N (%) 695 415 87 56 136 70 YMRS score at baseline, mean (SD) 30.08 (5.936) 29.88 (6.603) 28.8 (5.535) 28.64 (6.019) 33.07 (7.483) 33.01 (6.736) Moderating effect of ethnicity on treatment effect. Figure 1 presents the result of the one-stage IPD meta-analysis. It shows that the effect modifying properties on the YMRS change from baseline between placebo and active modification, is almost identical for being White, Black or Asian. This is represented by a β that is respectively 0.898 (95% CI -0.289 to 2.068), 0.890 (95% CI -0.279 to 2.057) and 0.889 (-0.276 to 2.989). There was nog statistically significant difference between these groups. Figure 2 presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variab White or Black). There is no significant overall treatment condition*ethnicityeffect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Black patients. This is represented by an over-all pooled beta of -0.063 (95% CI of -1,189 to 0,063) for mean percentual (Y)MRS change as the dependent variable (Fig. 2 a) and a pooled beta of -0,406 (95%CI of -1,198 to 0,387) for response as the dependent variable (Fig. 2 b), the latter translating to a to an OR of 0.663 (95% CI of 0.302 to 1.473). Adding confounders to the model did not substantially change results (Figure S1 ). Figure 3 presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variable White or Asian). There is no significant overall treatment condition*ethnicity effect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Asian patients. This is represented by an over-all pooled beta of -0.332 (95% CI of -1,266 to 0,602) for mean percentual (Y)MRS change as the dependent variable (Fig. 3 a) and a pooled beta of -0,111 (95%CI of -0,355 to 0,134) for response as the dependent variable (Fig. 3 b), the latter translating to a to an OR of 0.895 (95% CI of 0.701 to 0.875). Adding confounders to the model did not substantially change results (Fig. 32). Figure 4 presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variable Black or Asian). There is no significant overall treatment condition*ethnicity effect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Asian patients. This is represented by an over-all pooled beta of -0.069 (95% CI of -0,457 to 0,319) for mean percentual (Y)MRS change as the dependent variable (Fig. 4 a) and a pooled beta of -0,001 (95%CI of -2,335 to 2,334) for response as the dependent variable (Fig. 4 b), the latter translating to a to an OR of 0.999 (95% CI of 0.097 to 10.319). Adding confounders to the model did not substantially change results (Figure S3 Conventional meta-analysis of treatment effect separately for the two ethnicity-groups Figure 5 shows the over-all pooled effect sizes of (Y)MRS change and response separately for Black and White patients. The effect sizes show a statistically significant beneficial effect of active treatment compared to placebo in both White and Black patients. In White patients, there is a statistically significant pooled standardized mean difference of 0.340 (95% CI of 0.184 to 0.496) in (Y)MRS change (figure 5a) and a statistically significant pooled odds ratio of 2.122 (95% CI of 1.537 to 2.930) for response (figure 5b). In Black patients, there is a statistically significant pooled standardized mean difference of 0.158 (95% CI of 0.042 to 0.661) in (Y)MRS change (figure 5c) and a pooled odds ratio of 1.428 (95% CI of 0.698-2.922) for response, which was not significant (figure 5d). In Asian patients, there is a statistically significant pooled standardised mean difference of 0.240 (95% CI 0.110 to 0.894) in (Y)MRS change (figure Asian patients (figure 5e) and a pooled odds ratio of 2.122 (95% CI of 1.537 to 2.930). Discussion In this individual patient data (IPD) meta-analysis we did not find a significant moderating effect of ethnicity (White patients vs. Black patients vs. Asian patients) in the effect of antipsychotics or mood stabilisers in the treatment of an acute manic episode of bipolar disorder (BD). This finding was independent of baseline severity, age, and gender. Thus, medication was equally effective in these three ethnic groups. Our selection of studies resulted in the inclusion of more White patients than Black or Asian patients (60,1% White patients compared to 8.0% Black patients an 12.% Asian patients) (Table 1 indicating that these ethnicities were adequately represented when compared to the ethnic distribution of the United States population(25). Our main analysis showed that the effect of being of White, Black, or Asian ethnicity is clinically irrelevant, as none of these variables were significan in moderating the effect of YMRS symptom change when comparing the placebo-group to the active medicationgroup. In a comparable study performing IPD meta-analysis on 22 short term randomised controlled registration trials for atypical antipsychotics in schizophrenia we found very similar results: drug treatment was equally effective in Black (N = 1328) and White (N-2552) patients with schizophrenia. (16). It is of note that although Black patients were not adequately included in the registration trials for schizophrenia compared to the ethnic distribution of schizophrenia in the US population, the total absolute number of Black patients in these trials was higher than in this current study. This leads us to a possible explanation for not finding a difference in efficacy of medication treatment in acute mania between Black and White patients in this study. Although we pooled individual patient data from ten different registration trials, creating the largest dataset investigating effect size differences between ethnicities to date, it could still be underpowered to find these differences, with only 175 Black participants allowing for false negative results. Also, ethnicity may be associated with many factors that could increase or decrease efficacy of medication (26). We were not able to control for underlying or associated factors that may have influenced treatment efficacy. There are some indications that there is a difference in side effects between different ethnic groups (17, 18) and that genetic ancestry may influence the pharmacodynamic profile (27, 28). A review of 51 studies describing side effects of antipsychotic medication in patients with schizophrenia found evidence of ethnic differences in the risk of adverse events (29). In addition, genetic profiles vary widely within ethnic groups and there is no proof of an underlying explanation for possible differences in the prevalence of side effects. The main strength of our study is the inclusion of individual patient data from a relatively large group of patients with acute mania from double-blind randomised placebo-controlled trials. This increases the reliability and generalisability of our findings, by quantifying the effect modification while accounting for heterogeneity between studies. Our study is, however, not without limitations. Only a few of the studies analysed in the main analysis could be included in the sensitivity analysisdue to an insufficient number of participants per study arm (n > 5) s. This may limit the generalisability of our findings. Second, because the enrolment of included studies was between 1991 and 2004, the newest medications were not examined. However, medications included in the current study are still the most prescribed drugs in current clinical practice (30). In addition, due to agreements with pharmaceutical companies, we were not able to examine the effect of ethnicity for specific (types of) medications. This may be an important limitation as antipsychotics were found to be significantly more effective in the treatment of acute mania than mood stabilisers, with haloperidol, risperidone, and olanzapine ranked as the most potent(31). The fact that we could not examine the drugs individually may mask possible ethnic differences for specific medications. Finally, it should be noted that meta-analysis even with data from randomized controlled trials should be viewed as a naturalistic experiment with a serious risk of confounding. Fortunately, we were able to control for several potential confounders, but residual confounding cannot be excluded. For example, patients with a rapid cycling course or with mixed episodes are associated with a more severe course and could be associated with ethnicity and treatment outcome (32, 33). These data were not available in our dataset. Due to a lack of complete information on the inclusion date of patients, we were not able to examine the inclusion date as a confounder to the model. However, the forest plots were sorted on publication date of the studies (with ascending date ranging from 1990 to 2004). When viewing these forest plots, there does not seem to be an influence of publication date on the moderating effect of ethnicity. In conclusion, our findings show that in medication is equally effective in White and in Black patients with acute mania. Declarations Ethical approval Internal Review Boards of the various pharmaceutical companies have approved of the randomised controlled trials that were included in this study. All participants of these trials gave informed consent to participate. Funding No funding was sought or received for the purposes of this research project. Author Contribution B.W.C. Storosum: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Visualization, , S.E. Cohen: Methodology, Formal analysis, Validation, Cedrine Steinz: Formal analysis, Validation, Dr. T. Mattila: Methodology, Supervision, Writing - Review & Editing, Data Curation, Prof. dr. K.C.B. Roes: Methodology, Prof. Dr. C.C. Welten: Methodology, Writing - Review & Editing, Data Curation, Prof. Dr. W. van den Brink: Writing - Review & Editing, Supervision, Prof. Dr. L. de Haan: Writing - Review & Editing, Supervision, Conceptualisation, Prof. Dr. D.A.J.P. Denys: Writing - Review & Editing, Supervision, Conceptualisation J.B. Zantvoord:Writing - Review & Editing, Supervision, Conceptualisation, Project administration, Methodology Data Availability Restrictions apply to the availability of these data, especially regarding the specific compounds that were investigated. Dataare available from the authors with the permission of the pharmaceutical companies References Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19. Breslau J, Aguilar-Gaxiola S, Kendler KS, Su M, Williams D, Kessler RC. Specifying race-ethnic differences in risk for psychiatric disorder in a USA national sample. Psychol Med. 2006;36(1):57-68. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. 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A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978;35(7):837-44. CPMP. Note for guidance on clinical investigation of medicinal product of the treatment and prevention of bipolar disorder.: The European Agency for the Evaluation of Medicinal Products; 2001. Bureau USC. The 2020 Census. 2020. Stronks K, Snijder MB, Peters RJ, Prins M, Schene AH, Zwinderman AH. Unravelling the impact of ethnicity on health in Europe: the HELIUS study. BMC Public Health. 2013;13:402. Wiers CE, Towb PC, Hodgkinson CA, Shen PH, Freeman C, Miller G, et al. Association of genetic ancestry with striatal dopamine D2/D3 receptor availability. Mol Psychiatry. 2018;23(8):1711-6. Chaudhry I, Neelam K, Duddu V, Husain N. Ethnicity and psychopharmacology. J Psychopharmacol. 2008;22(6):673-80. Arnold JG, Miller AL, Canive JM, Rosenheck RA, Swartz MS, Mintz J. Comparison of outcomes for African Americans, Hispanics, and Non-Hispanic Whites in the CATIE study. Psychiatr Serv. 2013;64(6):570-8. Hálfdánarson Ó, Zoëga H, Aagaard L, Bernardo M, Brandt L, Fusté AC, et al. International trends in antipsychotic use: A study in 16 countries, 2005-2014. Eur Neuropsychopharmacol. 2017;27(10):1064-76. Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-15. Valenti M, Pacchiarotti I, Undurraga J, Bonnin CM, Popovic D, Goikolea JM, et al. Risk factors for rapid cycling in bipolar disorder. Bipolar Disord. 2015;17(5):549-59. Vieta E, Popovic D, Rosa AR, Sole B, Grande I, Frey BN, et al. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry. 2013;28(1):21-9. Additional Declarations No competing interests reported. Supplementary Files PRISMA2020checklist.pdf Cite Share Download PDF Status: Published Journal Publication published 23 Feb, 2025 Read the published version in International Journal of Bipolar Disorders → Version 1 posted Editorial decision: Revision requested 11 Jan, 2025 Reviews received at journal 04 Jan, 2025 Reviewers agreed at journal 27 Nov, 2024 Reviewers agreed at journal 22 Nov, 2024 Reviews received at journal 04 Nov, 2024 Reviewers agreed at journal 21 Oct, 2024 Reviewers agreed at journal 28 Aug, 2024 Reviewers agreed at journal 26 Aug, 2024 Reviewers invited by journal 26 Aug, 2024 Editor assigned by journal 14 Aug, 2024 Submission checks completed at journal 14 Aug, 2024 First submitted to journal 07 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4875496","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":350072552,"identity":"f5485651-38da-4cad-ac5c-fdabceead96e","order_by":0,"name":"Bram W.C. 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E.","lastName":"Cohen","suffix":""},{"id":350072554,"identity":"84af96a7-c6b1-4d67-bfb5-70222ba0723d","order_by":2,"name":"Cedrine Steinz","email":"","orcid":"","institution":"University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Cedrine","middleName":"","lastName":"Steinz","suffix":""},{"id":350072555,"identity":"b8103b0b-a565-44c9-b459-052a04cf292c","order_by":3,"name":"Taina Mattila","email":"","orcid":"","institution":"Medicines Evaluation Board","correspondingAuthor":false,"prefix":"","firstName":"Taina","middleName":"","lastName":"Mattila","suffix":""},{"id":350072556,"identity":"422fb0f5-0633-44c7-bbcd-93a493b21a78","order_by":4,"name":"Carlijn Welten","email":"","orcid":"","institution":"Het Huis","correspondingAuthor":false,"prefix":"","firstName":"Carlijn","middleName":"","lastName":"Welten","suffix":""},{"id":350072557,"identity":"97714bac-24f2-4eca-8e6f-c80579f2d558","order_by":5,"name":"Wim Brink","email":"","orcid":"","institution":"University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Wim","middleName":"","lastName":"Brink","suffix":""},{"id":350072558,"identity":"17ff4350-7a95-48f4-9d62-a77c6fbbe661","order_by":6,"name":"Kit Roes","email":"","orcid":"","institution":"Radboud University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kit","middleName":"","lastName":"Roes","suffix":""},{"id":350072559,"identity":"1818f791-1108-4231-9cf6-ca3dfaeac6d3","order_by":7,"name":"Lieuwe Haan","email":"","orcid":"","institution":"University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Lieuwe","middleName":"","lastName":"Haan","suffix":""},{"id":350072560,"identity":"0750d6c4-83d4-4da4-bac5-b1a476dc294f","order_by":8,"name":"Damiaan A.J.P. Denys","email":"","orcid":"","institution":"University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Damiaan","middleName":"A.J.P.","lastName":"Denys","suffix":""},{"id":350072561,"identity":"0d719b88-69a2-43dd-8a45-6b044e470afa","order_by":9,"name":"Jasper B. 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Although, the prevalence rates of BD are similar in the White and the Black population (1\u0026ndash;3), ranging from 2\u0026ndash;4% (3\u0026ndash;5), Black patients with BD often are misdiagnosed with schizophrenia (6\u0026ndash;10). Mania, is characterised by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and is the hallmark of a bipolar I disorder(11). Besides mood stabilizers and lithium, antipsychotic medications are an important mainstay in the treatment of patients with an acute manic episode. Black patients with BD are receiving antipsychotics more often than White BD patients (12) with no ethnic differences in the use of atypical vs. typical antipsychotics (13). Different clinical and demographic factors as well as trial characteristics have been associated with the effect sizes of drug treatment in an acute manic episode: a larger number of collaborating study sites is associated with a smaller treatment effect and the presence of higher baseline mania symptom ratings predicts greater improvement in the active medication arm but not in the placebo arm of studies (14). In an individual patient data (IPD) meta-analysis, we investigated the effect of gender on drug treatment response in patients with an acute manic episode and found a significant difference in effect size between men and women(15), with a higher response in men relative to women. In a recent IPD meta-analysis we have shown that atypical antipsychotic medication is equally effective in White andBlack patients with schizophrenia (16). To the best of our knowledge, so far only two studies investigated the moderating effect of ethnicity on response to antipsychotic drug treatment in patients with an acute manic episode. One study compared Black patients (n\u0026thinsp;=\u0026thinsp;41) to White patients (n\u0026thinsp;=\u0026thinsp;190) treated with olanzapine. Post-hoc analysis showed similar symptom improvement for both ethnic groups(17). In the second study, treatment with olanzapine was compared between Latin American patients and White patients. Latin American patients treated with olanzapine (n\u0026thinsp;=\u0026thinsp;51) or haloperidol (n\u0026thinsp;=\u0026thinsp;48) had similar remission rates (64.7% vs. 68.8%) at week 6, whereas White patients treated with olanzapine (n\u0026thinsp;=\u0026thinsp;120) had higher remission rates than White patients treated with haloperidol (n\u0026thinsp;=\u0026thinsp;113): 49.2% vs. 32.7% (p\u0026thinsp;=\u0026thinsp;0.012) (18) The relative paucity of research on ethnic differences in the response to drug treatment in acute mania is in contrast to other fields in medicine. For instance, regarding antihypertensives in which Black patients respond less to beta-blockers and ACE-inhibitors than White patients (19).\u003c/p\u003e \u003cp\u003eThe aim of the current individual patient data (IPD) meta-analysis is the first meta-analysis to test whether ethnicity moderates the response to drug treatment in patients with acute mania, and whether a potential moderating effect is independent on baseline severity, age, or gender.\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003eIn the literature, the terms \u0026lsquo;race\u0026rsquo; and \u0026lsquo;ethnicity\u0026rsquo; are often used interchangeably. Due to the negative connotations to the term \u0026lsquo;race\u0026rsquo;, we will use the term \u0026lsquo;ethnicity\u0026rsquo;, even though \u0026lsquo;race\u0026rsquo; was used in some of the quoted literature and in the databases. Current guidelines of describing specific ethnic groups are followed (e.g., capitalizing and using adjectival forms instead of nouns): \u0026lsquo;White\u0026rsquo; and \u0026lsquo;Black\u0026rsquo; are used instead of \u0026lsquo;Caucasian\u0026rsquo; and \u0026lsquo;African-American\u0026rsquo;.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eSelection of studies\u003c/h2\u003e\n \u003cp\u003eWe included all studies (n\u0026thinsp;=\u0026thinsp;10) submitted to the Dutch Medicines Evaluation Board during an 11-year period (1991\u0026ndash;2004) as part of market authorization applications in Europe for the indication acute manic episode of BD. All studies were short-term double-blind randomized, placebo-controlled trials involving patients diagnosed with an acute manic episode of BD (DSM IV criteria). Pharmaceutical companies provided data to enable an IPD meta-analysis. All studies were approved by the ethic committees of their respective research-centers, and all participants gave informed consent.Restrictions apply to the availability of these data, especially regarding the specific compounds that were investigated. Data were available from the authors with the permission of the pharmaceutical companies. The drugs investigated were antipsychotics and anticonvulsant mood stabilizers. Active comparators were included and analyzed as treatment. Availability of data on ethnicity was a prerequisite for inclusion. In the database, the following predefined ethnic groups were available: Caucasian, Black, Asian, Oriental, Hispanic, Native American, and Other. The original studies were identified for the purpose of collecting manuscripts and corresponding authors were contacted in case of unclarities or missing information (e.g., on the definition of ethnic subgroups). In addition, the ethnic subgroups were examined and redefined according to the current JAMA Network guidelines as: American Indian or Alaska Native, Asian, \u0026lsquo;Black\u0026rsquo;, Native Hawaiian or Other Pacific Islander, \u0026lsquo;White\u0026rsquo; and \u0026lsquo;Some Other Race\u0026rsquo; (20). In the original studies, the term \u0026lsquo;race\u0026rsquo; was used, or may have been used interchangeably with \u0026lsquo;ethnicity\u0026rsquo;.\u003c/p\u003e\n \u003cp\u003eWe further restricted the analyses to subjects that were given a potential effective dose of the medication, as indicated in the Summary of Product Characteristics (SmPC). Risk of bias was assessed using the Cochrane Risk of Bias tool (21). The guideline for the preferred reporting items for systematic reviews and meta-analyses (PRISMA) was followed except for items pertaining specifically to systematic reviews (20). We pre-specified our methods and analysis plan in the PROSPERO database for systematic reviews (ID: CRD42024543671).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eInstruments\u003c/h2\u003e\n \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n \u003ch2\u003eSeverity of manic episode\u003c/h2\u003e\n \u003cp\u003eThe severity of the acute manic episode of BD at baseline and at study endpoint was assessed with two instruments. The Young Mania Rating Scale (YMRS) comprises 11 items: seven items are scored on a 0\u0026ndash;4 scale and four items are scored on a 0\u0026ndash;8 scale. The total score thus ranges from 0 (no symptoms) to 60 (severe symptoms) (22). The Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia \u0026ndash; Change Version (MRS from SADS-C) also comprises 11 items: one item is scored on a 0\u0026ndash;2 scale and ten items are scored on a 0\u0026ndash;5 scale (higher score indicates higher severity). The total score thus ranges from 0 (no symptoms) to 52 (severe symptoms) (23) .\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eOutcome\u003c/h2\u003e\n \u003cp\u003eWe used two efficacy outcomes: the standardised difference in mean change score on the (Y)MRS from baseline to follow-up and the difference in percentage of responders. Patients were considered a responder if their score on the YMRS or MRS decreased by 50% or more from baseline to follow-up (23). Since two different rating scales were used in the studies, we decided to use mean percent improvement as primary outcome measure. The endpoint was defined as the three-week post-baseline assessment, since this is the time point recommended for establishing short-term efficacy in the EMA Committee for Proprietary Medicinal Products (CPMP) guideline on the clinical investigation of medicinal products for the treatment of mania (24). For any missing individual (Y)MRS item, we imputed the average of the other (Y)MRS items for that patient for that visit. For patients who dropped out before week three, the last observation was carried forward (LOCF) to week three. The difference in mean improvement and the difference in percent responders between active treatment and placebo at endpoint (LOCF) were considered as the main outcome measures.\u003c/p\u003e\n \u003cp\u003eTo examine possible confounding effects, baseline severity, age, and gender were used as covariates in the various statistical models. To provide an impression of the possible influence of the publication date of the individual studies on the results, the studies were ranked in chronological order.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eWe used a one-stage, random effects IPD meta-analysis (Borenstein, 2009). Traditional methods for meta-analysis synthesis use aggregate study level data that are generally obtained from publications. Meta-analysis synthesis of individual patient data uses the crude data from individual patients from each study. To explore participant-level variations and to control for potential confounders and between-study heterogeneity, IPD meta-analysis was chosen over pooled linear regression analysis or study aggregate meta-analysis Because of existing heterogeneity between studies (e.g., different patient populations, different types of medications, and different companies), random effect rather than fixed effect models were used. The one-stage approach was chosen over the two-stage for primary analysis, as it can analyse predictors at the subject-level, has more power to detect treatment-covariate interactions and leads to less bias when few studies or studies with small sample sizes are included (Panayidou et al., 2016).\u003c/p\u003e\n \u003cp\u003eIn case of missing data for some subjects in one or more studies, the last observation will be carried forward (LOCF). Forest plots for each primary outcome will be visualized as it provides an overview in which combined estimates, inconsistency across studies and the precision of individual studies can be examined (Brignardello-Petersen et al., 2020). Between-study heterogeneity was in part be mitigated by the study-specific fixed intercept and random treatment effect, and was further be corrected by adjusting for confounders such as baseline severity, age, and gender in order to determine the effect of a treatment*ethnicity interactionterm in addition to an ethnicity variable.\u003c/p\u003e\n \u003cp\u003eAs a sensitivity analysis for the one-stage IPD, a two stage approach was used. The two-stage IPD analysed studies that included at least 5 patients from each ethnicity group in each study arm in order to ensure adequately powered analysis.. In the two stage analysis ethnicity was defined as a dichotomous variable, alternating two ethnicity subgroups so every effect between them can be compared.\u003c/p\u003e\n \u003cp\u003eFor the first step, we calculated the total scores on the respective questionnaires at baseline and week three. We also calculated response rate, defined as at least 50% reduction of (Y)MRS score between baseline and week three. Subsequently, for each study, multivariate linear regression analyses were performed with mean percentual (Y)MRS change from baseline as the dependent variable and treatment condition, ethnicity, and treatment condition*ethnicity as the independent variables\u003c/p\u003e\n \u003cp\u003eSimilarly, for each study, a multivariate logistic regression analysis was performed with response as dependent variable. Thus, in both analyses (symptom change from and response as the dependent variable), for each study, the interaction of ethnicity*treatment condition (active medication vs placebo) was added to the main effects (ethnicity and treatment condition) as an independent variable for a modifier effect of ethnicity on treatment effect. Subsequently, to examine the effect of baseline severity, age, and gender these variables were cumulatively added as independent variables to the main effects and the interaction of ethnicity by treatment. For these analyses, the Statistical Package for the Social Sciences (SPSS) version 26 was used.\u003c/p\u003e\n \u003cp\u003eAs the second step, a random effect meta-analysis was performed with the regression-coefficients and odds ratios (ORs) for the treatment condition*ethnicity interactions in the different studiesa. In these analyses, the 95% confidence interval (CI) indicates the scope of uncertainty in the effect estimate of the treatment condition*ethnicity interactions considering heterogeneity between studies. For these analyses, the Comprehensive Meta-Analysis (CMA) version 2 software was used.\u003c/p\u003e\n \u003cp\u003eFinally, the treatment effect in the different ethnic subgroups (White, Black and Asian) was examined separately. A conventional IPD meta-analysis for each ethnic group was performed, yielding ethnicity-specific pooled mean differences in outcomes (symptom change and response) between participants receiving active medication and participants receiving placebo.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and baseline characteristics\u003c/h2\u003e \u003cp\u003eThe original database consisted of 10 studies with a total of 2199 patients. Of these, 1281 (58.3%) were White patients, 175 (8.0%) were Black patients 269 (12.2%)were Asian, 41 (1.8%), were Oriental,, 45(1.8%) were Hispanic, and 384 (17.5)were described as having \u0026ldquo; Other\u0026rdquo; ethnicity. All patients could be included in the one-stage IPD. Six of these studies, with a total of 874 patients, had enough participants per study arm (n\u0026thinsp;\u0026gt;\u0026thinsp;5) to perform adequately powered comparisons between White and Black patients: 700 White patients (80.1%) and 174 Black patients (19.9%). Four of the studies had enough participants per study arm to perform adequately powered coomparisons between Asian and white patients: 662 (72.5) white patients and 251 (27.5%) asian patients. Two studies had enough participants per study arm to compare Black and Asian patients: 79 (51.6%) black and 74 Asian (48.4%). Nkone of the studies had enough patients included of ethnicities other than White, Black, or Asian to perform adequately powered analyses. The \u0026lsquo;Other\u0026rsquo; group had patients with mixed ethnicities, rendering them unsuitable to be subdivided into the existing groups.\u003c/p\u003e \u003cp\u003eBased on the Cochrane Risk of Bias Tool, all studies were determined as low risk (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents demographic and clinical baseline characteristics per ethnic group. There were no relevant baseline differences between ethnic groups.\u003c/p\u003e \u003cp\u003eFor a list of demographic charactersitics per study, please see appendix 1.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003eWhite\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003eBlack\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003eAsian\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eActive compound\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePlacebo\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eActive compound\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ePlacebo\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eActive compound\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003ePlacebo\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003e1281 (60.4)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003e175 (8.0)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003e269 (12.7)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e763 (59.6)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e518 (40.4)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e102 (58.3)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e73 (41.7)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e159 (59.1)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e110 (40.9)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN using mood stabiliser\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003e118\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003e15\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003e71\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAge in years, mean (SD)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.9 (12.769)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e40.54 (12.20)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e38.79 (11.00)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e39.9 (9.470)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e33.50 (10.708)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e34.5 (11.63)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eGender f %\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e415 (54.4)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e257 (49.6)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e40 (39.2)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e32 (43.8)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e23 (74.2)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e11 (78.2)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMRS\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003e171\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003e32\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003e63\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e68\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e103\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e15\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e17\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e23\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e40\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMRS score at baseline, mean (SD)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e27.35 (6.8)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e26.31 (6.52)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e29.5 (8.749)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e32.8 (7.248)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e28.43 (4.143)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e28.1 (4.971)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eYMRS\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003e795\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cem\u003e143\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eN (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e695\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e415\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e87\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e56\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e136\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e70\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eYMRS score at baseline, mean (SD)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003e30.08 (5.936)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003e29.88 (6.603)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003e28.8 (5.535)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003e28.64 (6.019)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003e33.07 (7.483)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003e33.01 (6.736)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eModerating effect of ethnicity on treatment effect.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the result of the one-stage IPD meta-analysis. It shows that the effect modifying properties on the YMRS change from baseline between placebo and active modification, is almost identical for being White, Black or Asian. This is represented by a β that is respectively 0.898 (95% CI -0.289 to 2.068), 0.890 (95% CI -0.279 to 2.057) and 0.889 (-0.276 to 2.989). There was nog statistically significant difference between these groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variab White or Black). There is no significant overall treatment condition*ethnicityeffect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Black patients. This is represented by an over-all pooled beta of -0.063 (95% CI of -1,189 to 0,063) for mean percentual (Y)MRS change as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea) and a pooled beta of -0,406 (95%CI of -1,198 to 0,387) for response as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb), the latter translating to a to an OR of 0.663 (95% CI of 0.302 to 1.473). Adding confounders to the model did not substantially change results (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variable White or Asian). There is no significant overall treatment condition*ethnicity effect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Asian patients. This is represented by an over-all pooled beta of -0.332 (95% CI of -1,266 to 0,602) for mean percentual (Y)MRS change as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) and a pooled beta of -0,111 (95%CI of -0,355 to 0,134) for response as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), the latter translating to a to an OR of 0.895 (95% CI of 0.701 to 0.875). Adding confounders to the model did not substantially change results (Fig.\u0026nbsp;32).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents the results of the two-stage IPD meta-analysis of the interaction term ethnicity*treatment (with ethnicity defined as a dichotomous variable Black or Asian). There is no significant overall treatment condition*ethnicity effect, indicating that ethnicity does not moderate the effect of drug treatment in these studies on acute mania between White and Asian patients. This is represented by an over-all pooled beta of -0.069 (95% CI of -0,457 to 0,319) for mean percentual (Y)MRS change as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea) and a pooled beta of -0,001 (95%CI of -2,335 to 2,334) for response as the dependent variable (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb), the latter translating to a to an OR of 0.999 (95% CI of 0.097 to 10.319). Adding confounders to the model did not substantially change results (Figure S3\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eConventional meta-analysis of treatment effect separately for the two ethnicity-groups\u003c/h2\u003e \u003c/div\u003e \n\u003cp\u003eFigure 5 shows the over-all pooled effect sizes of (Y)MRS change and response separately for Black and White patients. The effect sizes show a statistically significant beneficial effect of active treatment compared to placebo in both White and Black patients. In White patients, there is a statistically significant pooled standardized mean difference of 0.340 (95% CI of 0.184 to 0.496) in (Y)MRS change (figure 5a) and a statistically significant pooled odds ratio of 2.122 (95% CI of 1.537 to 2.930) for response (figure 5b). In Black patients, there is a statistically significant pooled standardized mean difference of 0.158 (95% CI of 0.042 to 0.661) in (Y)MRS change (figure 5c) and a pooled odds ratio of 1.428 (95% CI of 0.698-2.922) for response, which was not significant (figure 5d). In Asian patients, there is a statistically significant pooled standardised mean difference of 0.240 (95% CI 0.110 to 0.894) in (Y)MRS change (figure Asian patients (figure 5e) and a pooled odds ratio of 2.122 (95% CI of 1.537 to 2.930).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this individual patient data (IPD) meta-analysis we did not find a significant moderating effect of ethnicity (White patients vs. Black patients vs. Asian patients) in the effect of antipsychotics or mood stabilisers in the treatment of an acute manic episode of bipolar disorder (BD). This finding was independent of baseline severity, age, and gender. Thus, medication was equally effective in these three ethnic groups.\u003c/p\u003e \u003cp\u003eOur selection of studies resulted in the inclusion of more White patients than Black or Asian patients (60,1% White patients compared to 8.0% Black patients an 12.% Asian patients) (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e indicating that these ethnicities were adequately represented when compared to the ethnic distribution of the United States population(25).\u003c/p\u003e \u003cp\u003eOur main analysis showed that the effect of being of White, Black, or Asian ethnicity is clinically irrelevant, as none of these variables were significan in moderating the effect of YMRS symptom change when comparing the placebo-group to the active medicationgroup.\u003c/p\u003e \u003cp\u003eIn a comparable study performing IPD meta-analysis on 22 short term randomised controlled registration trials for atypical antipsychotics in schizophrenia we found very similar results: drug treatment was equally effective in Black (N\u0026thinsp;=\u0026thinsp;1328) and White (N-2552) patients with schizophrenia. (16). It is of note that although Black patients were not adequately included in the registration trials for schizophrenia compared to the ethnic distribution of schizophrenia in the US population, the total absolute number of Black patients in these trials was higher than in this current study.\u003c/p\u003e \u003cp\u003eThis leads us to a possible explanation for not finding a difference in efficacy of medication treatment in acute mania between Black and White patients in this study. Although we pooled individual patient data from ten different registration trials, creating the largest dataset investigating effect size differences between ethnicities to date, it could still be underpowered to find these differences, with only 175 Black participants allowing for false negative results.\u003c/p\u003e \u003cp\u003eAlso, ethnicity may be associated with many factors that could increase or decrease efficacy of medication (26). We were not able to control for underlying or associated factors that may have influenced treatment efficacy. There are some indications that there is a difference in side effects between different ethnic groups (17, 18) and that genetic ancestry may influence the pharmacodynamic profile (27, 28). A review of 51 studies describing side effects of antipsychotic medication in patients with schizophrenia found evidence of ethnic differences in the risk of adverse events (29). In addition, genetic profiles vary widely within ethnic groups and there is no proof of an underlying explanation for possible differences in the prevalence of side effects.\u003c/p\u003e \u003cp\u003eThe main strength of our study is the inclusion of individual patient data from a relatively large group of patients with acute mania from double-blind randomised placebo-controlled trials. This increases the reliability and generalisability of our findings, by quantifying the effect modification while accounting for heterogeneity between studies. Our study is, however, not without limitations. Only a few of the studies analysed in the main analysis could be included in the sensitivity analysisdue to an insufficient number of participants per study arm (n\u0026thinsp;\u0026gt;\u0026thinsp;5) s. This may limit the generalisability of our findings. Second, because the enrolment of included studies was between 1991 and 2004, the newest medications were not examined. However, medications included in the current study are still the most prescribed drugs in current clinical practice (30). In addition, due to agreements with pharmaceutical companies, we were not able to examine the effect of ethnicity for specific (types of) medications. This may be an important limitation as antipsychotics were found to be significantly more effective in the treatment of acute mania than mood stabilisers, with haloperidol, risperidone, and olanzapine ranked as the most potent(31). The fact that we could not examine the drugs individually may mask possible ethnic differences for specific medications. Finally, it should be noted that meta-analysis even with data from randomized controlled trials should be viewed as a naturalistic experiment with a serious risk of confounding. Fortunately, we were able to control for several potential confounders, but residual confounding cannot be excluded. For example, patients with a rapid cycling course or with mixed episodes are associated with a more severe course and could be associated with ethnicity and treatment outcome (32, 33). These data were not available in our dataset.\u003c/p\u003e \u003cp\u003eDue to a lack of complete information on the inclusion date of patients, we were not able to examine the inclusion date as a confounder to the model. However, the forest plots were sorted on publication date of the studies (with ascending date ranging from 1990 to 2004). When viewing these forest plots, there does not seem to be an influence of publication date on the moderating effect of ethnicity.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings show that in medication is equally effective in White and in Black patients with acute mania.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical approval\u003c/strong\u003e \u003cp\u003eInternal Review Boards of the various pharmaceutical companies have approved of the randomised controlled trials that were included in this study. All participants of these trials gave informed consent to participate.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was sought or received for the purposes of this research project.\u003c/p\u003e \u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eB.W.C. Storosum: Conceptualization, Methodology, Formal analysis, Investigation, Writing - Original Draft, Visualization, , S.E. Cohen: Methodology, Formal analysis, Validation, Cedrine Steinz: Formal analysis, Validation, Dr. T. Mattila: Methodology, Supervision, Writing - Review \u0026amp; Editing, Data Curation, Prof. dr. K.C.B. Roes: Methodology, Prof. Dr. C.C. Welten: Methodology, Writing - Review \u0026amp; Editing, Data Curation, Prof. Dr. W. van den Brink: Writing - Review \u0026amp; Editing, Supervision, Prof. Dr. L. de Haan: Writing - Review \u0026amp; Editing, Supervision, Conceptualisation, Prof. Dr. D.A.J.P. Denys: Writing - Review \u0026amp; Editing, Supervision, Conceptualisation J.B. Zantvoord:Writing - Review \u0026amp; Editing, Supervision, Conceptualisation, Project administration, Methodology\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eRestrictions apply to the availability of these data, especially regarding the specific compounds that were investigated. Dataare available from the authors with the permission of the pharmaceutical companies\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8-19.\u003c/li\u003e\n\u003cli\u003eBreslau J, Aguilar-Gaxiola S, Kendler KS, Su M, Williams D, Kessler RC. Specifying race-ethnic differences in risk for psychiatric disorder in a USA national sample. Psychol Med. 2006;36(1):57-68.\u003c/li\u003e\n\u003cli\u003eMerikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007;64(5):543-52.\u003c/li\u003e\n\u003cli\u003eKessler RC, Angermeyer M, Anthony JC, R DEG, Demyttenaere K, Gasquet I, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization\u0026apos;s World Mental Health Survey Initiative. World Psychiatry. 2007;6(3):168-76.\u003c/li\u003e\n\u003cli\u003eAkiskal HS, Bourgeois ML, Angst J, Post R, Moller H, Hirschfeld R. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord. 2000;59 Suppl 1:S5-S30.\u003c/li\u003e\n\u003cli\u003eChen YR, Swann AC, Johnson BA. Stability of diagnosis in bipolar disorder. J Nerv Ment Dis. 1998;186(1):17-23.\u003c/li\u003e\n\u003cli\u003eJones BE, Gray BA. Problems in diagnosing schizophrenia and affective disorders among blacks. Hosp Community Psychiatry. 1986;37(1):61-5.\u003c/li\u003e\n\u003cli\u003eKilbourne AM, Haas GL, Mulsant BH, Bauer MS, Pincus HA. Concurrent psychiatric diagnoses by age and race among persons with bipolar disorder. Psychiatr Serv. 2004;55(8):931-3.\u003c/li\u003e\n\u003cli\u003eStrakowski SM, Keck PE, Jr., Arnold LM, Collins J, Wilson RM, Fleck DE, et al. Ethnicity and diagnosis in patients with affective disorders. J Clin Psychiatry. 2003;64(7):747-54.\u003c/li\u003e\n\u003cli\u003eZhang AY, Snowden LR. Ethnic characteristics of mental disorders in five U.S. communities. Cultur Divers Ethnic Minor Psychol. 1999;5(2):134-46.\u003c/li\u003e\n\u003cli\u003eAssociation AP. The Diagnostical and Statistical manual of Mental Disorders, version 52013.\u003c/li\u003e\n\u003cli\u003eFleck DE, Hendricks WL, DelBello MP, Strakowski SM. Differential prescription of maintenance antipsychotics to African American and white patients with new-onset bipolar disorder. J Clin Psychiatry. 2002;63(8):658-64.\u003c/li\u003e\n\u003cli\u003eSzarek BL, Goethe JW. Racial differences in use of antipsychotics among patients with bipolar disorder. J Clin Psychiatry. 2003;64(5):614-5; author reply 5.\u003c/li\u003e\n\u003cli\u003eYildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36(2):375-89.\u003c/li\u003e\n\u003cli\u003eStorosum BWC CS, Mattila T, Roes K, Welten CCM, Brink van den W, Haan de L, Denys, DAJP, Zantvoord JB. Gender differences in the response to antipsychotic and mood stabilisers medication in patients with acute mania: An individual patient data meta-analysis of placebo-controlled studies. submitted to Bipolar Disorders 2022.\u003c/li\u003e\n\u003cli\u003eStorosum BWC CS, Mattila T, Roes K, Welten CCM, Brink van den W, Haan de L, Denys, DAJP, Zantvoord JB. Ethnic differences in response to atypical antipsychotics in patients with schizophrenia: an individual patient data meta-analysis of randomized placebo-controlled trials. 2022.\u003c/li\u003e\n\u003cli\u003eDegenhardt EK, Tamayo JM, Jamal HH, Gatz J, Tohen M, Durell TM. Relationship between African-American or Caucasian origin and outcomes in the olanzapine treatment of acute mania: a pooled analysis of three adult studies conducted in the United States of America. Int Clin Psychopharmacol. 2011;26(3):141-5.\u003c/li\u003e\n\u003cli\u003eTamayo JM, Mazzotti G, Tohen M, Gattaz WF, Zapata R, Castillo JJ, et al. Outcomes for Latin American versus White patients suffering from acute mania in a randomized, double-blind trial comparing olanzapine and haloperidol. J Clin Psychopharmacol. 2007;27(2):126-34.\u003c/li\u003e\n\u003cli\u003eBrewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med. 2004;141(8):614-27.\u003c/li\u003e\n\u003cli\u003eFlanagin A, Frey T, Christiansen SL. Updated Guidance on the Reporting of Race and Ethnicity in Medical and Science Journals. Jama. 2021;326(7):621-7.\u003c/li\u003e\n\u003cli\u003eStewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, et al. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313(16):1657-65.\u003c/li\u003e\n\u003cli\u003eYoung RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-35.\u003c/li\u003e\n\u003cli\u003eEndicott J, Spitzer RL. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978;35(7):837-44.\u003c/li\u003e\n\u003cli\u003eCPMP. Note for guidance on clinical investigation of medicinal product of the treatment and prevention of bipolar disorder.: The European Agency for the Evaluation of Medicinal Products; 2001.\u003c/li\u003e\n\u003cli\u003eBureau USC. The 2020 Census. 2020.\u003c/li\u003e\n\u003cli\u003eStronks K, Snijder MB, Peters RJ, Prins M, Schene AH, Zwinderman AH. Unravelling the impact of ethnicity on health in Europe: the HELIUS study. BMC Public Health. 2013;13:402.\u003c/li\u003e\n\u003cli\u003eWiers CE, Towb PC, Hodgkinson CA, Shen PH, Freeman C, Miller G, et al. Association of genetic ancestry with striatal dopamine D2/D3 receptor availability. Mol Psychiatry. 2018;23(8):1711-6.\u003c/li\u003e\n\u003cli\u003eChaudhry I, Neelam K, Duddu V, Husain N. Ethnicity and psychopharmacology. J Psychopharmacol. 2008;22(6):673-80.\u003c/li\u003e\n\u003cli\u003eArnold JG, Miller AL, Canive JM, Rosenheck RA, Swartz MS, Mintz J. Comparison of outcomes for African Americans, Hispanics, and Non-Hispanic Whites in the CATIE study. Psychiatr Serv. 2013;64(6):570-8.\u003c/li\u003e\n\u003cli\u003eH\u0026aacute;lfd\u0026aacute;narson \u0026Oacute;, Zo\u0026euml;ga H, Aagaard L, Bernardo M, Brandt L, Fust\u0026eacute; AC, et al. International trends in antipsychotic use: A study in 16 countries, 2005-2014. Eur Neuropsychopharmacol. 2017;27(10):1064-76.\u003c/li\u003e\n\u003cli\u003eCipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378(9799):1306-15.\u003c/li\u003e\n\u003cli\u003eValenti M, Pacchiarotti I, Undurraga J, Bonnin CM, Popovic D, Goikolea JM, et al. Risk factors for rapid cycling in bipolar disorder. Bipolar Disord. 2015;17(5):549-59.\u003c/li\u003e\n\u003cli\u003eVieta E, Popovic D, Rosa AR, Sole B, Grande I, Frey BN, et al. The clinical implications of cognitive impairment and allostatic load in bipolar disorder. Eur Psychiatry. 2013;28(1):21-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4875496/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4875496/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLittle is known about the effect of ethnicity on drug treatment in patients with an acute manic episode. The aim of this study is to determine whether ethnicity moderates the response to drug treatment in patients with an acute manic episode, and whether this moderation is independent of potential confounders.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe analysed ten short-term placebo-controlled registration trials of atypical antipsychotics and anticonvulsive mood stabilizers in patients with an acute manic episode (n\u0026thinsp;=\u0026thinsp;2199). A one-step random effects individual patient data meta-analysis (IPD) was applied to establish the moderating effect of ethnicity on symptom improvement on the Young Mania Rating Scale (Y)MRS and on response defined as 50% (Y)MRS symptom reduction. These analyses were corrected for baseline severity, age, and gender. A two-step IPD comparing these outcomes between White, Black and Asian patients. Additionally, a conventional meta-analysis was performed to determine the effect size of drug treatment separately for these ethnic groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the complete dataset, 60.4% of the patients was White, 8.0% was Black, 12.7% was Asian, 33.7% was of other ethnicities. Ethnicity did not significantly moderate the efficacy of drug treatment: pooled beta-coefficient (β) for the interaction between treatment and the ethnicities White, Black and Asian, varying from 0.889 to 0.899 with overlapping confidence-intervals ranging from 2.356\u0026ndash;2.430 in the main analysis. The drug treatment effects were significant in all three analysable ethnicity groups compared to placebo.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eIn White,Black, and Asian patients with an acute manic episode drug treatment is equally effective.\u003c/p\u003e","manuscriptTitle":"Ethnic differences in efficacy of drug treatment in patients with an acute manic episode: an individual patient data meta-analysis of randomized placebo-controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-11 08:35:09","doi":"10.21203/rs.3.rs-4875496/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-11T14:38:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-04T12:07:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"169661286117843438383681735803608100419","date":"2024-11-27T15:03:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129674435239243017399289660223581044121","date":"2024-11-22T14:54:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-04T20:45:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"61717282145076082491254346048092523972","date":"2024-10-21T18:44:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196297948759082121151934173534891979105","date":"2024-08-28T14:27:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66005592584287120754924442834647489017","date":"2024-08-26T18:00:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-26T13:57:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-14T09:45:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-14T09:43:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Bipolar Disorders","date":"2024-08-07T14:28:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-bipolar-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbd","sideBox":"Learn more about [International Journal of Bipolar Disorders](http://journalbipolardisorders.springeropen.com/)","snPcode":"40345","submissionUrl":"https://submission.nature.com/new-submission/40345/3","title":"International Journal of Bipolar Disorders","twitterHandle":"@SpringerOpen","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fb411a67-2d13-4d3d-ac72-e9f1e868fcef","owner":[],"postedDate":"October 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T16:02:58+00:00","versionOfRecord":{"articleIdentity":"rs-4875496","link":"https://doi.org/10.1186/s40345-025-00371-0","journal":{"identity":"international-journal-of-bipolar-disorders","isVorOnly":false,"title":"International Journal of Bipolar Disorders"},"publishedOn":"2025-02-23 15:57:41","publishedOnDateReadable":"February 23rd, 2025"},"versionCreatedAt":"2024-10-11 08:35:09","video":"","vorDoi":"10.1186/s40345-025-00371-0","vorDoiUrl":"https://doi.org/10.1186/s40345-025-00371-0","workflowStages":[]},"version":"v1","identity":"rs-4875496","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4875496","identity":"rs-4875496","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}