Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis

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1 Acta Psychiatr Scand 2014: 130: All rights reserved DOI: /acps John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA PSYCHIATRICA SCANDINAVICA Meta-analysis Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multipletreatments meta-analysis. Objective: Treatment of bipolar depression is complicated by variable response and risk of switch to mania. Guidance is informed by the strength of evidence rather than by comparative data. Method: We performed a multiple-treatments meta-analysis of randomised, double-blind, controlled comparisons of 4 16 weeks in adults in bipolar depression. The primary efficacy outcome was effect size. The primary acceptability outcome was switch to mania. Secondary outcomes were likelihood of response and withdrawals from trials. Results: Twenty-nine studies were included (8331 participants). Olanzapine + fluoxetine and olanzapine performed best on primary outcome measure being ranked highest for effect size. Switch to mania was least likely with ziprasidone and then quetiapine. Olanzapine + fluoxetine was also ranked the highest for response with lurasidone second, but olanzapine + fluoxetine and olanzapine had the optimal effect on response and withdrawal from treatment when the two parameters were considered together. Several treatments [monoamine oxidase inhibitors (MAOIs), ziprasidone, aripiprazole and risperidone] have limited or no therapeutic activity in bipolar depression. Conclusion: Olanzapine + fluoxetine should be first-line treatment. Olanzapine, quetiapine, lurasidone, valproate and selective serotonin re-uptake inhibitors are also recommended. Tricyclic antidepressants and lithium are worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole and risperidone (no evidence of efficacy) should not be used. D. M. Taylor 1,2, V. Cornelius 3, L. Smith 4, A. H. Young 5 1 Pharmacy Department, Maudsley Hospital, Denmark Hill, London, 2 Institute of Pharmaceutical Science, King s College London, London, 3 Department of Primary Care & Public Health Sciences, School of Medicine, King s College London, London, 4 Department of Psychology, Social Work and Public Health, Faculty of Health and Life Sciences, Oxford Brookes University, Marston, Oxford, and 5 Centre for Affective Disorders, Institute of Psychiatry, King s College London, London, UK Key words: bipolar disorder; depression; antidepressives; antipsychotics David M. Taylor, Pharmacy Department, Maudsley Hospital, Denmark Hill, London SE5 8AZ, UK. david.taylor@slam.nhs.uk Accepted for publication September 9, 2014 Summations Olanzapine + fluoxetine is the optimal treatment for bipolar depression Olanzapine, quetiapine, lurasidone, valproate, SSRIs, lithium and TCAs also appear to be effective in bipolar depression, but with varied acceptability The use of lamotrigine, MAOIs, ziprasidone, aripiprazole and risperidone is not supported by this analysis Considerations Our multiple-treatments model could not for the most part distinguish statistically between treatments because of the sparse network of trials and the limited number of trial subjects Outcomes of individual trials are likely to have been affected by the co-administration or otherwise of other mood-stabilising drugs 452

2 Treatment of bipolar depression Introduction Bipolar disorder is an important cause of disability (1) and is dominated, in terms of duration of symptoms, by bipolar depression (2). The treatment of an episode of bipolar depression is complicated by variable response according to prior mood episode (3) and by the need to relieve depression without precipitating mania or hypomania or decreasing cycling time. Bipolar depression is often qualitatively different from unipolar or major depression, in that hypersomnolence, hyperphagia and psychosis are more commonly seen (4). These differences are not always present, and a considerable proportion of what is thought to be unipolar depression may be revealed to be bipolar depression only when hypomanic symptoms are fully taken into account (5, 6). The evidence base supporting drug treatment of bipolar depression differs somewhat from that of unipolar depression [for which antidepressants are universally prescribed (7)]. In bipolar depression, there are doubts about the efficacy of standard antidepressants (8) and well-grounded fears about their tendency to induce a switch to mania (9) and provoke rapid cycling (10) or suicidality (11). Mood stabilisers such as lithium are often used for bipolar depression either as a sole treatment or in an attempt to reduce the risk of switching with concomitant antidepressants. Some antipsychotics (quetiapine, olanzapine, lurasidone, amongst others) appear to have some efficacy in bipolar depression as do the mood-stabilising anticonvulsants valproate, carbamazepine and lamotrigine. Current guidance on the treatment of bipolar depression is informed largely by the strength of evidence supporting particular drugs or drug combinations and by direct comparative data (12). In other areas of psychiatry, multiple-treatments meta-analyses (13 15) strongly inform practice and drug selection. Aims of the study We undertook multiple-treatments meta-analysis of drug treatments for bipolar depression in an attempt to identify the most efficacious and best-accepted drugs or drug combinations in this disorder. Material and methods We set out to compare drugs or drug combinations in the treatment of bipolar depression as defined by DSM or ICD at the time of the study. Drugs or drug combinations included were those licensed for therapeutic use as psychotropics in the USA or Europe on or before April Studies examining outcome in subjects described as refractory or resistant were excluded. Studies of mixed populations of bipolar and unipolar depression or mixed states with hypomanic/depression were also excluded. Included studies were randomised, double-blind, controlled comparisons of 4 16 weeks in duration of adult (>18) subjects using validated rating scales [Montgomery Asberg Depression Rating Scale, MADRS, (16) or Hamilton Depression Rating Scale, HAM-D (17)] and reporting continuous outcomes (i.e. change in rating scale score). The primary efficacy outcome for this review was thus change in scores on the depression scale (MADRS or HAMD) (18). If authors reported both MADRS and HAMD, only the MADRS result was included in the analysis as this is considered to be a more sensitive and appropriate rating scale. The primary acceptability outcome was switch to mania as defined by each individual study. Secondary efficacy and acceptability outcomes were response (defined by a 50% reduction in the depression scale) and withdrawal from treatment (for any reason) respectively. Studies reporting response results only were excluded. Where possible, the number of randomised participants was included in the denominator of binary outcomes measures. The quality of included studies was assessed using the Cochrane Risk of Bias Tool (19). Where it was not possible to estimate the standard deviation for the continuous outcome via data report in the trial, we imputed SDs using the method proposed by Furukawa (20). Missing response rates were calculated from the means and standard deviations using an accepted method (21). We searched PubMed, PsychLit, Google Scholar, Medline and Embase in March 2013 using the terms bipolar depression and clinical trial covering the period 1950 to April 2014 and restricting the search to human trials published in English. All study reports retrieved in full were searched for further references to relevant trials. Multiple-treatment meta-analyses are weakened when a large number of interventions are included (22). To simplify the analysis and to facilitate sensible and meaningful comparisons, we planned to group drugs as follows: Monoamine oxidase inhibitors (MAOIs): tranylcypromine, iproniazid, phenelzine and moclobemide; Selective serotonin re-uptake inhibitors (SSRIs): citalopram, escitalopram, sertraline, fluoxetine, fluvoxamine and paroxetine; tricyclic antidepressants (TCAs): amitriptyline, 453

3 Taylor et al. desipramine, imipramine and nortriptyline. The validity of this grouping was later examined by comparing treatment effect estimates within drug class for each direct comparison available. We also planned to combine drug doses where outcomes from fixed dose studies were indistinguishable. Antipsychotic drugs and antimanic drugs were not grouped (having a chemistry and/or pharmacology not amenable to grouping) but examined individually. We planned to include treatments (either single drugs or combinations) examined as initial treatments for nonrefractory bipolar depression. Many trials in bipolar depression allow the use of concurrent cotherapies, so even apparently single-drug treatment might be more correctly considered as combination therapy. Subjects are often enrolled into trials already taking other agents such as mood stabilisers or benzodiazepines. We disregarded the use of these background drugs (and did not count them as combination treatment) on the basis that the background drugs had failed to prevent the current episode of bipolar depression and therefore were unlikely to contribute to acute treatment effects. We included in the analysis only those true combinations where participants were randomised to both drugs in the combination which were started at the same time and examined as if one treatment. Initially, pairwise comparisons were undertaken to calculate the direct treatment effect estimates using a random effects model. A pooled standardised mean difference (SMD) was calculated using Hedge s g for the depression scale meta-analysis, and odds ratios (OR) were calculated for binary outcomes. Statistical heterogeneity was assessed using the I 2 statistic (23), which provides an estimate for the percentage of variability due to heterogeneity. As some comparisons only contained a few studies, we supplemented this assessment by examining the forest plots of all comparisons. The inclusion/exclusion criteria and trial methodology was examined for consistency across included trials. Conceptual heterogeneity for multiple-treatment analysis was assessed informally by examining inconsistency (24). This was achieved by comparing direct and indirect treatment effect estimates in closed triangle and quadrilateral loops and examining the 95% confidence interval with respect to the value zero. We then performed a multiple-treatments metaanalysis to combine direct and indirect evidence to estimate treatment effects (25) using Bayesian methodology that enabled us to perform a probabilistic analysis to estimate rank probabilities. The rank probabilities were summarised for each drug by calculating the surface under the cumulative ranking curve (SUCRA) (26). The random effects 342 records identified in original database search 12 records identified through other sources 275 excluded from title and abstract 80 full articles obtained and assessed for eligibility 37 studies selected for inclusion 29 studies included in meta-analysis 42 excluded: Duplicates -4 Unipolar subjects - 3 Refractory subjects 7 Not double-blind 6 Cross-over design - 2 Longer than 16 weeks - 4 Ineligible treatment* - 15 Mixed antidepressants excluded: No continuous rating scale score data 6 Unable to extract efficacy data 1 Other 1** Fig. 1. Results of literature search. *EPA (3), Modafinil/armodafinil (2), pramipexole (2), N-acetylcysteine (1), topiramate (1), Inositol (1), Idazoxan (1), L-sulpiride (1), herbal remedy (1), celecoxib (1), Flax oil (1). ** A very small trial (n = 23) of aripiprazole vs. aripiprazole + citalopram was excluded post hoc so as to minimise the number of treatments included in the network analysis. 454

4 Treatment of bipolar depression Table 1. Characteristics of included studies Author Study reference Drug A Drug B Drug C Drug D Follow-up (weeks) Setting Diagnosis Inclusion criterion Schaffer (28) Lamotrigine Citalopram 12 out BP I/II HAMD (17) 16 All subjects received MS van der Loos (29) Lamotrigine Placebo 8 out BP I or II MADRS 18 and CGI-BP 4. All subjects received MS (lithium) Shelton (30) Risperidone Paroxetine Risperidone + Paroxetine 12 Unclear BP I/II HAMD (17) 18 and YMRS 8. All subjects received MS Cohn (31) Fluoxetine Imipramine Placebo 6 out Bipolar depression Nemeroff (32) Imipramine Placebo Bipolar depression Silverstone (33) Moclobemide Imipramine 8 In and out Bipolar depression Pilhatsch (34) Paroxetine Amitriptyline 6 Unclear Bipolar depression Tohen (35) Olanzapine Olanzapine and Fluoxetine HAMD (21) 20 and RASKIN 8. MS (lithium) allowed HAMD (21) 15. All subjects received MS (lithium) HAMD 16. Most subjects received MS HAMD (21) 15. All subjects received MS (lithium) Placebo 8 In and out BP I MADRS 20. Thase (36) Aripiprazole Placebo 8 Out BP I HAMD (17) 18 and 2on item 1, major depressive episode > 2 weeks < 2 years, YMRS 12. Thase (36) Aripiprazole Placebo 8 out BP I HAMD (17) 18 and 2on item 1, major depressive Sample size Dose A B C D A B C mg/day mg/day mg mg/day mg/day 1 4 mg and mg/day mg/day mg/day mg/day mg/day mg mg mg/day 6 and 25, 6 and 50, 12 and mg/day mg/day 455

5 Taylor et al. Table 1. (Continued) Author Study reference Drug A Drug B Drug C Drug D Follow-up (weeks) Setting Diagnosis Inclusion criterion episode > 2 weeks < 2 years, YMRS 12. Calabrese (37) Quetiapine Quetiapine Placebo 8 Out BP I/II HAMD 20 and item 1 2, and YMRS 12. McElroy (38) Quetiapine Quetiapine Paroxetine Placebo 8 unclear BP I/II HAMD (17) 20 and item 1 2 and YMRS < 12. Suppes (40) Quetiapine Placebo 8 Out BP I/II HAMD (17) 20 and item 1 2 and YMRS 12. Young (39) Quetiapine Quetiapine Lithium Placebo 8 Out BP I/II HAMD (17) 20 and item 1 2. Thase (41) Quetiapine Quetiapine Placebo 8 Out BP I HAMD (17) 18 and 2 on item 1, major depressive episode > 2 weeks < 2 years, YMRS 12. Sachs (42) Placebo 6 Out BP I HAMD (17) 20 and YMRS 12. All subjects received MS Calabrese study 1 Calabrese study 2 Calabrese study 3 (43) Lamotrigine Placebo 7 BP I Major depressive episode at least 2 weeks, 18 on HAM-D 17. (43) Lamotrigine Placebo 19 BP I/II Major depressive episode at least 2 weeks, 18 on HAM-D 17. (43) Lamotrigine Placebo 8 BP I major depressive episode at least Sample size Dose A B C D A B C mg/day 300 mg/day mg/day 300 mg/day 20 mgs mg/day mg/day 300 mg/day mg/day 300 mg/day mg/day mg mg mg 456

6 Treatment of bipolar depression Table 1. (Continued) Author Study reference Drug A Drug B Drug C Drug D Follow-up (weeks) Setting Diagnosis Inclusion criterion Calabrese study 4 Calabrese study 5 2 weeks, 18 on HAM-D 17. (43) Lamotrigine Placebo 8 BPII Major depressive episode at least 8 weeks, 18 on HAM-D 17, at least 3 on HAM- D item 1 or item 7. (43) Lamotrigine Placebo 8 BPI Major depressive episode at least 8 weeks, 18 on HAM-D 17, at least 3 on HAM- D item 1 or item 7. Davis (44) Divalproex Placebo 8 In and out BPI depressed phase, HAMD 17 score 16, MRS score < 12. Ghaemi (45) Valproate semisodium ER Muzina (46) Valproate semisodium ER Placebo 6 Out BPI/II NOS Major depressive episode MADRS score > 17, MRS score < 12. Placebo 6 Out BPI/II Major depressive episode MADRS score 20, YMRS score < 12, mood stabiliser na ıve. Loebel (48) Lurasidone Lurasidone Placebo 6 Out BPI Major depressive episode 4 weeks, MADRS score 20, YMRS score < 12. Loebel (49) Lurasidone Placebo 6 out BPI Major depressive episode 4 weeks, MADRS Sample size Dose A B C D A B C mg mg mg/day mg/day mg/day 2000 mg/day mg/day mg/day mg/day 457

7 Taylor et al. Table 1. (Continued) Author Study reference Drug A Drug B Drug C Drug D Follow-up (weeks) Setting Diagnosis Inclusion criterion Brown (47) Olanzapine and Fluoxetine score 20, YMRS score < 12. All subjects received MS Lamotrigine 7 In and out BPI Major depressive episode based on SCID for DSM-IV, MADRS score 20, CGI Score 4. Tohen (50) Olanzapine Placebo 6 BPI Major depressive episode 90 days, HAMD 17 score 18, YMRS score < 8. Wang (51) Olanzapine Placebo 8 Out BPI Major depressive episode MADRS 20, CGI 4, YMRS < 15. MS, Mood stabiliser. Sample size Dose A B C D A B C /25, 12/25, 6/50 or 12/50 mg/day mg/day mg/day mg/day Mean 14.4 mg/day 458

8 Olanz +Fluox Aripiprazole Lamotrigine Treatment of bipolar depression 40,000 iterations thinned from 80,000 (after a burn-in period of 5000 iterations). Valproate models described by Salanti et al. (27) were fitted using winbugs software ( uk/bugs) with noninformative prior distributions. Analyses were performed in STATA 11.0, R and WINBUGS 1.4. Results TCA SSRI Included studies In total, 29 studies (28 51) met criteria for inclusion (8331 participants). Figure 1 outlines the results of the literature search, and Table 1 describes the included studies. Figure 2 shows the network of studies included, and Table 1 lists characteristics of these studies. Data grouping Results from the planned fixed dosing regimens in trials of quetiapine (300 mg/day and 600 mg/day) and lurasidone ( mg/day and mg/ day) were combined as the treatment effect estimates for all were virtually identical and the dosing regimens for lurasidone were deemed to be sufficiently similar. We excluded the lamotrigine 50 mg/day arm from a single study (52) because outcome was uniformly numerically worse than with 200 mg a day. Random effects models Risperidone Quetiapine Placebo Lithium Lurasidone MAOI Olanzapine Fig. 2. Network showing the treatment comparisons for efficacy. The size of the nodes is proportional to the number of randomised participants, and the width of the lines is proportional to the number of trials comparing treatment pairs. In random effects models, noninformative prior distributions were used and each sample contained Pairwise comparisons The results of pairwise comparisons for primary outcomes are described in Table 2. Compared with placebo, lamotrigine, lurasidone, olanzapine, olanzapine + fluoxetine, quetiapine, TCA and valproate were significantly more efficacious for depression scale change. Quetiapine, valproate, lurasidone, olanzapine and olanzapine + fluoxetine were associated with a significantly increased risk of response compared with placebo. Withdrawal was significantly less likely with olanzapine and olanzapine + fluoxetine than with placebo. Quetiapine was more efficacious than SSRIs and TCAs more efficacious than MAOIs. Olanzapine + fluoxetine was more efficacious than lamotrigine and olanzapine. Olanzapine + fluoxetine was also superior to lamotrigine and olanzapine in terms of likelihood of response and superior to olanzapine with respect to likelihood of withdrawal. No other statistically significant differences were noted. Multiple treatment-effects estimates Primary outcomes. Table 3 shows effects estimates for efficacy (SMD based on depression scale score change) and tolerability (likelihood of switch to mania). These outcomes are reflected in the rankograms for efficacy (Fig. 3) and switch to mania (Fig. 5). SUCRA rankings for these outcomes are shown in Figs 4 and 6 and expressed graphically in Fig. 7. Overall, olanzapine + fluoxetine had the highest probability of being ranked first for efficacy and MAOIs the highest probability of being ranked last (with the exception of placebo itself). SUCRA rankings suggested all active treatments were more efficacious than placebo but only with respect to olanzapine + fluoxetine and olanzapine was this advantage statistically significant. was most likely to be ranked first for switch to mania (i.e. has the lowest risk of switch) and lamotrigine most likely to be ranked last. SUCRA rankings revealed no statistically significant differences in likelihood of switch to mania. Considering together, the estimates of the two primary outcomes suggested that olanzapine + fluoxetine and quetiapine can be said to have the most optimal balance of efficacy and safety with respect to switching (Table 4). Secondary outcomes. Rankograms for response and withdrawal are shown in Figs 8 and 10, 459

9 Taylor et al. Table 2. Meta-analysis results for all pairwise comparisons No. of studies Total no. participants SMD < 0 favours bold treatment Depression Scale Standardised Mean Difference (95%CI) OR < 1 favours bold treatment Switch to Mania Odds Ratio (95%CI) OR > 1 favours bold treatment Response rate Odds Ratio (95%CI) OR < 1 favours bold treatment Withdrawal Odds Ratio (95%CI) Aripiprazole v Placebo ( 0.25, 0.05) 1.68 (0.60, 4.68) 1.04 (0.77, 1.39) 1.64 (1.22, 2.20) Lamotrigine v Placebo ( 0.32, 0.02) 2.34 (0.44, 12.5) 1.56 (1.23, 1.97) 1.10 (0.77, 1.57) SSRI ( 0.91, 0.99) 1.00 (0.05, 18.6) 0.44 (0.07, 2.67) 0.43 (0.07, 2.68) Olan + Fluox (0.09, 0.48) 1.25 (0.48, 3.23) 0.67 (0.44, 1.00) 1.14 (0.76, 1.72) Lithium v Placebo ( 0.38, 0.10) 2.93 (0.30, 28.6) 1.41 (0.87, 2.30) 0.86 (0.50, 1.49) Quetiapine ( 0.04, 0.34) 0.77 (0.22, 2.65) 0.81 (0.55, 1.21) 1.05 (0.68, 1.63) Lurasidone v Placebo ( 0.51, 0.22) 0.61 (0.12, 3.05) 2.60 (1.94, 3.48) 1.15 (0.82, 1.60) MAOI v TCA (0.08, 0.72) 0.66 (0.20, 2.17) 0.74 (0.39, 1.38) 1.20 (0.61, 2.37) Olanzapine v Placebo ( 0.95, 0.10) 0.79 (0.43, 1.45) 1.58 (1.15, 2.16) 0.68 (0.54, 0.87) Olanz + Fluox (0.03, 0.51) 0.84 (0.31, 2.32) 0.51 (0.32, 0.82) 1.89 (1.17, 3.08) Placebo v Aripiprazole ( 0.05, 0.25) 0.60 (0.21, 1.66) 0.97 (0.72, 1.29) 0.61 (0.45, 0.82) Lamotrigine (0.02, 0.32) 0.43 (0.08, 2.29) 0.64 (0.51, 0.81) 0.91 (0.64, 1.30) Lithium ( 0.10, 0.38) 0.34 (0.04, 3.32) 0.71 (0.44, 1.15) 1.16 (0.67, 1.99) Olanzapine (0.10, 0.95) 1.26 (0.69, 2.31) 0.63 (0.46, 0.87) 1.46 (1.16, 1.85) Quetiapine (0.15, 0.43) 1.68 (0.90, 3.15) 0.54 (0.45, 0.65) 1.05 (0.82, 1.34) SSRI ( 0.12, 1.18) 0.94 (0.43, 2.09) 0.52 (0.19, 1.42) 1.54 (0.88, 2.69) TCA (0.02, 0.97) 0.39 (0.07, 2.09) 0.59 (0.20, 1.75) 1.45 (0.73, 2.87) Valproate (0.03, 0.84) 0.68 (0.20, 2.31) 0.26 (0.09, 0.70) 1.31 (0.58, 2.96) ( 0.21, 0.25) 4.93 (0.23, 103) 1.01 (0.63, 1.60) 1.54 (0.96, 2.49) Lurasidone (0.22, 0.51) 1.63 (0.33, 8.14) 0.38 (0.29, 0.51) 0.87 (0.63, 1.22) Olanz + Fluox (0.21, 0.71) 0.82 (0.30, 2.23) 0.35 (0.22, 0.56) 2.84 (1.74, 4.62) Quetiapine v SSRI ( 0.42, 0.01) 0.26 (0.12, 0.57) 1.51 (1.03, 2.29) 0.90 (0.60, 1.35) Lithium ( 0.34, 0.04) 1.31 (0.38, 4.55) 1.23 (0.83, 1.82) 0.95 (0.61, 1.47) Placebo ( 0.43, 0.15) 0.59 (0.32, 1.11) 1.85 (1.53, 2.23) 0.96 (0.74, 1.23) Risperidone v SSRI ( 0.56, 1.21) 0.33 (0.01, 9.26) 0.44 (0.03, 5.88) 0.25 (0.17, 29.8) SSRI v TCA ( 0.56, 0.19) 0.45 (0.07, 3.10) 1.55 (0.84, 2.84) 0.73 (0.37, 1.44) Lamotrigine ( 0.99, 0.81) 1.00 (0.05, 18.6) 2.25 (0.38, 13.47) 2.33 (0.37, 14.61) Placebo ( 1.18, 0.12) 1.06 (0.48, 2.34) 1.94 (0.71, 5.31) 0.65 (0.37, 1.13) Quetiapine (0.01, 0.42) 3.80 (1.76, 8.20) 0.65 (0.44, 0.97) 1.11 (0.74, 1.68) Risperidone ( 1.21, 0.56) 3.00 (0.11, 83.4) 2.25 (0.17, 29.8) 4.00 (0.55, 29.10) TCA v SSRI ( 0.19, 0.56) 2.22 (0.32, 15.2) 0.65 (0.35, 1.19) 1.37 (0.70, 2.70) MAOI ( 0.72, 0.08) 1.52 (0.46, 5.03) 1.36 (0.72, 2.55) 0.83 (0.42, 1.64) Placebo ( 0.97, 0.02) 2.57 (0.48, 13.8) 1.70 (0.57, 5.03) 0.69 (0.35, 1.37) Valproate v Placebo ( 0.84, 0.03) 1.47 (0.43, 4.97) 3.90 (1.43, 10.66) 0.76 (0.34, 1.71) v Placebo ( 0.25, 0.21) 0.20 (0.01, 4.26) 0.99 (0.63, 1.58) 0.65 (0.40, 1.05) Olanz + Fluox v Lamot ( 0.48, 0.09) 0.80 (0.31, 2.07) 1.50 (1.00, 2.25) 0.88 (0.58, 1.32) Placebo ( 0.70, 0.21) 1.22 (0.45, 3.33) 2.86 (1.77, 4.62) 0.35 (0.22, 0.57) Olanzapine ( 0.51, 0.03) 1.19 (0.43, 3.27) 1.96 (1.22, 3.14) 0.53 (0.33, 0.86) SMD: Negative values favour first treatment; Response an OR > 1 favours 1st treatment; Withdrawal and switch to mania OR <1 favours bold treatment. Bold figures indicate statistically significant outcomes (95% CIs do not include 0.0). SUCRA estimates for these outcomes in Figs 9 and 11 and graphical representation of SUCRA rankings in Fig. 12. Olanzapine + fluoxetine was most likely to be ranked first for efficacy with respect to response (lurasidone second) and MAOIs most likely to be ranked last. SUCRA estimates placed all treatments except MAOIs as superior to placebo but only lurasidone, olanzapine + fluoxetine and quetiapine were significantly superior. 460

10 Treatment of bipolar depression Table 3. Primary efficacy (SMD) and tolerability (switch to mania) multiple-treatment-effect estimates Arip 0.11 ( 0.37, 0.56) 1.47 (0.27, 4.71) 2.76 (0.42, 9.26) 1.61 (0.25, 5.42) 3.88 (0.49, 14.4) 2.22 (0.45, 6.49) 2.59 (0.80, 6.32) 5.35 (1.29, 14.3) 2.92 (0.27, 12.0) 3.38 (0.75, 9.96) 3.81 (0.71, 12.2) 2.66 (0.38, 9.49) 11.4 (1.16, 47.2) 2.67 (0.49, 8.50) 0.06 ( 0.62, 0.) Lamot 0.05 ( 0.64, 0.52) 2.40 (0.39, 7.87) 1.41 (0.23, 4.81) 3.38 (0.45, 12.3) 1.91 (0.44, 5.30) 2.27 (0.74, 5.38) 4.66 (1.21, 12.2) 2.56 (0.25, 10.4) 2.90 (0.74, 8.20) 3.31 (0.65, 10.4) 2.32 (0.35, 8.08) 9.99 (1.04, 40.7) 2.12 (0.62, 5.37) 0.26 ( 0.33, 0.85) 0.15 ( 0.33, 0.63) Lith 0.20 ( 0.48, 0.87) 0.82 (0.12, 3.03) 1.96 (0.23, 7.59) 1.12 (0.22, 3.50) 1.31 (0.37, 3.54) 2.59 (0.70, 6.86) 1.49 (0.13, 6.49) 1.72 (0.36, 5.61) 1.93 (0.33, 6.55) 1.36 (0.18, 5.19) 5.72 (0.56, 23.9) 1.36 (0.24, 4.67) 0.14 ( 1.02, 0.74) 0.25 ( 1.06, 0.56) 0.20 ( 1.13, 0.74) Lursa 0.40 ( 1.28, 0.49) 3.39 ( ) 1.95 (0.36, 6.21) 2.27 (0.61, 6.26) 4.69 (1.02, 13.9) 2.56 (0.21, 10.9) 2.96 (0.59, 9.58) 3.34 (0.54, 11.3) 2.33 (0.30, 8.83) 9.93 (0.91, 42.0) 2.35 (0.39, 8.02) 0.41 ( 0.12, 0.97) 0.31 ( 0.07, 0.71) 0.35 ( 0.27, 1.00) 0.15 ( 0.38, 0.71) MAOI 0.55 ( 0.29, 1.42) 0.90 (0.14, 3.12) 1.06 (0.22, 3.19) 2.17 (0.39, 6.99) 1.19 (0.09, 5.35) 1.35 (0.24, 4.53) 1.33 (0.31, 3.87) 1.09 (0.12, 4.44) 4.64 (0.37, 20.6) 1.10 (0.15, 4.06) 0.10 ( 0.52, 0.32) 0.21 ( 0.45, 0.00) 0.16 ( 0.69, 0.38) 0.36 ( 0.78, 0.06) 0.05 ( 0.74, 0.82) Olanz 0.51 ( 0.87, 0.17) 1.39 (0.57, 3.02) 2.85 (0.91, 6.90) 1.58 (0.17, 6.39) 1.83 (0.51, 5.18) 2.04 (0.47, 6.11) 1.43 (0.25, 4.86) 6.08 (0.75, 23.9) 1.38 (0.39, 3.80) 0.23 ( 0.26, 0.73) 0.12 ( 0.22, 0.47) 0.18 ( 0.35, 0.70) 0.03 ( 0.52, 0.47) 0.38 ( 0.43, 1.18) 0.18 ( 0.62, 0.25) Placebo 0.33 (0.07, 0.59) 2.06 (1.06, 3.45) 1.14 (0.16, 4.03) 1.31 (0.57, 2.75) 1.47 (0.49, 3.52) 1.03 (0.25, 2.88) 4.41 (0.72, 15.5) 1.04 (0.36, 2.45) 0.01 ( 1.14, 1.14) 0.12 ( 1.19, 0.96) 0.07 ( 1.23, 1.12) 0.27 ( 1.40, 0.87) 0.14 ( 1.12, 1.40) 0.42 ( 1.53, 0.69) 0.09 ( 0.96, 1.15) Quet 0.24 ( 1.31, 0.84) 0.60 (0.07, 2.27) 0.68 (0.26, 1.63) 0.78 (0.22, 2.07) 0.55 (0.11, 1.70) 2.32 (0.33, 8.63) 0.55 (0.16, 1.5) 0.31 ( 0.22, 0.87) 0.20 ( 0.19, 0.61) 0.26 ( 0.35, 0.89) 0.05 ( 0.48, 0.61) 0.46 ( 0.31, 1.22) 0.10 ( 0.58, 0.39) 0.41 (0.08, 0.76) 0.08 ( 0.31, 0.49) Risp 0.32 ( 0.68, 1.31) 2.15 (0.29, 8.11) 2.49 (0.26, 10.3) 1.76 (0.14, 7.83) 7.63 (0.44, 37.9) 1.79 (0.17, 7.45) 0.25 ( 0.35, 0.87) 0.15 ( 0.34, 0.64) 0.20 ( 0.48, 0.89) 0.01 ( 0.61, 0.60) 0.40 ( 0.24, 1.03) 0.15 ( 0.72, 0.40) 0.35 ( 0.09, 0.80) 0.02 ( 0.47, 0.52) 0.26 ( 0.82, 1.34) SSRI 0.06 ( 0.47, 0.35) 1.26 (0.37, 3.19) 0.92 (0.16, 2.91) 3.99 (0.47, 15.5) 0.92 (0.22, 2.56) 0.34 ( 0.31, 1.01) 0.24 ( 0.33, 0.81) 0.29 ( 0.45, 1.03) 0.09 ( 0.57, 0.75) 0.49 ( 0.45, 1.41) 0.06 ( 0.69, 0.55) 0.44 ( 0.07, 0.96) 0.11 ( 0.46, 0.69) 0.35 ( 0.81, 1.53) 0.03 ( 0.59, 0.65) TCA 0.09 ( 0.58, 0.77) 0.90 (0.14, 3.14) 3.86 (0.40, 15.9) 0.91 (0.18, 2.78) 0.08 ( 0.82, 0.66) 0.46 ( 0.12, 1.06) 0.19 ( 0.84, 0.45) 0.35 ( 0.07, 0.78) 0.14 ( 0.94, 0.67) 0.40 ( 0.26, 1.09) 0.34 ( 1.07, 0.40) 0.20 ( 0.38, 0.80) 0.07 ( 0.92, 1.03) 0.61 ( 0.28, 1.48) 0.49 ( 1.20, 0.19) 0.05 ( 0.43, 0.51) 0.02 ( 0.58, 0.62) 0.56 (0.15, 0.98) 0.31 ( 0.97, 0.34) 0.23 ( 0.26, 0.72) 0.07 ( 1.29, 1.14) 0.47 ( 0.66, 1.60) 0.39 ( 1.10, 0.29) 0.15 ( 0.39, 0.68) 0.33 ( 1.09, 0.41) 0.21 ( 0.40, 0.81) Valp 0.42 ( 1.22, 0.36) 0.12 ( 0.55, 0.78) 6.33 (0.54, 27.5) 1.49 (0.23, 5.20) Zipra 0.54 ( 0.19, 1.28) 0.44 (0.05, 1.75) Olan + Fluox Efficacy measured using Standardised Mean Difference (SMD) of depression scale shown in the top RHS of the table. SMD <0 favour first treatment reading across (first treatment) and then down (comparison treatment). Tolerability measured using Odds Ratio (OR) for switch to mania shown in the bottom LHS of the table. OR <1 favours first treatment reading down (first treatment) and then across (comparison treatment). Statistically significant results are indicated in bold and the blue text highlights results where the first treatment has a favourable result compared to the comparison treatment. 461

11 Taylor et al. Aripiprazole Lamotrigine Lithium Lurasidone Probability of rank MAOI Olanzapine Placebo Quetiapine Risperidone SSRI TCA Valproate Olan+Fluox Rank Fig. 3. Rankogram showing the probability of rank for efficacy (SMD) by treatment. Higher probability of lower rank (i.e. 1) is favourable. Olanzapine + fluoxetine was most likely to be ranked first in terms of withdrawal from treatment and aripiprazole most likely to be ranked last. No treatment was statistically superior to placebo with respect to withdrawal, but withdrawal was more likely with aripiprazole than with olanzapine + fluoxetine. SUCRA SMD Olan+Fluox Olanzapine Valproate SSRI Lurasidone TCA Quetiapine Fig. 4. SUCRA and 95% CIs for efficacy (SMD) in rank order. SUCRA: Surface under the cumulative ranking curve (SUCRA), higher value is favourable. Lamotrigine Lithium Risperidone Aripiprazole MAOI Placebo Considering together the results for the two secondary outcomes suggested that olanzapine + fluoxetine and olanzapine had the best balance of likelihood of response with lower likelihood of withdrawal. Rankings for the four outcomes considered are summarised in Table 5. Evaluation of coherence in closed loops Figure 13 shows that there was no statistical difference between direct and indirect estimates of efficacy. Discussion This multiple-treatments meta-analysis of drug treatment of bipolar depression found that olanzapine + fluoxetine performed best on primary outcome measures and also that olanzapine + fluoxetine had the most favourable effect on secondary outcomes. Estimates of effect on efficacy outcomes suggest that several treatments (MAOIs, ziprasidone, aripiprazole and risperidone) have limited or no therapeutic activity in bipolar depression. 462

12 Treatment of bipolar depression Aripiprazole Lamotrigine Lithium Lurasidone Probability of rank MAOI Olanzapine Placebo Quetiapine Risperidone SSRI TCA Valproate Olan+Fluox Rank Fig. 5. Rankogram showing probability of rank of switch to mania by treatment. Higher probability of lower rank (i.e. 1) is favourable. SUCRA switch to mania Quetiapine TCA SSRI MAOI Placebo Lithium Olan+Fluox Valproate Risperidone Olanzapine Lurasidone Lamotrigine Aripiprazole SUCRA efficacy Olanz + Fluox Olanzapine Valproate SSRI Lurasidone TCA Quetiapine Lamotrigine Lithium Risperidone Aripiprazole MAOI Placebo SUCRA switch to mania Fig. 6. SUCRA and 95% CIs for switch to mania in rank order. SUCRA: Surface under the cumulative ranking curve (SUCRA), higher value is favourable. Overall, these results are in some contrast to prevailing clinical practice where standard antidepressants tend to be withheld because of concerns overswitching to mania and where quetiapine (supported by the greatest strength of trial evidence), lithium and valproate (based on traditional practice) are widely used. Fig. 7. SUCRA point estimates for efficacy (SMD) and switch to mania. SUCRA: Surface under the cumulative ranking curve (SUCRA), higher value is favourable for both outcomes. Methodological considerations In general, the results of pairwise comparisons were relatively more in line with clinical practice. SSRIs were not statistically superior in efficacy to placebo, whereas established treatments such as 463

13 Taylor et al. Table 4. Secondary efficacy (Response) and tolerability (Withdrawal) multiple-treatment-effect estimates Arip 0.68 (0.45, 1.00) 1.65 (0.91, 2.74) 1.69 (0.73, 3.38) 1.44 (0.70, 2.62) 1.79 (0.56, 4.34) 2.11 (1.06, 3.65) 1.65 (1.01, 2.54) 1.65 (0.92, 2.72) 3.72 (0.70, 11.8) 1.92 (0.97, 3.45) 2.10 (0.92, 4.19) 2.33 (0.84, 5.16) 2.51 (1.02, 5.10) 2.86 (1.40, 5.21) 0.75 (0.42, 1.23) Lamot 1.12 (0.68, 1.76) 1.05 (0.50, 1.97) 0.89 (0.49, 1.51) 1.11 (0.38, 2.59) 1.31 (0.77, 2.04) 1.03 (0.75, 1.37) 1.02 (0.66, 1.51) 2.31 (0.46, 7.18) 1.20 (0.69, 1.96) 1.31 (0.63, 2.43) 1.45 (0.57, 3.04) 1.56 (0.71, 2.99) 1.76 (1.05, 2.76) 0.43 (0.26, 0.66) 0.64 (0.42, 0.93) Lith 0.59 (0.34, 0.97) 0.94 (0.39, 1.88) 1.17 (0.33, 2.99) 1.37 (0.60, 2.63) 1.08 (0.55, 1.88) 1.06 (0.55, 1.84) 2.42 (0.42, 7.82) 1.25 (0.56, 2.44) 1.37 (0.53, 2.95) 1.52 (0.49, 3.66) 1.64 (0.59, 3.59) 1.87 (0.78, 3.72) 1.38 (0.51, 2.98) 0.71 (0.45, 1.04) 1.07 (0.76, 1.45) 0.57 (0.38, 0.81) 1.01 (0.18, 3.14) 0.44 (0.44, 1.15) 0.99 (0.48, 1.78) 0.55 (0.22, 1.17) 1.11 (0.59, 1.89) 0.42 (0.25, 0.66) 2.06 (0.79, 4.33) 1.06 (0.74, 1.45) 1.59 (1.26, 1.98) 0.85 (0.62, 1.13) 1.52 (0.28, 4.76) 1.11 (0.71, 1.65) 1.48 (0.76, 2.5) 0.83 (0.34, 1.72) 1.66 (0.93, 2.73) 0.63 (0.43, 0.87) 1.92 (0.69, 4.31) 0.99 (0.57, 1.57) 1.49 (0.95, 2.22) 0.79 (0.50, 1.16) 1.42 (0.25, 4.61) 1.03 (0.58, 1.67) 1.38 (0.63, 2.58) 0.77 (0.29, 1.70) 1.55 (0.76, 2.80) 0.59 (0.32, 1.00) Lursa 3.33 (1.22, 7.39) 1.71 (1.09, 2.51) 2.57 (1.82, 3.51) 1.37 (0.91, 1.96) 2.45 (0.44, 7.89) 1.79 (1.05, 2.81) 2.38 (1.16, 4.31) 1.34 (0.52, 2.87) 2.67 (1.42, 4.56) 1.02 (0.61, 1.60) 1.32 (0.41, 3.25) 1.56 (0.78, 2.74) 1.22 (0.73, 1.91) 1.21 (0.67, 2.03) 2.75 (0.51, 8.83) 1.42 (0.71, 2.59) 1.56 (0.67, 3.15) 1.72 (0.62, 3.84) 1.85 (0.75, 3.81) 2.11 (1.01, 3.92) MAOI 0.61 (0.24, 1.33) 0.92 (0.37, 1.93) 0.49 (0.20, 1.03) 0.87 (0.12, 3.09) 0.63 (0.26, 1.32) 0.79 (0.40, 1.43) 0.48 (0.13, 1.22) 0.96 (0.33, 2.24) 0.36 (0.14, 0.81) 1.47 (0.47, 3.47) Olanz 1.53 (1.18, 1.99) 0.82 (0.58, 1.12) 1.46 (0.27, 4.66) 1.07 (0.66, 1.60) 1.42 (0.72, 2.48) 0.80 (0.33, 1.68) 1.59 (0.89, 2.68) 0.60 (0.40, 0.88) 1.15 (0.41, 2.58) 0.81 (0.54, 1.19) Placebo 0.53 (0.43, 0.65) 0.95 (0.18, 2.99) 0.70 (0.47, 0.97) 0.93 (0.50, 1.55) 0.52 (0.22, 1.06) 1.04 (0.62, 1.65) 0.40 (0.28, 0.56) 1.14 (0.39, 2.65) 0.80 (0.49, 1.27) 0.99 (0.74, 1.31) Quet 1.80 (0.34, 5.77) 1.31 (0.90, 1.84) 1.75 (0.98, 2.98) 1.01 (0.44, 2.04) 1.97 (1.11, 3.22) 0.75 (0.49, 1.11) 2.55 (0.37, 8.99) 1.83 (0.35, 5.76) 2.26 (0.47, 6.80) 2.30 (0.47, 7.04) Risp 1.19 (0.23, 3.75) 1.60 (0.27, 5.23) 0.90 (0.14, 3.22) 1.80 (0.32, 6.01) 0.68 (0.13, 2.26) 1.31 (0.46, 3.01) 0.94 (0.51, 1.66) 1.17 (0.73, 1.78) 1.18 (0.72, 1.87) 0.81 (0.17, 2.44) SSRI 1.35 (0.75, 2.25) 0.77 (0.31, 1.63) 1.55 (0.81, 2.72) 0.59 (0.35, 0.95) 1.35 (0.57, 2.73) 1.04 (0.48, 2.00) 1.28 (0.67, 2.24) 1.31 (0.64, 2.40) 0.90 (0.16, 2.91) 1.13 (0.58, 2.01) TCA 0.61 (0.22, 1.38) 1.22 (0.53, 2.39) 0.46 (0.23, 0.86) 1.62 (0.40, 4.44) 1.13 (0.44, 2.44) 1.41 (0.60, 2.83) 1.44 (0.57, 3.01) 0.99 (0.16, 3.44) 1.27 (0.46, 2.81) 1.22 (0.40, 2.89) Valp 2.33 (0.83, 5.27) 0.88 (0.35, 1.88) 1.75 (0.47, 4.57) 1.23 (0.54, 2.45) 1.52 (0.74, 2.77) 1.56 (0.71, 2.97) 1.08 (0.18, 3.56) 1.37 (0.57, 2.76) 1.31 (0.48, 2.87) 1.27 (0.40, 3.08) Zipra 0.41 (0.21, 0.70) 1.99 (0.61, 4.83) 1.41 (0.80, 2.36) 1.74 (1.04, 2.71) 1.77 (0.98, 2.96) 1.23 (0.23, 3.90) 1.56 (0.77, 2.80) 1.49 (0.64, 2.97) 1.44 (0.52, 3.23) 1.27 (0.52, 2.64) Olan + Fluox Secondary efficacy measured using Odds Ratio (OR) for Response shown in the top RHS of the table. OR >1 favour first treatment reading across (first treatment) and then down (comparison treatment). Tolerability measured using Odds Ratio (OR) for Withdrawal shown in the bottom LHS of the table. OR <1 favours first treatment reading down (first treatment) and then across (comparison treatment). Significant results are indicated in bold and the blue text highlights results where the first treatment has a favourable result compared to the comparison treatment significant results are indicated in bold and the blue text highlights results where the first treatment has a favourable result compared to the comparison treatment. 464

14 Treatment of bipolar depression Aripiprazole Lamotrigine Lithium Lurasidone MAOI Olanzapine Placebo Quetiapine Probability of rank Risperidone SSRI TCA Valproate Olan+Fluox Rank Fig. 8. Rankogram for probability of rank of response by treatment. Higher probability of lower rank (i.e. 1) is favourable. lamotrigine, quetiapine, valproate (and TCAs) were superior in effect size. Interestingly, quetiapine was statistically superior to SSRIs in pairwise comparison (based on the results from one large study) but was not statistically differentiated from SSRIs in SUCRA estimates. This is because the multiple-treatment estimates put equal weight on SUCRA response Olan+Fluox Lurasidone Valproate Quetiapine Lamotrigine Olanzapine SSRI Fig. 9. SUCRA and 95% CIs for response in rank order. SUCRA: Surface under the cumulative ranking curve (SUCRA), higher value is favourable. Lithium Risperidone TCA Aripiprazole Placebo MAOI direct and nondirect comparisons and SSRIs performed better than quetiapine against other comparators. Many would argue that direct comparisons should carry more weight; however, multiple-treatment analysis assesses the totality of the evidence for specified outcomes across trials in an unbiased approach. Sources of error in our analysis include duration of study (longer studies may allow greater improvement and more switching), study setting (in- or out-patient) and possible additive or synergistic action between trial drugs and (failed) background drugs such as mood stabilisers. Notably, studies of olanzapine + fluoxetine, the best performing treatment, were 7 or 8 weeks in duration in both in- and outpatients and in the absence of background mood stabilisers. A further limitation is the small number of subjects included in some individual trials which reduced precision and so our ability properly to distinguish between treatments. Overlap of SU- CRA confidence intervals indicates considerable uncertainty in many of our rankings. Future, large RCTs would strengthen the network and improve the precision of these estimates. 465

15 Taylor et al Aripiprazole Lamotrigine Lithium Lurasidone Probability of rank MAOI Olanzapine Placebo Quetiapine Risperidone SSRI TCA Valproate Olan+Fluox Rank Fig. 10. Rankogram for probability of rank of withdrawal by treatment. Higher probability of lower rank (i.e. 1) is favourable. SUCRA withdrawal Olan+Fluox Risperidone Olanzapine Valproate TCA SSRI Fig. 11. SUCRA and 95% CIs for withdrawal in rank order. SUCRA: Surface under the cumulative ranking curve (SU- CRA), higher value is favourable. MAOI Placebo Lithium Quetiapine Lamotrigine Lurasidone Aripiprazole SUCRA response (efficacy) Aripiprazole Lurasidone Quetiapine Lamotrigine Lithium Placebo MAOI SSRI TCA Valproate Olanzapine Risperidone Olanz + Fluox SUCRA withdrawal Fig. 12. SUCRA point estimates for efficacy (SMD) and withdrawal. SUCRA: Surface under the cumulative ranking curve (SUCRA), higher value is favourable for both outcomes. We excluded studies of patients with mixed symptoms (manic or hypomanic symptoms with depression) and so our results cannot be generalised to these patients. Another potential confounding factor is that, in bipolar depression, improvement in depression may represent exactly that or part of a process of switching to mania/hypomania. Clearly, the aim of treatment is to relieve depression without causing a switch to mania/hypomania, but many studies did not report whether or not switchers and responders were one and the same. Indeed, the thymoleptic activity of drugs might be expected to be reflected both by improvement in depression and by switch to mania/hypomania (the 466

16 Treatment of bipolar depression Table 5. Summary of rankings Symptom score change (effect size highest first) Response (highest likelihood first) Switch to mania (lowest risk first) Withdrawal (lowest risk first) Olanzapine + fluoxetine Olanzapine + fluoxetine Olanzapine + fluoxetine Olanzapine Lurasidone Quetiapine Risperidone Valproate Valproate TCA SSRI Quetiapine SSRI Olanzapine Lurasidone Lamotrigine MAOI Valproate bgj bgn ghj gjk fgn cgh Key: b c f g h j k n Lamotrigine Lithium Olanzapine Placebo Quetiapine SSRI: TCA: Olanzapine & Fluoxetine 0.27 [ 0.85, 1.39 ] 0.00 [ 0.34, 0.35 ] 0.46 [ 0.24, 1.17 ] 0.58 [ 0.07, 1.24 ] 0.60 [ 0.59, 1.79 ] 0.00 [ 0.35, 0.36 ] Fig. 13. Evaluation of coherence in closed loops. Graph shows the estimates of difference between direct and indirect estimates with 95% CIs. better the antidepressant effect, the greater the risk of switching). In this regard, intrinsic antimanic effect (olanzapine, quetiapine, valproate, lurasidone, etc.) is important in allowing relief of depression while protecting against switch to mania/ hypomania, as is the coprescription of background mood stabilisers which might have failed to treat or prevent depression but serve as protection against switching. Note, however, that there was no clear advantage identified in this analysis for antimanic drugs with respect to protection against switching. Interestingly, however, ziprasidone provided the best protection against switching but was ineffective in treating bipolar depression (and so is not thymoleptic). Quetiapine was ranked second with respect to switch to mania, but all trials were of quetiapine monotherapy, whereas ziprasidone, to its advantage it might be assumed, was added to mood stabilisers. A further complexity is that it is also likely that response in bipolar depression and switch to mania/hypomania follow a different but overlapping timescale. In a study of bupropion, sertraline and venlafaxine (53), rates of switching did not differ at 6 weeks (rate of <10% for all drugs), but at 12 weeks, nearly 70% of venlafaxine subjects had switched compared with fewer than 20% on sertraline and bupropion. Thus, the results of shorter term studies may not reflect the true risk of switch to mania. It is also important to note the results of studies not included in this analysis. Early studies with lithium, although often of poor quality, esoteric design (e.g. brief periods of treatment interspersed with abrupt switching) and brief duration, demonstrated a fairly robust effect for the drug (54 58) hence its popularity in practice. A recent study (n = 366), not included here because of the absence of continuous data of paroxetine or bupropion added to mood stabiliser, showed no effect at all for the additional antidepressants vs. placebo (59) (in some contrast to findings here). Also, numerous studies suggest the possible benefit of other excluded drugs in the treatment bipolar depression (60 68). Implications for practice Based on our analysis, olanzapine + fluoxetine should be recommended as the first-line treatment for bipolar depression. Olanzapine and quetiapine can be recommended as alternative first-line treatments. Lurasidone and SSRIs may also be used, but both performed relatively poorly compared with our first-line drugs with respect to switching and withdrawal and SSRIs did not separate from placebo in pairwise comparisons. Valproate and, although less well supported in this analysis, lithium are also worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole, risperidone and TCAs (dubious efficacy) should perhaps not be used. Putting these findings into practice may be difficult. Outside the United States, the combination of olanzapine and fluoxetine is not widely used and concerns about the long-term metabolic effects of olanzapine militate against its use. SSRIs continue to decline in use, whereas lurasidone is relatively new to therapy. Quetiapine, lithium and valproate are established treatments and their use in bipolar depression is likely to continue, as it should. Overall, a move towards greater use of olanzapine + fluoxetine is likely to be of benefit to patients if metabolic effects can be controlled. 467

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