Comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression in adults: a systematic review and network meta-analysis

May combine two claims.

Except for one network meta-analysis on antipsychotics (sponsored by the manufacturer of lurasidone), no studies that the authors know of employed any assessment of the confidence in the evidence.

“Except for one network meta-analysis on antipsychotics (sponsored by the manufacturer of lurasidone), 6 no studies that we know of employed any assessment of the confidence in the evidence, which is necessary to draw evidence-based conclusions.8,9”

• cites [6] Kadakia, 2021, Efficacy and tolerability of atypical antipsychotics for acute bipolar depression: a network meta-analysis, BMC Psychiatry sourcePartly supported

  The Methods, ‘Quality of evidence and heterogeneity’ (page unavailable), identifies this as a network meta-analysis that used GRADE to assess confidence in the evidence; the Results report its quality ratings. The passages found do not establish that the analysis was sponsored by lurasidone’s manufacturer. The statement that the citing authors know of no other such studies is their own qualification, not a finding attributed to this paper. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [8] Bahji, 2020, Comparative efficacy and tolerability of pharmacological treatments for the treatment of acute bipolar depression: a systematic review and network meta-analysis, J Affect Disord sourceNot checked — no full text of the source
• cites [9] Bahji, 2021, Comparative efficacy and tolerability of adjunctive pharmacotherapies for acute bipolar depression: a systematic review and network meta-analysis, Can J Psychiatry sourceDisputed

  The paper’s “Risk of Bias across Studies” section says it followed GRADE recommendations to evaluate overall network quality and risk of bias, including assessments of imprecision and publication bias. This adjunctive-pharmacotherapy network meta-analysis therefore reports an assessment relevant to confidence in the evidence, contrary to the claim that no other studies employed any such assessment. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Meta-analyses of trials of patients with schizophrenia found that antipsychotics, except sertindole, amisulpride and arguably ziprasidone, were relatively benign.

“Meta-analyses of trials of patients with schizophrenia found that antipsychotics (except sertindole, amisulpride and, arguably, ziprasidone) were relatively benign.38”

• cites [38] Huhn, 2019, Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis, Lancet sourceDisputed

  The Results (page unavailable) do not describe antipsychotics other than the three named as relatively benign. They report significantly increased use of antiparkinson medication for 21 of 32 drugs and significantly greater sedation for 18 of 32; sertindole, amisulpride, and ziprasidone are not the only drugs associated with adverse effects. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Confidence in the evidence for the primary outcomes was evaluated using CINeMA, and conclusions were drawn using a minimally contextualised framework of the GRADE approach.

“We evaluated confidence in the evidence for the primary outcomes using CINeMA (Confidence-In-Network-Meta-Analysis), 14 and conclusions were drawn using a minimally contextualised framework of the GRADE approach.15”

• cites [14] Nikolakopoulou, 2020, CINeMA: an approach for assessing confidence in the results of a network meta-analysis, PLoS Med sourceSupported
• cites [15] Brignardello-Petersen, 2020, GRADE approach to drawing conclusions from a network meta-analysis using a minimally contextualised framework, BMJ sourceSupported

Classified as probably not a substantial claim. May combine two claims.

Risk of bias for the primary outcomes was evaluated using the RoB 2 tool and confirmed by other authors.

“AY evaluated the risk of bias for the primary outcomes using the risk of bias tool 2 (RoB 2), 18 and this was confirmed by BA, SS, and SL.”

• cites [18] Sterne, 2019, RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ sourceSupported

May combine two claims.

Available systematic reviews either focused on antipsychotics alone or did not apply meta-analysis.

“However, evidence-based pharmacological treatments differ in their efficacy and tolerability, and available systematic reviews either focused on antipsychotics alone, 6 or did not apply metaanalysis.7”

• cites [6] Kadakia, 2021, Efficacy and tolerability of atypical antipsychotics for acute bipolar depression: a network meta-analysis, BMC Psychiatry sourceSupported
• cites [7] Cai, 2023, Efficacy and safety profiles of mood stabilizers and antipsychotics for bipolar depression: a systematic review, Int Clin Psychopharmacol sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

An umbrella review including bipolar depression pointed out that most antipsychotics have an unfavourable risk profile.

“An umbrella review including bipolar depression also pointed out that most antipsychotics have an unfavourable risk profile.36”

• cites [36] Croatto, 2023, The impact of pharmacological and non-pharmacological interventions on physical health outcomes in people with mood disorders across the lifespan: an umbrella review of the evidence from randomised controlled trials, Mol Psychiatry sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

The robustness of the primary outcomes was examined with predefined sensitivity analyses.

“We examined the robustness of the primary outcomes with predefined sensitivity analyses by using a fixedeffects model (or a random-effects model if originally a fixed-effects was used), excluding studies based on the above-mentioned potential effect-modifiers, excluding studies with imputed values, excluding studies from less developed countries (post-hoc), 25 completers-only data, and studies”

• cites [25] Panagiotou, 2013, Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment, BMJ sourcePartly supported

  The Statistical analysis section reports sensitivity analyses, including one that excluded trials from countries that had evolved from less developed to more developed. It does not say these analyses were predefined, and the exclusion cited in the sentence is broader than the one the source describes: it did not exclude all studies from less developed countries. No page number is available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Fluoxetine, which was especially recommended by Bahji and colleagues' 2021 study, had a sample size of only 38 participants.

“For example, fluoxetine which was especially recommended by Bahji and colleagues' 2021 study 9 had a sample size of only 38 participants.”

• cites [9] Bahji, 2021, Comparative efficacy and tolerability of adjunctive pharmacotherapies for acute bipolar depression: a systematic review and network meta-analysis, Can J Psychiatry sourcePartly supported

  The Conclusions identify fluoxetine as having the most consistent evidence for augmentation in bipolar depression, supporting the characterization that the study favored it. But the Summary of Evidence reports a pooled fluoxetine sample size of 529, not 38 participants. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

The mean increases in msec compared to placebo were very small, in line with a recent review.

“The mean increases in msec compared to placebo were very small, in line with a recent review.36”

• cites [36] Croatto, 2023, The impact of pharmacological and non-pharmacological interventions on physical health outcomes in people with mood disorders across the lifespan: an umbrella review of the evidence from randomised controlled trials, Mol Psychiatry sourcePartly supported

  The Cardiovascular and respiratory system section (page unavailable) reports no difference in QTc change when antipsychotics were added to mood stabilizers in adults with bipolar disorder. The Results table (page unavailable) gives a nonsignificant standardized difference for that comparison, but the review does not report small mean increases in milliseconds versus placebo. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

May combine two claims.

Lamotrigine has a good tolerability profile apart from rare but potentially life-threatening Stevens-Johnson syndrome.

“Apart from rare, but potentially lifethreatening Stevens-Johnson syndrome, 11,37 it has a good tolerability profile”

• cites [11] Yatham, 2018, Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder, Bipolar Disord sourceSupported
• cites [37] Grande, 2016, Bipolar disorder, Lancet sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The mean weight gain results are in line with those in schizophrenia.

“The mean weight gain results are in line with those in schizophrenia.36,38”

• cites [36] Croatto, 2023, The impact of pharmacological and non-pharmacological interventions on physical health outcomes in people with mood disorders across the lifespan: an umbrella review of the evidence from randomised controlled trials, Mol Psychiatry sourceCould not verify

  The Body weight and body mass index section reports weight gain in people with mood disorders, but does not compare mean weight gain with results in schizophrenia. Searches for schizophrenia and comparable weight gain found no passage making that comparison in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [38] Huhn, 2019, Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis, Lancet sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Small-study effects and potential publication bias were investigated by visual inspection of contour-enhanced, comparison-adjusted funnel plots, and an Egger's test.

“Small-study effects and potential publication bias were investigated by visual inspection of contour-enhanced, comparison-adjusted funnel plots, and an Egger's test.[26][27][28]”

• cites [26] Peters, 2008, Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry, J Clin Epidemiol sourceNot checked — no full text of the source
• cites [27] Chaimani, 2013, Graphical tools for network meta-analysis in STATA, PLoS One sourcePartly supported

  Materials and Methods §4 describes comparison-adjusted funnel plots for assessing small-study effects. It does not describe contour-enhanced plots or an Egger’s test; Egger appears only in the references. The section also cautions that funnel-plot asymmetry should not itself be interpreted as evidence of publication bias. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [28] Egger, 1997, Bias in meta-analysis detected by a simple, graphical test, BMJ sourceNot checked — no full text of the source

May combine two claims.

The evidence on antidepressants is mainly constituted by small randomised controlled trials, which can exaggerate treatment effects.

“The evidence on antidepressants is mainly constituted by small randomised controlled trials, which can exaggerate treatment effects.42”

• cites [42] Dechartres, 2013, Influence of trial sample size on treatment effect estimates: meta-epidemiological study, BMJ sourcePartly supported

  The Conclusions report that smaller trials had stronger treatment-effect estimates than the largest trials and that these effects might not reflect the true effect. The Data sources section describes trials of therapeutic interventions across medical areas; it does not establish that antidepressant evidence is mainly made up of small trials or that the finding applies specifically to antidepressants. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

A recent network meta-analysis on maintenance treatment of BD reported lamotrigine and valproate in combination with each other and other drugs to reduce recurrence or relapse of depressive episodes.

“Supportively, a recent network metaanalysis on maintenance treatment of BD reported lamotrigine and valproate in combination with each other and other drugs to reduce recurrence or relapse of depressive episodes.44”

• cites [44] Kishi, 2021, Mood stabilizers and/or antipsychotics for bipolar disorder in the maintenance phase: a systematic review and network meta-analysis of randomized controlled trials, Mol Psychiatry sourceSupported

May combine two claims.

Neither the present network meta-analysis nor a recent systematic review on use of lithium in BD based on 78 studies found lithium efficacious for acute bipolar depression.

“By contrast, neither the present network meta-analysis nor a recent systematic review on use of lithium in BD based on 78 studies found lithium efficacious for acute bipolar depression.43”

• cites [43] Fountoulakis, 2022, Lithium treatment of bipolar disorder in adults: a systematic review of randomized trials and meta-analyses, Eur Neuropsychopharmacol sourceSupported

May combine two claims.

Quetiapine was the only drug which clearly reduced the switching risk compared to placebo (risk 1.0% vs 2.0%, OR 0.49, 95% CI 0.33-0.75), with moderate confidence in the evidence.

“Quetiapine was the only drug which clearly reduced the switching risk compared to placebo (risk 1•0% vs 2•0%, odds ratio [OR] 0•49, 95% CI 0•33-0•75), and the confidence in the evidence was moderate.”

May combine two claims.

Some other interventions might also be efficacious, but the quality of the evidence was low or very low, mainly due to imprecision and small sample sizes.

“Some other interventions might also be efficacious, but the quality of the evidence was low or very low, mainly due to imprecision and small sample sizes.”

May combine two claims.

Patterns for remission rates were similar to response rates, except that the 95% CI for lumateperone did not exclude the null (1.12, 0.84-1.50).

“Patterns for remission rates were similar, except that the 95% CI for lumateperone did not exclude the null (1•12, 0•84-1•50).”

May combine two claims.

All other drugs were not clearly different from placebo for manic switch, with confidence in the evidence being low or very low.

“All other drugs were not clearly different from placebo, with confidence in the evidence being low or very low, although some point estimates were rather low, suggesting decreased risk, such as for lithium (1•2%, 0•57, 0•19-1•73) and olanzapine (1•3%, 0•63, 0•36-1•08), or high, suggesting increased risk, such as for imipramine (4•4%, 2•22, 0•64-7•67; figure 4).”

May combine two claims.

The review analysed data from 101 randomised controlled trials covering 20,081 participants, 8063 men (41.7%) and 11,263 women (58.3%; sex not available in four studies), mean age 41.0 years (range of means 28.7-53.6 years), and 68 medications and placebo.

“We analysed data from 101 randomised controlled trials covering 20 081 participants, 8063 men (41•7%) and 11 263 women (58•3%; sex not available in four studies), mean age 41•0 years (range of means 28•7-53•6 years), and 68 medications and placebo.”

May combine two claims.

All-cause discontinuation was less frequent with olanzapine plus fluoxetine (11.7%, OR 0.35, 95% CI 0.22-0.57) and olanzapine (20.4%, 0.68, 0.54-0.87), compared with placebo (27.3%).

“It was less frequent with olanzapine plus fluoxetine (11•7%, OR 0•35, 95% CI 0•22-0•57) and olanzapine (20•4%, 0•68, 0•54-0•87), compared with placebo (27•3%).”

May combine two claims.

There were no material differences when medications were analysed separately as monotherapy or adjunctive to mood stabilisers, and in studies including more or fewer patients with bipolar II than the median of the studies.

“Moreover, there were no material differences when we analysed separately medications given as monotherapy or adjunctive to mood stabilisers (appendix 1 pp 181), and studies including more or fewer patients with bipolar II than the median of the studies (27%, appendix 1 p 182).”

May combine two claims.

The risk of akathisia compared with placebo (0.2%) was higher for all of these medications, ranging from 0.9% for cariprazine (OR 4.00, 95% CI 2.20-7.28) to 0.4% for quetiapine (1.75, 1.04-2.95); the 95% CIs for olanzapine and lumateperone were wide and did not exclude the null effect.

“Similarly, the risk of akathisia compared with placebo (0•2%) was higher for all of these medications, ranging from 0•9% for cariprazine (OR 4•00, 95% CI 2•20-7•28) to 0•4% for quetiapine (1•75, 1•04-2•95); the 95% CIs for olanzapine and lumateperone were wide and did not exclude the null effect (appendix 1 pp 165-166).”

May combine two claims.

Several other drugs might also be efficacious in reducing depressive symptoms, but the confidence in the evidence was very low to low.

“Several other drugs might also be efficacious, but the confidence in the evidence was very low to low.”

May combine two claims.

Although none of the medications clearly increased the risk of mania switch, antidepressants as a class had a higher risk compared to antipsychotics, while quetiapine clearly decreased the risk based on good quality evidence.

“Although none of the medications clearly increased the risk of mania switch, antidepressants as a class had a higher risk compared to antipsychotics, while quetiapine clearly decreased the risk based on good quality evidence.”

May combine two claims.

There was some heterogeneity for depressive symptoms (τ2=0.015, low-to-moderate), and some incoherence in the co-primary outcomes according to the number of incoherent loops (18.9%, 16.7%) but not according to the design-by-treatment test (p=0.30, p=0.15).

“There was some heterogeneity for depressive symptoms (τ²=0•015, low-to-moderate), and some incoherence in the co-primary outcomes according to the number of incoherent loops (18•9%, 16•7%) but not according to the design-by-treatment test (p=0•30, p=0•15, respectively; appendix 1 pp 132-143).”

May combine two claims.

Both lumateperone and quetiapine had higher risk of discontinuation due to adverse events compared with olanzapine (6.0%), lamotrigine (5.1%) and olanzapine plus fluoxetine (4.5%).

“Both lumateperone and quetiapine had higher risk of discontinuation compared with olanzapine (6•0%), lamotrigine (5•1%) and olanzapine plus fluoxetine (4•5%).”

May combine two claims.

Olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were efficacious in reducing depressive symptoms with small-to-medium effect sizes and supported by good quality evidence.

“Olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were efficacious in reducing depressive symptoms with small-to-medium effect sizes and supported by good quality evidence.”

May combine two claims.

Distribution of bipolar types across medications revealed that antipsychotics were primarily investigated in patients with bipolar I, while antidepressants were studied more frequently in patients with bipolar II.

“Distribution of bipolar types across medications revealed that antipsychotics were primarily investigated in patients with bipolar I, while antidepressants were studied more frequently in patients with bipolar II (appendix 1 p 117).”

May combine two claims.

A post-hoc analysis revealed that, as a class, antidepressants, and with a smaller effect size antiepileptics, may be as efficacious as antipsychotics.

“A post-hoc analysis revealed that, as a class, antidepressants (and with a smaller effect size antiepileptics) may be as efficacious as antipsychotics (figure 6).”

May combine two claims.

All antipsychotics were sedating, and quetiapine and lumateperone were the most sedating.

“All antipsychotics were sedating, and quetiapine and lumateperone were the most sedating.”

May combine two claims.

There were no clear differences in patients with QTc prolongation except olanzapine being worse than quetiapine.

“There were no clear differences in patients with QTc prolongation except olanzapine being worse than quetiapine.”

May combine two claims.

Olanzapine and olanzapine plus fluoxetine were associated with the highest number of participants experiencing weight gain greater than or equal to 7% increase from baseline, followed by lurasidone, quetiapine, and cariprazine, which were approximately equal, while lumateperone and lamotrigine were weight neutral.

“Olanzapine (and olanzapine plus fluoxetine) were associated with the highest number of participants experiencing weight gain greater than or equal to 7% increase from their total baseline body weight, followed by lurasidone, quetiapine, and cariprazine, which were approximately equal, while lumateperone and lamotrigine were weight neutral.”

May combine two claims.

Lurasidone, lumateperone, and lamotrigine did not produce significantly more weight gain than placebo.

“lurasidone, lumateperone, and lamotrigine did not produce significantly more weight gain than placebo.”

May combine two claims.

Antidepressants were more frequently studied in patients with bipolar II and antipsychotics in patients with bipolar I.

“Antidepressants were more frequently studied in patients with bipolar II and antipsychotics in patients with bipolar I (appendix 1 p 117).”

May combine two claims.

Exceptions were lamotrigine (0.4%, OR 0.35, 95% CI 0.08-1.49) and lumateperone (0.8%, OR 0.79, 95% CI 0.21-2.98).

“Exceptions were lamotrigine (0•4%, 0•35, 0•08-1•49) and lumateperone (0•8%, 0•79, 0•21-2•98).”

May combine two claims.

Post-hoc analysis of mean change in weight revealed mean differences of 3.19 kg (95% CI 2.57-3.81) with olanzapine plus fluoxetine, 2.87 kg (2.56-3.19) with olanzapine, and 1.25 kg (1.01-1.49) with quetiapine as compared to placebo.

“Post-hoc analysis of mean change in weight revealed mean differences (MDs) of 3•19 kg (95% CI 2•57-3•81) with olanzapine plus fluoxetine, 2•87 kg (2•56-3•19) with olanzapine, and 1•25 kg (1•01-1•49) with quetiapine as compared to placebo (appendix 1 pp 159-160).”

May combine two claims.

The risk of EPS was higher, yet still low, compared with placebo (0.4%), ranging from 1.1% for quetiapine (OR 2.38, 95% CI 1.56-3.64) to 0.8% for lurasidone (1.90, 1.26-2.86), and the 95% CIs for olanzapine plus fluoxetine and lumateperone were wide and did not exclude the null effect.

“The risk of EPS was higher, yet still low, compared with placebo (0•4%), ranging from 1•1% for quetiapine (OR 2•38, 95% CI 1•56-3•64) to 0•8% for lurasidone (1•90, 1•26-2•86), and the 95% CIs for olanzapine plus fluoxetine and lumateperone were wide and did not exclude the null effect (appendix 1 pp 163 -164).”

May combine two claims.

Olanzapine did not differ from placebo for EPS (0.4%, OR 0.78, 95% CI 0.36-1.70) and had a lower risk of EPS than the other medications.

“An exeption was olanzapine, which did not differ from placebo (0•4%, 0•78, 0•36-1•70) and had a lower risk of EPS than the other medications (appendix 2).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

34 trials (33.7%) included only patients with bipolar I, six (5.9%) only patients with bipolar II, and 58 (57.4%) included both or mixed groups.

“34 trials (33•7%) included only patients with bipolar I, six (5•9%) only patients with bipolar II, and 58 (57•4%) included both or mixed groups”

Probably not a substantial claim: may not pass S3 (load-bearing).

21 studies included participants who had experienced prior treatment failure.

“21 studies included participants who had experienced prior treatment failure.”

May combine two claims. The quote only partly states this claim.

The risk of weight gain greater than or equal to 7% was 40.3% with olanzapine plus fluoxetine (OR 40.65, 95% CI 13.43-123.02) and 28.4% with olanzapine (37.20, 13.89-99.63), falling to 5.4% with lurasidone (5.39, 1.62-18.00), 3.5% with quetiapine (3.39, 2.14-5.35), and 3.1% with cariprazine (2.98, 1.28-6.94) as compared to 1.1% risk with placebo.

“•3% with olanzapine plus fluoxetine (OR 40•65, 95% CI 13•43-123•02) and 28•4% with olanzapine (37•20, 13•89-99•63) falling to 5•4% with lurasidone (5•39, 1•62-18•00), 3•5% with quetiapine (3•39, 2•14-5•35), and 3•1% with cariprazine (2•98, 1•28-6•94) as compared to 1•1% risk with placebo (appendix 1 pp 157-158).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The participants had a median age of 41.3 years (IQR 38.9-43.8), 58.8% (IQR 53.3-64.2) were female, and 41.2% (IQR 35.8-46.7) were male.

“The participants had a median age of 41•3 years (IQR 38•9-43•8), 58•8% (IQR 53•3-64•2) were female; 41•2% (IQR 35•8-46•7) were male”

Probably not a substantial claim: may not pass S3 (load-bearing).

The mean baseline severity was 48.0% (IQR 42.5-50.6) of the maximum scale score.

“The mean baseline severity was 48•0% (IQR 42•5-50•6) of the maximum scale score”

May combine two claims.

Seven treatments fell in category I: olanzapine plus fluoxetine (SMD 0.41, 95% CI 0.19-0.64), quetiapine (0.35, 0.23-0.47), olanzapine (0.35, 0.17-0.54), lurasidone (0.29, 0.14-0.45), lumateperone (0.27, 0.09-0.45), cariprazine (0.23, 0.06-0.39), and lamotrigine (0.16, 0.03-0.29).

“Seven treatments fell in category I: olanzapine plus fluoxetine (SMD 0•41, 95% CI 0•19-0•64), quetiapine (0•35, 0•23-0•47), olanzapine (0•35, 0•17-0•54), lurasidone (0•29, 0•14-0•45), lumateperone (0•27, 0•09-0•45), cariprazine (0•23, 0•06-0•39), and lamotrigine (0•16, 0•03-0•29; figure 3).”

May combine two claims.

Weight gain with cariprazine was small (MD 0.67 kg, 95% CI 0.41-0.93), while with lurasidone, lumateperone, and lamotrigine it was not clearly distinguishable from placebo.

“Weight gain with cariprazine was small (MD 0•67 kg, 95% CI 0•41-0•93), while with lurasidone, lumateperone, and lamotrigine it was not clearly distinguishable from placebo (appendix 1 pp 159-160).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Antidepressants can also lead to mixed states, but this was usually not recorded.

“Similarly, antidepressants can also lead to mixed states, but this was usually not recorded.”

May combine two claims.

Antipsychotics plus antidepressants, lithium, and antiepileptics were neutral for risk of switching to mania.

“antipsychotics plus antidepressants (0•98, 0•52 to 1•87), lithium (1•05, 0•48 to 2•29), and antiepileptics (1•12, 0•73 to 1•72) were neutral.”

May combine two claims.

Antidepressants were not clearly different from placebo for risk of switching to mania (OR 1.39, 95% CI 0.86 to 2.23) but were associated with more switches than antipsychotics.

“Antidepressants were not clearly different from placebo (1•39, 0•86 to 2•23) but were associated with more switches than antipsychotics (figure 6, appendix 1 pp 353-356).”

Probably not a substantial claim: may not pass S3 (load-bearing).

There were no data for olanzapine plus fluoxetine and lamotrigine for QTc prolongation.

“There were no data for olanzapine plus fluoxetine and lamotrigine.”

May combine two claims.

The following medications had an increased risk of sedation ranging from 24.2% for quetiapine (OR 6.89, 95% CI 5.58-8.50) and 18.4% for lumateperone (4.89, 2.23-10.69) to 11.4% for olanzapine (2.79, 2.05-3.78), 8.4% for lurasidone (1.98, 1.31-3.01), 7.9% for olanzapine plus fluoxetine (1.86, 1.02-3.40), and 7.7% for cariprazine (1.80, 1.09-2.97) compared with placebo (4.4%).

“The following medications had an increased risk ranging from 24•2% for quetiapine (OR 6•89, 95% CI 5•58-8•50) and 18•4% for lumateperone (4•89, 2•23-10•69) to 11•4% for olanzapine (2•79, 2•05-3•78), 8•4% for lurasidone (1•98, 1•31-3•01), 7•9% for olanzapine plus fluoxetine (1•86, 1•02-3•40), and 7•7% for cariprazine (1•80, 1•09-2•97) compared with placebo (4•4%) (appendix 1 pp 161-162).”

May combine two claims.

No drug was associated with a clearly increased number of participants with QTc prolongation compared with placebo (0.1%), ranging from 0.4% for lurasidone (OR 2.72, 95% CI 0.11-67.25) to 0.0% for lumateperone (0.33, 0.03-3.22).

“No drug was associated with a clearly increased number of participants with QTc prolongation compared with placebo (0•1%), ranging from 0•4% for lurasidone (OR 2•72, 95% CI 0•11-67•25) to 0•0% for lumateperone (0•33, 0•03-3•22, appendix 1 p 167).”

May combine two claims.

Antipsychotics plus antidepressants, antipsychotics alone, antidepressants alone, and antiepileptics as a group were significantly more efficacious than placebo, while the confidence interval for lithium included no effect.

“(SMD 0•40, 95% CI 0•17 to 0•63), antipsychotics alone (0•28, 0•21 to 0•35), antidepressants alone (0•28, 0•12 to 0•43), and antiepileptics as a group (0•16, 0•04 to 0•28) were significantly more efficacious than placebo, while the confidence interval for lithium included no effect (0•09, -0•13 to 0•32).”

May combine two claims.

The evidence was downgraded in CINeMA, and the results did not materially change in sensitivity analyses excluding the incoherent loops.

“We therefore downgraded the evidence in CINeMA (appendix 1 pp 197-199), and the results did not materially change in sensitivity analyses excluding the incoherent loops (appendix 1 pp 169-182).”

May combine two claims.

Antipsychotics were associated with multiple side-effects but with differing profiles, while lamotrigine may have a more benign profile but may also be less efficacious.

“Moreover, antipsychotics were associated with multiple side-effects but with differing profiles, while lamotrigine may have a more benign profile but may also be less efficacious.”

Classified as probably not a substantial claim.

The transitivity assumption of network meta-analysis was assessed by examining the distribution of clinical and methodological variables that might act as effect modifiers.

“The transitivity assumption of network meta-analysis was assessed by examining the distribution of clinical and methodological variables that might act as effect modifiers-ie, age and sex (post-hoc), baseline severity of depressive and mania symptoms, presence of psychotic or rapid cycling features, comorbid anxiety, previous treatment failure, background mood stabilisers, type of BD, route of”

• AssumptionThe authors state this as an assumption: The network meta-analysis relies on the transitivity assumption.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Weight gain is extremely important, as atypical symptoms including hyperphagia occur as frequently as in 90% of patients with BD.

“Weight gain is extremely important, as atypical symptoms including hyperphagia occur as frequently as in 90% of patients with BD. 37”

• cites [37] Grande, 2016, Bipolar disorder, Lancet sourceNot checked — no full text of the source

May combine two claims.

All category I drugs except lamotrigine were antipsychotics, which are problematic due to their side effects.

“All category I drugs except lamotrigine were antipsychotics, which are problematic due to their side effects.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The review followed PRISMA-NMA reporting guidelines and had a registered protocol (PROSPERO-ID: CRD42020171726).

“We followed the PRISMA-NMA 16 reporting guidelines (appendix 1 pp 3-5) and had a registered protocol (appendix 1 pp 6-9, PROSPERO-ID: CRD42020171726).”

• cites [16] Hutton, 2015, The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations, Ann Intern Med sourceNot checked — no full text of the source

May combine two claims.

There was no indication of small-study effects in the funnel plot analyses, yet there were unpublished data that could not be obtained for a few comparisons and the evidence was downrated accordingly.

“There was no indication of small-study effects in the funnel plot analyses, yet there were unpublished data that we could not obtain for a few comparisons and the evidence was downrated accordingly (appendix 1 pp 185-196).”

May combine two claims.

Antidepressants and, with a smaller effect size, antiepileptics, as a class, could be almost as efficacious as antipsychotics; however, larger trials are required to confirm this finding.

“Antidepressants and (with a smaller effect size) antiepileptics, as a class, could be almost as efficacious as antipsychotics; however, larger trials are required to confirm this finding.”

Classified as probably not a substantial claim.

Data from the first phase of crossover studies were used to avoid carryover effects.

“Data from the first phase of crossover studies were used to avoid carryover effects.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Patients with BD often receive polypharmacy, and QTc prolongation can be cumulative.

“Nevertheless, patients with BD often receive polypharmacy, and QTc prolongation can be cumulative.4,5,[11][12][13]36,37”

• cites 4,5,[11][12][13]36,37Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

All-cause discontinuation was analysed with pairwise meta-analysis due to incoherence.

“All-cause discontinuation was analysed with PMA due to incoherence (appendix 1 pp 132, 151-152).”

Probably not a substantial claim: may not pass S3 (load-bearing).

EPS are dose related.

“it should be noted that EPS are dose related.39”

• cites [39] Siafis S, Wu H, Wang D, et al. Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose response meta-analysis. Mol Psychiatry (in press).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The occurrence of EPS in the short term is associated with tardive dyskinesia in the long term.

“Moreover, the occurrence of EPS in the short term is associated with tardive dyskinesia in the long term.40”

• cites [40] Tenback, 2006, Evidence that early extrapyramidal symptoms predict later tardive dyskinesia: a prospective analysis of 10,000 patients in the European Schizophrenia Outpatient Health Outcomes (SOHO) study, Am J Psychiatry sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Study screening and data extraction were conducted by AY and confirmed by the authors of the included studies.

“Study screening and data extraction were conducted by AY and confirmed by the authors of the included studies,”

Probably not a substantial claim: may not pass S3 (load-bearing).

Only pairwise meta-analysis was performed when there was substantial incoherence (significant design-by-treatment-interaction test at alpha 0.1 and/or ≥20% incoherent closed loops).

“We performed only PMA when there was substantial incoherence (significant design-bytreatment-interaction test at alpha 0•1 and/or ≥20% incoherent closed loops).”

May combine two claims.

In terms of secondary outcomes, there was low heterogeneity and no important concerns of incoherence, except for dropouts due to any reason and sedation, which were analysed with pairwise meta-analysis.

“In terms of secondary outcomes, there was low heterogeneity and no important concerns of incoherence, except for dropouts due to any reason and sedation, which were analysed with PMA (appendix 1 pp 132-143).”

May combine two claims.

Antipsychotics have multiple side-effects, but these differ between individual drugs and not all patients will develop them.

“Antipsychotics have multiple side-effects, but these differ between individual drugs and not all patients will develop them.”

May combine two claims.

We could not substantively address differences in terms of patients with bipolar I and bipolar II, because only 6% of the studies included only patients with bipolar II, and most populations were mixed.

“We could not substantively address differences in terms of patients with bipolar I and bipolar II, because only 6% of the studies included only patients with bipolar II, most populations were mixed.”

Classified as probably not a substantial claim. May combine two claims.

We downrated the evidence and explored potential reasons with meta-regression and sensitivity analyses.

“For this reason, we downrated the evidence and explored potential reasons with meta-regression and sensitivity analyses.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

Meta-analyses are usually better at answering global questions than specific ones; for example, we did not address which drug should be used if the first failed.

“Finally, as a general limitation, metaanalyses are usually better at answering global questions than specific ones, for example, we did not address which drug should be used if the first failed.”

Probably not a substantial claim: may not pass S3 (load-bearing).

There were some concerns about overall risk of bias in about 10% of the studies.

“There were some concerns about overall risk of bias in about 10% of the studies (appendix 1 pp 100-109).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Due to substantial incoherence, sedation was analysed with PMA.

“Due to substantial incoherence (appendix 1 pp 132, 161-162), sedation was analysed with PMA.”

May combine two claims.

The network was sparse and most randomised controlled trials were placebo controlled.

“In addition, the network was sparse and most randomised controlled trials were placebo controlled.”

Classified as probably not a substantial claim. May combine two claims.

The short duration of the trials, median eight weeks, and the fact that antidepressants were usually added to mood stabilisers must be considered.

“but the short duration of the trials (median eight weeks), and the fact that antidepressants were usually added to mood stabilisers, must be considered.”

• AssumptionRests on an assumption: Protection against switch to mania by mood stabilisers is necessary in bipolar disorder.

May combine two claims.

Lamotrigine is a more tolerated choice, but its small efficacy effect size must be considered.

“Lamotrigine is a more tolerated choice, but its small efficacy effect size must be considered.”

May combine two claims.

There was very little flow of indirect evidence and treatment effect estimates were mainly informed by direct evidence.

“Hence, there was very little flow of indirect evidence and treatment effect estimates were mainly informed by direct evidence.”

May combine two claims.

Olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine are efficacious for bipolar depression with sufficient confidence in the evidence, and without increased risk for switch to mania.

“In conclusion, olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine are efficacious for bipolar depression with sufficient confidence in the evidence, and without increased risk for switch to mania.”

• AssumptionRests on an assumption: Protection against switch to mania by mood stabilisers is necessary in bipolar disorder.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

When treatment starts to work, it can be challenging to differentiate between improvement of depressive symptoms and switch to hypomania.

“When treatment starts to work, it can be challenging to differentiate between improvement of depressive symptoms and switch to hypomania.”