Evidence-Based Mental Health Online First, published on May 19, 2015 as 10.1136/eb-2015-102062 Pharmacological interventions
Pharmacotherapy for bipolar depression: comparative efficacy and acceptability is in the eye of the beholder Leslie Citrome,1 Terence A Ketter2 1
New York Medical College, Valhalla, New York, USA; 2Stanford University School of Medicine, Stanford, California, USA Correspondence to Dr Leslie Citrome; [email protected] ABSTRACT FROM: Taylor DM, Cornelius V, Smith L, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014;130:452–69.
WHAT IS ALREADY KNOWN ON THIS TOPIC Bipolar disorder is principally a depressive illness, given the amount of time spent symptomatic in the depressed phase.1 Despite this, there are very few approved treatments.2 Consequently, several unapproved drugs are used with varying degrees of efficacy and tolerability. METHODS OF THE STUDY The data for this study were from English language clinical trial study reports published from 1950 to April 2014. Studies that were included were randomised, double blind, 4–16 weeks, controlled trials of adults, with acute bipolar depression. Studies of refractory/resistant patients or mixed populations with mood disorders were excluded. 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. The direct treatment effect estimates using a random-effects model was followed by a network meta-analysis using Bayesian methodology. The rank probabilities were summarised for each drug by calculating the surface under the cumulative ranking curve. WHAT DOES THIS PAPER ADD ▸ By including 29 studies (8331 participants), this is the most current and comprehensive network meta-analysis regarding drug treatments for bipolar depression. For example, data regarding the use of lurasidone, were not included in the text of the recent update of the UK National Institute for Health and Care Excellence bipolar treatment guidelines.3 ▸ Olanzapine plus fluoxetine (OFC) was ranked the highest for efficacy, with lurasidone second. Several treatments (monoamine oxidase inhibitors, ziprasidone, aripiprazole and risperidone) demonstrated limited or no therapeutic activity in bipolar depression, consistent with what is already known. ▸ OFC was recommended as first-line treatment, but olanzapine, quetiapine, lurasidone, valproate and, surprisingly, selective serotonin reuptake inhibitors (SSRIs), were also recommended. LIMITATIONS ▸ The authors have noted that their implementation of multiple treatment estimates put equal weight on direct and indirect comparisons, potentially providing unexpected results such as when comparing quetiapine with SSRIs. ▸ Durations of included studies varied markedly, ranging between 6 and 19 weeks; information about maintenance treatment was unavailable. ▸ There were a small number of patients (as few as 18) in some of the included studies. Such studies can yield less precise estimates of treatment effect. WHAT NEXT IN RESEARCH This meta-analysis is a welcome update, however, more primary studies of prevention of bipolar depression and, eventually, meta-analyses of such data, are needed. Practice-based evidence, such as what treatments for bipolar depression are in actual use in the ‘real-world’, can prompt performance of randomised controlled studies that can determine whether or not these treatments are indeed effective and how they compare with the approved EvidCopyright Based Mental Health Monthauthor 2015 Vol 0(or No 0their Article
interventions for where robust data are available. In particular, maintenance treatments for people with an index episode of bipolar depression are understudied, yet crucial, critical components for continuity of care. To date, most studies for the maintenance treatment of bipolar disorder have enrolled subjects stabilised from a manic or mixed episode and assessed agents with acute mania indications more often than agents with acute bipolar depression indications. DO THESE RESULTS CHANGE YOUR PRACTICES AND WHY? Some clinicians may opine that these results will only modestly affect clinical practice. For example, although OFC was recommended as firstline treatment based on the balance of likelihood of response and lower likelihood of withdrawal, and olanzapine and quetiapine recommended as alternative first-line treatments, specific tolerability outcomes such as clinically relevant weight gain and potential for somnolence were not assessed. In clinical practice, specific tolerability issues are commonly central to individual patients’ values and preferences, placing OFC (and olanzapine) as relatively unacceptable for people desiring to avoid weight gain, and quetiapine potentially problematic if sedation/somnolence persists. Thus, lurasidone may have substantial tolerability advantages compared to OFC and quetiapine. Of note, almost all data available for lurasidone, as well as for quetiapine or OFC, for the treatment of bipolar depression, come from studies conducted by the respective manufacturers. Although ‘switch to mania’ is an important harm, other side effects are more common reasons for treatment discontinuation in clinical practice. In addition, several other conclusions of this meta-analysis are at variance with current practice. Valproate and lithium, although clearly effective for acute mania, and commonly used for bipolar preventive treatment, have very limited evidence of efficacy in acute bipolar depression. The use of SSRIs in acute bipolar depression is controversial. Although with less risk of somatic side effects and ‘switch to mania’ compared to tricyclic antidepressants, they still lack compelling evidence of efficacy in acute bipolar depression. Finally, in non-urgent situations entailing a substantial need for tolerability, the efficacy limitations of lamotrigine may be considered acceptable by some clinicians. Competing interests In the past 36 months, LC has engaged in collaborative research with, or received consulting or speaking fees from: Actavis (Forest), Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant. In the past 36 months, TK has engaged in collaborative research with, or received consulting or speaking fees from: Abbott, Allergan, AstraZeneca, Avanir, Cephalon, Depotmed, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Otsuka, Pfizer and Sunovion. In addition, Dr Ketter’s spouse is an employee and stockholder of Janssen. doi:10.1136/eb-2015-102062 Received 6 February 2015; Revised 19 April 2015; Accepted 28 April 2015
REFERENCES 1. 2. 3.
Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar disorder. Arch Gen Psychiatry 2002;59:530–7. Citrome L. Treatment of bipolar depression: making sensible decisions. CNS Spectr 2014;19(Suppl 1):1–12. Kendall T, Morriss R, Mayo-Wilson E, et al. Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ 2014;349:g5673.
employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
1
Pharmacotherapy for bipolar depression: comparative efficacy and acceptability is in the eye of the beholder Leslie Citrome,1 Terence A Ketter2 1
New York Medical College, Valhalla, New York, USA; 2Stanford University School of Medicine, Stanford, California, USA Correspondence to Dr Leslie Citrome; [email protected] ABSTRACT FROM: Taylor DM, Cornelius V, Smith L, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand 2014;130:452–69.
WHAT IS ALREADY KNOWN ON THIS TOPIC Bipolar disorder is principally a depressive illness, given the amount of time spent symptomatic in the depressed phase.1 Despite this, there are very few approved treatments.2 Consequently, several unapproved drugs are used with varying degrees of efficacy and tolerability. METHODS OF THE STUDY The data for this study were from English language clinical trial study reports published from 1950 to April 2014. Studies that were included were randomised, double blind, 4–16 weeks, controlled trials of adults, with acute bipolar depression. Studies of refractory/resistant patients or mixed populations with mood disorders were excluded. 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. The direct treatment effect estimates using a random-effects model was followed by a network meta-analysis using Bayesian methodology. The rank probabilities were summarised for each drug by calculating the surface under the cumulative ranking curve. WHAT DOES THIS PAPER ADD ▸ By including 29 studies (8331 participants), this is the most current and comprehensive network meta-analysis regarding drug treatments for bipolar depression. For example, data regarding the use of lurasidone, were not included in the text of the recent update of the UK National Institute for Health and Care Excellence bipolar treatment guidelines.3 ▸ Olanzapine plus fluoxetine (OFC) was ranked the highest for efficacy, with lurasidone second. Several treatments (monoamine oxidase inhibitors, ziprasidone, aripiprazole and risperidone) demonstrated limited or no therapeutic activity in bipolar depression, consistent with what is already known. ▸ OFC was recommended as first-line treatment, but olanzapine, quetiapine, lurasidone, valproate and, surprisingly, selective serotonin reuptake inhibitors (SSRIs), were also recommended. LIMITATIONS ▸ The authors have noted that their implementation of multiple treatment estimates put equal weight on direct and indirect comparisons, potentially providing unexpected results such as when comparing quetiapine with SSRIs. ▸ Durations of included studies varied markedly, ranging between 6 and 19 weeks; information about maintenance treatment was unavailable. ▸ There were a small number of patients (as few as 18) in some of the included studies. Such studies can yield less precise estimates of treatment effect. WHAT NEXT IN RESEARCH This meta-analysis is a welcome update, however, more primary studies of prevention of bipolar depression and, eventually, meta-analyses of such data, are needed. Practice-based evidence, such as what treatments for bipolar depression are in actual use in the ‘real-world’, can prompt performance of randomised controlled studies that can determine whether or not these treatments are indeed effective and how they compare with the approved EvidCopyright Based Mental Health Monthauthor 2015 Vol 0(or No 0their Article
interventions for where robust data are available. In particular, maintenance treatments for people with an index episode of bipolar depression are understudied, yet crucial, critical components for continuity of care. To date, most studies for the maintenance treatment of bipolar disorder have enrolled subjects stabilised from a manic or mixed episode and assessed agents with acute mania indications more often than agents with acute bipolar depression indications. DO THESE RESULTS CHANGE YOUR PRACTICES AND WHY? Some clinicians may opine that these results will only modestly affect clinical practice. For example, although OFC was recommended as firstline treatment based on the balance of likelihood of response and lower likelihood of withdrawal, and olanzapine and quetiapine recommended as alternative first-line treatments, specific tolerability outcomes such as clinically relevant weight gain and potential for somnolence were not assessed. In clinical practice, specific tolerability issues are commonly central to individual patients’ values and preferences, placing OFC (and olanzapine) as relatively unacceptable for people desiring to avoid weight gain, and quetiapine potentially problematic if sedation/somnolence persists. Thus, lurasidone may have substantial tolerability advantages compared to OFC and quetiapine. Of note, almost all data available for lurasidone, as well as for quetiapine or OFC, for the treatment of bipolar depression, come from studies conducted by the respective manufacturers. Although ‘switch to mania’ is an important harm, other side effects are more common reasons for treatment discontinuation in clinical practice. In addition, several other conclusions of this meta-analysis are at variance with current practice. Valproate and lithium, although clearly effective for acute mania, and commonly used for bipolar preventive treatment, have very limited evidence of efficacy in acute bipolar depression. The use of SSRIs in acute bipolar depression is controversial. Although with less risk of somatic side effects and ‘switch to mania’ compared to tricyclic antidepressants, they still lack compelling evidence of efficacy in acute bipolar depression. Finally, in non-urgent situations entailing a substantial need for tolerability, the efficacy limitations of lamotrigine may be considered acceptable by some clinicians. Competing interests In the past 36 months, LC has engaged in collaborative research with, or received consulting or speaking fees from: Actavis (Forest), Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant. In the past 36 months, TK has engaged in collaborative research with, or received consulting or speaking fees from: Abbott, Allergan, AstraZeneca, Avanir, Cephalon, Depotmed, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Otsuka, Pfizer and Sunovion. In addition, Dr Ketter’s spouse is an employee and stockholder of Janssen. doi:10.1136/eb-2015-102062 Received 6 February 2015; Revised 19 April 2015; Accepted 28 April 2015
REFERENCES 1. 2. 3.
Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar disorder. Arch Gen Psychiatry 2002;59:530–7. Citrome L. Treatment of bipolar depression: making sensible decisions. CNS Spectr 2014;19(Suppl 1):1–12. Kendall T, Morriss R, Mayo-Wilson E, et al. Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ 2014;349:g5673.
employer) 2015. Produced by BMJ Publishing Group Ltd under licence.
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