The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Acute and long-term treatment of mixed states in bipolar disorder

Abstract

Objectives: Although clinically highly relevant, the recognition and treatment of bipolar mixed states has played only an underpart in recent guidelines. This WFSBP guideline has been developed to supply a systematic overview of all scientific evidence pertaining to the acute and long-term treatment of bipolar mixed states in adults.

Methods: Material used for these guidelines is based on a systematic literature search using various data bases. Their scientific rigour was categorised into six levels of evidence (A–F), and different grades of recommendation to ensure practicability were assigned. We examined data pertaining to the acute treatment of manic and depressive symptoms in bipolar mixed patients, as well as data pertaining to the prevention of mixed recurrences after an index episode of any type, or recurrence of any type after a mixed index episode.

Results: Manic symptoms in bipolar mixed states appeared responsive to treatment with several atypical antipsychotics, the best evidence resting with olanzapine. For depressive symptoms, addition of ziprasidone to treatment as usual may be beneficial; however, the evidence base is much more limited than for the treatment of manic symptoms. Besides olanzapine and quetiapine, valproate and lithium should also be considered for recurrence prevention.

Limitations: The concept of mixed states changed over time, and recently became much more comprehensive with the release of DSM-5. As a consequence, studies in bipolar mixed patients targeted slightly different bipolar subpopulations. In addition, trial designs in acute and maintenance treatment also advanced in recent years in response to regulatory demands.

Conclusions: Current treatment recommendations are still based on limited evidence, and there is a clear demand for confirmative studies adopting the DSM-5 specifier with mixed features concept.

Keywords:

• Mixed states
• bipolar disorder
• guidelines
• pharmacotherapy
• acute treatment
• maintenance treatment
• antipsychotics
• antidepressants
• mood stabiliser
• electroconvulsive therapy

Notes

Acknowledgements

We would like to especially thank Mrs Monica Gratacos for her great support in the initial literature search, and Helen Sigurdardottir, WJBP editorial office, for editorial assistance.

Financial disclosures of principal authors

Heinz Grunze received grants/research support, consulting fees and honoraria within the last three years from Gedeon Richter, Genericon, Janssen-Cilag, Lundbeck, Otsuka, Pfizer and Servier.

Eduard Vieta received grants/research support, consulting fees and honoraria within the last three years from Ab-Biotics, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eli Lilly, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Johnson & Johnson, Lundbeck, Otsuka, Pfizer Inc, Sanofi-Aventis, Servier, Sunovion, Takeda, and Tecnifarma.

Siegfried Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier.

Guy Goodwin is a NIHR Senior Investigator, holds a grant from Wellcome Trust, holds shares in P1vital and has served as consultant, advisor or CME speaker for Angelini, Compass pathways, MSD, Lundbeck (/Otsuka or/Takeda), Medscape, P1Vital, Pfizer, Servier and Shire. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Charles Bowden has no conflicts of interest to report.

Rasmus W. Licht received research grants, consulting fees and honoraria within the last three years from Bristol-Myers Squibb, Janssen-Cilag, Lundbeck, Otsuka, Servier and Sunovion.

Jean-Michel Azorin received grants/research support, consulting fees and honoraria within the last three years from Allergan, AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka, Servier, Takeda and Teva.

Laksmi Yatham has been on speaker/advisory boards for, or has received research grants from Allergan, AstraZeneca, Bristol-Myers Squibb, CANMAT, CIHR, DSP, Eli Lilly, Forrest, GlaxoSmithKline, Janssen, the Michael Smith Foundation for Health Research, Pfizer, Servier, Sunovion, and the Stanley Foundation.

Sergey Mosolov has been a speaker or consultant for Gedeon Richter, Janssen-Cilag, Pfizer, Sanofi-Aventis, Servier and Minerva.

Hans-Jürgen Möller received grant/research support, consulting fees and honoraria within the last years from Eli Lilly, Lundbeck, Servier and Schwabe.

Notes

1 The appropriate grading of open, but randomized large studies, and of large, prospectively collected data sets with quasi-experimental designs, with patient-relevant outcomes in comparison to small RCTs triggered a vivid discussion among the task force members. Following the logic of the recent BAP Guideline (Goodwin et al. 2016), the recent commitment of the NIH to prioritize effectiveness studies (Lauer and Collins 2010), and based on the quantity and quality of the data, and reliability of the source, it was finally decided to attribute the study of Joas et al. (2017) the same weight as an RCT.

2 Although the combined post hoc analysis by Szegedi et al. (2013) and Berk et al. (2015), are conducted in reasonably large samples, it is not apparent whether they have been planned a priori as part of the investigational plan and study protocols. Therefore, the grading is ‘C’, not ‘B’.

3 The title of the analysis of Berk et al. (2015) ‘Effects of asenapine in BD-I patients meeting proxy criteriafor moderate-to-severe mixed major depressive episodes: a post hoc analysis’ is misleading; patients are still defined by having a DSM-IV mixed episode, which implies the preponderance of mania. This is also reflected by the YMRS baseline severity of >27 in all study arms. For this reason, the task force also feels that the inclusion of this post hoc analysis in the meta-analysis by Fornaro et al. (2016) entitled ‘Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials’ is not justified.

4 The Azorin et al. (2013) paper states that ‘These post hoc efficacy and safety analyses were based on the ITT dataset, which comprised all randomised patients who took at least one dose of study medication and had at least one valid post-baseline YMRS assessment‘, the ANCOVA of the YMRS and MADRS scores, however, were conducted on OC. Additionally, the paper does not supply the numbers of OC subject to analysis. Furthermore, the combined analysis reports on 295 ITT mixed patients, whereas adding the numbers of the individual studies leaves us with 302 ITT mixed patients, and the discrepancy between these numbers remains unclear. Due to these inconsistencies, the task force decided to dismiss the combined analysis as evidence in favour or against asenapine and olanzapine. In the opinion of the task force, this also makes the result for asenapine in the meta-analysis of Muralidharan et al. (2013) questionable, as the evidence for asenapine is only based on the publication by Azorin et al. (2013), and, in addition, questions the validity of the whole meta-analysis which obviously mixes OC and LOCF data.

5 Applying DSM-IV definition of dysphoric mania as a period that includes two to four symptoms of depression while someone is in a manic state.

6 As a result of a consensus process within the task force, we decided to grant a CE ‘B’ also to large size registry studies with real world endpoints and minimized risk of a selection bias, e.g., with each patient serving as his own control. This is the case for one study selected for this review (Joas et al. 2017).