PROSPERO International prospective register of systematic reviews
Comparative efficacy and acceptability of psychological interventions in the long term treatment of bipolar disorder: a network meta-analysis
Andrea Cipriani, David Miklowitz, Hannah McMahon, Ross McLaren, Anna Chaimani, Sarah Stockton, Georgia Salanti, John Geddes
Andrea Cipriani, David Miklowitz, Hannah McMahon, Ross McLaren, Anna Chaimani, Sarah Stockton, Georgia Salanti, John Geddes. Comparative efficacy and acceptability of psychological interventions in the long term treatment of bipolar disorder: a network meta-analysis.
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015016085
The objective of this review is to compare the efficacy and acceptability of different psychological interventions (either as monotherapy or add-on therapy) in the long term treatment of bipolar disorder.
We will search the Cochrane Central Register of Controlled Trials (CENTRAL). In order to identify randomised trials, we will use the search term of the Cochrane highly sensitive search strategy for identifying randomized trials in each databases with sensitivity-maximizing version (Cochrane handbook). Together with RCT filters, we will search generic terms for bipolar disorder and individual names of psychological interventions. References to trials will also be sourced the hand-searching of key journals, conference proceedings and other (non-Cochrane) systematic reviews and meta-analyses. No language restriction will be applied.
Only randomised controlled trials (RCTs) comparing any specific psychological interventions head-to-head against wait-list (or no treatment), or against a control intervention (including the so called treatment as usual) for long term treatment of bipolar disorder will be included. We define long term treatment any intervention aimed at preventing relapse with a follow up longer than three months (13 weeks or more). For a specific psychological intervention to qualify, it had to be implemented at the individual, group or family level, include face-to-face contact between the patient and the therapist (as opposed to telephone or internet-based interaction between patient and therapist), consist mainly of verbal communication, and directly address symptoms of bipolar disorder. We will only include trials reported as full text articles (we will not include studies reported as abstract only).
Quasi-randomized controlled trials, in which treatment assignment is decided through methods such as alternate days of the week, will be excluded. Medical or psychiatric comorbidity will not be an exclusion criterion. We will exclude studies in which participants will be randomly assigned to a maintenance treatment regimen while in an acute mood episode.
Condition or domain being studied
Bipolar disorders types I and II affect about 2% of the world’s population, with subthreshold forms of the disorder affecting another 2%. Even with treatment, about 37% of patients relapse into depression or mania within 1 year, and 60% within 2 years. There is increasing evidence that psychosocial interventions are effective adjuncts to pharmacotherapy in the stabilization and prevention of episodes of bipolar disorder. Treatment guidelines increasingly suggest that optimum management of bipolar disorder needs integration of pharmacotherapy with targeted psychotherapy. Randomized trials have found benefits for a variety of psychosocial approaches, including cognitive-behavioural therapy, family focused therapy, group psychoeducation and interpersonal and social rhythm therapy. Despite consistent reports of treatment efficacy, psychosocial treatments are by their nature complex, and it remains unclear which psychosocial procedures, techniques, or content ingredients are essential to a successful outcome in bipolar disorder or how the different treatment options rank against to each other. We hypothesized that the various active treatment modalities would have common elements (for example, a psychoeducational approach to disease management) that would differentiate these approaches from treatment as usual (however it is defined) and specific elements that would distinguish them from one another. We considered the identification of the common and the treatment-specific dimensions as a first step in determining which therapeutic ingredients bring about the most powerful clinical changes in patients with bipolar disorder. Some ingredients appear to be quite treatment-specific. Depending on the treatment approach, the predominant focus of psychotherapy may involve modifying dysfunctional cognitions, stabilizing sleep/wake cycles and disruptions in daily routines, modifying aversive communication styles in families, or learning adaptive coping strategies from other individuals with bipolar disorder. Other ingredients seem to be common to several, if not most, of the specific therapies, including encouraging a better understanding of bipolar illness, recognition and management of prodromal symptoms of relapse, adherence with medication regimens, and adapting to life stressors that may precipitate episodes.
Participants aged 18 or older, of both sexes with a primary diagnosis of bipolar disorder, diagnosed according to any of the following operationalized criteria: Research Diagnostic Criteria, DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, DSM-5 or ICD-10. Operationalised criteria essentially resembling these official ones will also be eligible. Studies conducted in both in inpatient and outpatient settings will be included. We will include studies recruiting participants who are euthymic, in full or partial remission (so called, partially symptomatic) for whom a long term relapse prevention treatment is clinically indicated.
We will exclude studies recruiting children and adolescents.
We will include all psychological and psychosocial interventions, like family therapy, cognitive-behavioural therapy, Interpersonal and Social Rhythm Therapy, individual or group psychoeducation, collaborative care, supportive treatments and brief psychoeducation.
Other potential control interventions, such as standard care involving pharmacological intervention or the use of pill placebos, will be eligible. We will obtain information about the interventions of interest either from head-to-head or placebo/no treatment/treatment as usual controlled trials. Hence the synthesis comparator set consists of all the interventions listed above, their combinations and placebo (if we will find other eligible interventions, we will include them in the network).
Grouping of interventions
Initially, we will group interventions which have common ingredients, in other words, which share common methods, assumptions or structure (see Introduction). In order not to be biased by the retrieved evidence, we will merge – if possible - the interventions “a priori” through a consensus process within the review group, before selecting the final list of references to be included in the review and before carrying out the statistical analyses.
- Efficacy: time to relapse.
- Acceptability of treatment, defined as the proportion of patients who left the study early by any cause.
- Efficacy: recurrence of any mood episode;
- Efficacy: recurrence of any depressive episode
- Efficacy: recurrence of any manic/mixed/hypomanic episode
- Psychosocial functioning
Data extraction, (selection and coding)
Two review authors will examine the abstracts of all publications obtained through the search strategy. Full articles of all the studies identified by either of the review authors will then be obtained and inspected by the same two review authors to identify trials meeting the following criteria:
(i) randomised controlled trial;
(ii) participants with bipolar disorder diagnosed by operationalized criteria;
Conflicts of opinion regarding eligibility of a study will be discussed with a third review author, having retrieved the full paper and consulted the authors if necessary, until consensus is reached. Methodological experts will be consulted if necessary.
Risk of bias (quality) assessment
Risk of bias will be assessed for each included study using the Cochrane Collaboration 'risk of bias' tool, as a model.13 The following 6 domains will be considered:
1. Sequence generation: was the allocation sequence adequately generated?
2. Allocation concealment: was allocation adequately concealed?
3. Blinding of outcome assessors (performance bias): was knowledge of the allocated treatment adequately prevented during assessment?
4. Incomplete outcome data for the primary outcomes: were incomplete outcome data adequately addressed?
5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?
6. Sponsorship (or intellectual) bias.
A description of what was reported to have happened in each study will be provided, and a judgment on the risk of bias will be made for each domain, based on the following three categories:
• High risk of bias
• Low risk of bias
• Unclear risk of bias.
Two independent review authors will assess the risk of bias in selected studies. Degree of agreement between the two independent raters will be reported. Any disagreement will be resolved through discussion and in consultation with the principal investigators. Where necessary, the authors of the studies will be contacted for further information.
Strategy for data synthesis
Methods for direct treatment comparisons
Initially, we will perform standard pairwise meta-analyses using a random effects model in STATA for every treatment comparison with at least two studies.
Methods for indirect and mixed comparisons
We will also perform network meta-analysis (NMA) to synthesise the available evidence from the entire network of trials by integrating direct and indirect estimates for each comparison into a single summary treatment effect. We will perform NMA using the methodology of multivariate meta-analysis where the different treatment comparisons are treated as different outcomes. This approach is described in detail in White et al. For this analysis we will use STATA (network and mvmeta packages).
Results from NMA will be presented as summary relative effect sizes (SMD or OR) for each possible pair of treatments. We will also estimate the ranking probabilities for all interventions of being at each possible rank. Then, we will obtain a treatment hierarchy using the surface under the cumulative ranking curve (SUCRA) and mean ranks. SUCRA can also be expressed as a percentage interpreted as the percentage of efficacy/safety of a treatment that would be ranked first without uncertainty. We will present jointly the relative ranking of treatments for efficacy and acceptability.34 Such outputs will be created in STATA (network graphs package).
Analysis of subgroups or subsets
In order to examine if the obtained results are preserved when we limit the included studies to those with lower risk of bias, we will examine the following variable:
1. Imputation - Trials where missing data have been imputed will be excluded.
2. Medical or psychiatric comorbidity - Trials with patients with medical or psychiatric comorbidity will be excluded.
3. Blinding - Trials without a blind assessor for efficacy outcomes will be excluded.
We will publish the results fro this review in scientific journals and will possibly disseminate these findings in international meetings, in order to have a direct feedback about our innovative approach from both clinicians and methodologists
Contact details for further information
Professor Andrea Cipriani
Department of Psychiatry
University of Oxford
OXFORD OX3 7JX
Organisational affiliation of the review
Department of Psychiatry, University of Oxford
Professor Andrea Cipriani, Department of Psychiatry, University of Oxford Professor David Miklowitz, University of California, Los Angeles Hannah McMahon, Department of Psychiatry, University of Oxford Ross McLaren, Department of Psychiatry, University of Oxford Dr Anna Chaimani, Department of Hygiene and Epidemiology, University of Ioannina Sarah Stockton, Department of Psychiatry, University of Oxford Professor Georgia Salanti, Department of Hygiene and Epidemiology, University of Ioannina Professor John Geddes, Department of Psychiatry, University of Oxford
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
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