Health Technology Assessment 2007; Vol 11: number 39
Executive SummaryView/Download full monograph in Adobe Acrobat format (890 kbytes)
K Soares-Weiser,1 Y Bravo Vergel,2 S Beynon,1 G Dunn,2 M Barbieri,3 S Duffy,1 J Geddes,4 S Gilbody,5 S Palmer2 and N Woolacott1*
1 Centre for Reviews and Dissemination, University of York, UK
2 Centre for Health Economics, University of York, UK
3 The Economic and Health Research Centre, Universitat Pompeu Fabra, Barcelona, Spain
4 Department of Psychiatry, University of Oxford, UK
5 Department of Health Sciences, University of York, UK
* Corresponding author
Bipolar disorder is a recurrent mood disorder associated with significant morbidity and mortality that places a considerable economic burden on UK society. Long-term treatment of bipolar disorder is necessary to prevent recurrence and reduce the loss of productivity and increased medical costs associated with this illness. Lithium has been the mainstay treatment for bipolar disorder for many years, but more recently, anticonvulsants, antidepressants, antipsychotics and adjunctive psychosocial therapies have been used in the maintenance treatment of bipolar disorder. However, the evidence for the effectiveness of these treatments is unclear.
The aims of this review were to determine the clinical effectiveness and cost-effectiveness of pharmacological and/or psychosocial interventions for the prevention of relapse in people with bipolar disorder.
This technology assessment comprised the following research.
The review of clinical effectiveness included 45 trials; all but one tested the intervention or comparator in adults. They were placebo- or active controlled trials of lithium, valproate, lamotrigine, carbamazepine, olanzapine, imipramine, quetiapine, amitriptyline, perphenazine, flupenthixol and psychosocial interventions [cognitive behaviour therapy (CBT); psychoeducation; family intervention; care management; and integrated group therapy].
For the prevention of all relapses, lithium, valproate, lamotrigine and olanzapine were statistically significantly better than placebo. The evidence was strongest for lithium and lamotrigine; that for olanzapine may be unreliable as only responders to olanzapine were studied.
For the prevention of depressive relapses, valproate, lamotrigine and imipramine were statistically significantly better than placebo. The evidence is probably strongest for lamotrigine; the evidence base for imipramine is very weak (two very small trials). For manic relapses, lithium and olanzapine were statistically significantly better than placebo, but again for olanzapine only responders to olanzapine were studied.
Only olanzapine demonstrated greater efficacy than lithium, and then for all relapses and manic relapse, but not for depressive relapse.
In order to investigate the relative efficacy of the treatments, an MTC was performed. The purpose of an MTC is to bring together the clinical evidence regarding the efficacy of all treatments for a specified indication in a 'network of evidence' linked by common comparators. Of all the treatments included in the systematic review, lithium, valproate, lamotrigine, carbamazepine, olanzapine, imipramine and lithium plus imipramine could be linked in a network of evidence. None of the psychosocial interventions could be linked into the network of evidence.
The results of the MTC indicate that carbamazepine is not an effective maintenance treatment for bipolar I disorder. In patients with mainly depressive symptoms the treatment with the highest probability of being the best for the prevention of all relapses appears to be valproate, followed by lithium plus imipramine. In patients with mainly manic symptoms, olanzapine is by far the best option for the prevention of all relapses, followed by valproate and lithium.
From the studies investigating psychosocial interventions, there were few data for each comparison and outcome. The evidence suggests that CBT, in combination with usual treatment, is effective for the prevention of relapse. Group psychoeducation and possibly family therapy may also have roles as adjunctive therapy for preventing relapse.
Following the review of economic evidence from the literature, a new decision analytic model was developed. This focused on the cost-effectiveness of long-term maintenance treatments of bipolar I patients with a range of alternative pharmacological treatments.
The results from the model suggest that the choice between alternative pharmacological treatments based on cost-effectiveness considerations is dependent upon a number of factors: the previous episode history of a patient (i.e. whether manic or depressive) and the mortality benefit assumed for lithium strategies.
The results from the base-case analysis for patients with a recent history of depression suggest that valproate, lithium and the combination of lithium and imipramine are potentially cost-effective depending upon the amount that a decision-maker is willing to pay for additional health gain [assessed here using quality-adjusted life-years (QALYs)]. Using conventional amounts that the NHS is prepared to pay for health gain (£20,000–40,000 per QALY), the lithium-based strategies appear to be potentially cost-effective for this group.
For patients with a recent history of mania, the choice of pharmacological intervention appears to be between olanzapine and lithium monotherapy. Again using conventional threshold as a reference point, the results suggest that lithium is the most cost-effective therapy.
Excluding the additional mortality benefit associated with lithium-based strategies resulted in all treatments for patients with a recent history of a depressive episode being dominated by valproate and, in the case of patients with a recent history of a manic episode, by olanzapine.
Lithium, valproate, lamotrigine and olanzapine are effective as maintenance therapy for the prevention of relapse in bipolar disorder. Olanzapine and lithium are efficacious for the prevention of manic relapses and valproate, lamotrigine and imipramine for the prevention of depressive relapse. Carbamazepine is not an effective maintenance treatment. There is no trials evidence for the efficacy of combination therapy.
Psychosocial therapies have not been investigated thoroughly. There is some evidence that CBT, group psychoeducation and family therapy might be beneficial as adjuncts to pharmacological maintenance treatments.
There is insufficient information to permit any meaningful assessment of the relative tolerability of the treatments or their relative effects on suicide rate and mortality.
For patients with a recent depressive episode, valproate, lithium monotherapy and the combination of lithium and imipramine are potentially cost-effective. For patients with a recent manic episode, olanzapine and lithium monotherapy are potentially cost-effective.
The cost-effectiveness estimates in both groups of patients were shown to be sensitive to the assumption of a reduced suicidal risk associated with lithium-based strategies.
The following areas are recommended for further research:
It is very important that future trials should be good-quality randomised controlled trials, involving an adequate number of participants and have sufficient duration of follow-up. Ideally, this research should be conducted via a properly resourced trial network.
Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder. Health Technol Assess 2007;11(39).
The Health Technology Assessment (HTA) programme, now part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the costs, effectiveness and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined to include all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care, rather than settings of care.
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