• S J Edwards, V Hamilton, L Nherera, and N Trevor.
• BMJ Technology Assessment Group (BMJ-TAG), London, UK.
• Health Technol Assess. 2013 Nov 1;17(54):1-190.

BackgroundPatients with treatment-resistant depression (TRD) are those with major depressive disorder that has not responded adequately to treatment. The causes of depression are not fully understood, although there is evidence to suggest that depression is a complex interaction among biological, genetic, psychosocial and environmental factors. Strategies available for the treatment of patients with TRD include pharmacological, non-pharmacological, and psychological and psychosocial interventions. Pharmacological treatment options include switching to a different antidepressant, the addition of another antidepressant of a different class, or use of an augmenting agent, such as anticonvulsants, lithium or atypical antipsychotics (AAPs). However, there is limited evidence available on the effectiveness of these strategies in the treatment of TRD.ObjectivesTo estimate the clinical effectiveness and cost-effectiveness of augmentation of selective serotonin reuptake inhibitor (SSRI) antidepressant therapy with either lithium or an AAP drug in the management of people with treatment-resistant unipolar depression, defined as failure to respond to two or more antidepressant drugs in their current episode of depression.Data SourcesDatabases searched were Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, PsycINFO and NHS Economic Evaluation Database (NHS EED). All databases were searched from inception to August 2011. Additional data were obtained from manufacturers.Review MethodsSystematic reviews of studies evaluating clinical effectiveness, economic analyses and quality of life (QoL) were executed. Quality assessment according to predefined criteria was undertaken independently by two reviewers. Pairwise meta-analyses and mixed-treatment comparisons (MTCs) using both fixed- and random-effects models were undertaken based on intention-to-treat analyses. A probabilistic de novo mathematical model was developed to synthesise the available data on costs and clinical outcomes from the UK NHS perspective over a 1-year time horizon (8 weeks of acute treatment captured by a decision tree and 10 months of maintenance treatment captured by a Markov model).ResultsTwelve randomised controlled trials (RCTs) were identified in the review of clinical effectiveness literature; 10 considered SSRI  +  AAP compared with SSRI  +  placebo/no treatment, one considered SSRI  +  AAP compared with SSRI  +  lithium and one considered SSRI  +  lithium compared with SSRI  +  placebo. The RCTs included in the primary analyses used fluoxetine as the background SSRI and olanzapine as the AAP. Results of the MTC showed a non-significant trend in favour of lithium augmentation for response [lithium a priori odds ratio (OR) 1.29; 95% credible interval (CrI) 0.11 to 5.32; lithium post hoc OR 4.15; 95% CrI 0.25 to 20.34 (the trial informing the comparison with lithium reported response using two different definitions)], mean change in Montgomery-Åsberg Depression Rating Scale score from baseline (mean difference -  1.47, 95% CrI -  9.10 to 6.41) and all-cause withdrawals (OR 0.74, 95% CrI 0.10 to 2.66). Four economic evaluations (none directly addressing the review question) and 17 studies that reported on QoL were identified and summarised in narrative reviews. The results of the de novo modelling indicate that augmentation of SSRI with lithium dominates augmentation of an SSRI with AAP (i.e. it resulted in cost savings of £905 per person per year and generated more health benefits, estimated to be 0.03 quality-adjusted life-years). However, sensitivity analyses showed that the model was highly sensitive to changes in acute treatment efficacy (response and remission) or discontinuation. The model was not sensitive to changes in other parameters.LimitationsIn patients with TRD, there is a lack of direct evidence comparing the clinical effectiveness of augmenting an SSRI with an AAP compared with augmenting with lithium. RCTs were identified which facilitated comparison of adding AAP with adding lithium via a MTC. However, variations in the definitions of response implemented in the RCTs, together with differences in patient baseline characteristics across RCTs, introduce bias into the analysis. The direction and extent of the bias is uncertain.ConclusionsAugmentation of SSRIs with lithium or AAP is likely to be beneficial in people with TRD. Clinical evaluation based on the limited evidence identified in this research indicates no statistically significant difference between the two augmentation strategies. Cost-effectiveness analyses suggest that augmentation with lithium is less expensive and more effective than augmentation with AAP. However, the uncertainty in the clinical estimates of discontinuation and treatment response is reflected in the model results. A RCT comparing the two augmentation strategies, reporting relevant outcomes, including QoL, is needed.Study RegistrationPROSPERO CRD42011001464.

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