Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial

Abstract

BackgroundAs lithium treatment might be effective in reducing the risk of deliberate self-harm (DSH) in adult patients with unipolar affective disorders, we designed a pragmatic randomised trial to assess its efficacy in more than 200 patients with treatment-resistant depression. However, we randomised 56 patients only. The aim of this report is therefore twofold: first, to disseminate the results of this underpowered study which may be incorporated into future meta-analytical reviews; second, to analyse some critical aspects of the study which might explain failure to reach the target sample size.MethodsWe carried out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode were allocated to add lithium to usual care (intervention arm) versus usual care alone (control arm). Suicide completion and acts of DSH during the 12 months of follow-up constituted the composite primary outcome.ResultsOf 58 patients screened for inclusion, 29 were allocated to lithium plus usual care and 27 were assigned to usual care without lithium. Six patients in the lithium plus usual care group and seven in the usual care group committed acts of DSH during the follow-up phase. The survival probability did not differ between the two treatment arms (Chi2 = 0.17, p =0.676). With regard to changes in the severity of depressive symptomatology from baseline to endpoint, no significant differences were detected.ConclusionsThe present study failed to achieve the minimum sample size needed to detect a clinically meaningful difference between the two treatment arms. Consequently, the finding that lithium, in addition to usual care, did not exert a positive effect in terms of reduction of DSH after 12 months of follow-up is likely due to the lack of sufficient statistical power to detect a difference, if a difference existed. The dissemination of the results of this underpowered study will inform future meta-analytical reviews on lithium and suicide-related outcomes.Trial registrationClinicalTrials.gov identifier: NCT00927550

Suicide and suicide risk

“…More recently, several methodologically rigorous pharmacoepidemiological studies have been conducted, with >10,000 patients in each study 295,296 and have strongly suggested that patients treated with lithium are relatively protected from suicide attempts, death by suicide, hospitalization for suicide attempts and other suicide related outcomes, compared with patients treated with valproate or other mood stabilizers. However, several RCTs that compared lithium to either placebo or to other mood stabilizers have been unable to demonstrate this effect 297,298 , although some had very modest sample sizes 299 . Of interest, two of these studies identified anti-suicidal effects based on secondary, post-hoc analyses 297,300 .…”

Lithium Treatment in Children and Adolescents

“…The available data include mostly investigations of the use of lithium for treating what was diagnosed as acute mania (although the episode duration was several years of chronic symptoms) and in small clinical case series of pediatric patients. This paucity is in striking contrast to a large volume of data and studies with acute and prophylactic lithium in adults [2][3][4][5][6][7].…”

Authors' reply

“…We thank Roberts and colleagues for their thoughtful critique of our meta-analysis. 1 They question our decision to include Girlanda et al 2 in our meta-analysis of trials of lithium for the prevention of death by suicide. Roberts et al aptly highlight that the Girlanda et al study had several methodological limitations.…”

“…We agree, however, with Roberts et al that we should have made it clear to the reader that the Girlanda et al trial used usual care, rather than placebo, as the control condition. 2…”