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

ABSTRACT: As 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.We 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.Of 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.The 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.ClinicalTrials.gov identifier: NCT00927550.

SUBMITTER: Girlanda F

PROVIDER: S-EPMC4210495 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Girlanda Francesca F Cipriani Andrea A Agrimi Emilia E Appino Maria Grazia MG Barichello Andrea A Beneduce Rossella R Bighelli Irene I Bisoffi Giulia G Bisogno Alfredo A Bortolaso Paola P Boso Marianna M Calandra Carmela C Cascone Liliana L Castellazzi Mariasole M Corbascio Caterina C Parise Vincenzo Fricchione VF Gardellin Francesco F Gennaro Daniele D Hanife Batul B Lintas Camilla C Lorusso Marina M Luca Antonina A Luca Maria M Luchetta Chiara C Lucii Claudio C Maio Francesca F Marsilio Alessandra A Mattei Chiara C Moretti Daniele D Nosè Michela M Occhionero Guglielmo G Papanti Duccio D Pecile Damiano D Percudani Mauro M Prestia Davide D Purgato Marianna M Restaino Francesco F Romeo Salvatore S Sciarma Tiziana T Strizzolo Stefania S Tamborini Stefania S Todarello Orlando O Tozzi Fiorella F Ziero Simona S Zotos Spyridon S Barbui Corrado C

BMC research notes 20141017

<h4>Background</h4>As 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; ...[more]

PMID: 25326163

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Project description:BACKGROUND:Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group. METHODS:The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects. DISCUSSION:The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies. TRIAL REGISTRATION:ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Project description:AimsLithium has long been believed to reduce the risk of suicide and suicidal behaviour in people with mood disorders. Previous meta-analyses appeared to support this belief, but excluded relevant data due to the difficulty of conducting meta-analysis of rare events. The current study is an updated systematic review and meta-analysis that includes all eligible data, and evaluates suicide, non-fatal suicidal behaviour (including suicidal ideation) and suicide attempts.MethodsWe searched PubMed, PsycINFO and Embase and some trial registers. We included all randomised trials comparing lithium and placebo or treatment as usual in mood disorders published after 2000, to ensure suicide was reliably reported. Trial quality was assessed using the Cochrane Risk of Bias tool. Pooled data were analysed using Fisher's Exact test. In addition, meta-analysis was conducted using various methods, prioritizing the Exact method. All trials were included in the analysis of suicide initially, regardless of whether they reported on suicide or not. We conducted a sensitivity analysis with trials that specifically reported on suicides and one that included trials published before 2000. Pre-specified subgroup analyses were performed involving suicide prevention trials, trials excluding people already taking lithium, trials involving people with bipolar disorder exclusively and those involving people with mixed affective diagnoses. Non-fatal suicidal behaviour and suicide attempts were analysed using the same methods, but only trials that reported these outcomes were included. PROSPERO registration: CRD42021265809.ResultsTwelve eligible studies involving 2578 participants were included. The pooled suicide rate was 0.2% for people randomised to lithium and 0.4% with placebo or treatment as usual, which was not a statistically significant difference; odds ratio (OR) = 0.41 (95% confidence interval 0.03-2.49), p = 0.45. Meta-analysis using the Exact method produced an OR of 0.42 (95% confidence interval 0.01-4.5). The result was not substantially different when restricted to 11 trials that explicitly reported suicides and remained statistically non-significant when including 15 trials published before 2000 (mostly in the 1970s). There were no significant differences in any subgroup analysis. There was no difference in rates of all non-fatal suicidal behaviour in seven trials that reported this outcome, or in five trials that reported suicide attempts specifically. Meta-analyses using other methods also revealed no statistically significant differences.ConclusionsEvidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour.

Project description:Brodmann Area 46 (BA46) has long been regarded as a hotspot of disease pathology in individuals with schizophrenia (SCH) and major depressive disorder (MDD). Pyramidal neurons in layer III of the Brodmann Area 46 (BA46) project to other cortical regions and play a fundamental role in corticocortical and thalamocortical circuits. The AutoCUTS-LM pipeline was used to study the 3-dimensional structural morphology and spatial organization of pyramidal cells. Using quantitative light microscopy, we used stereology to calculate the entire volume of layer III in BA46 and the total number and density of pyramidal cells. Volume tensors estimated by the planar rotator quantified the volume, shape, and nucleus displacement of pyramidal cells. All of these assessments were carried out in four groups of subjects: controls (C, n = 10), SCH (n = 10), MDD (n = 8), and suicide subjects with a history of depression (SU, n = 11). SCH subjects had a significantly lower somal volume, total number, and density of pyramidal neurons when compared to C and tended to show a volume reduction in layer III of BA46. When comparing MDD subjects with C, the measured parameters were inclined to follow SCH, although there was only a significant reduction in pyramidal total cell number. While no morphometric differences were observed between SU and MDD, SU had a significantly higher total number of pyramidal cells and nucleus displacement than SCH. Finally, no differences in the spatial organization of pyramidal cells were found among groups. These results suggest that despite significant morphological alterations in layer III of BA46, which may impair prefrontal connections in people with SCH and MDD, the spatial organization of pyramidal cells remains the same across the four groups and suggests no defects in neuronal migration. The increased understanding of pyramidal cell biology may provide the cellular basis for symptoms and neuroimaging observations in SCH and MDD patients.

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

Publications

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

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