Lithium and Standard Therapy in Resistant Depression. Randomized evaluation of the effectiveness of lithium in subjects with treatment resistant depression and suicide risk

Background: It has been estimated that under ordinary circumstances up to 30-40% of patients with unipolar depression do not respond well to initial antidepressant treatment and fail to make a satisfactory improvement. International guidelines define treatment-resistant depression (TRD) as failure to respond to two or more antidepressants given sequentially at an adequate dose for an adequate time. In TRD, self-harm and suicide ideas represent alarming psychopathological symptoms. These may lead to self-harm and suicide attempts and, in up to 10% of cases, to completed suicides. The intervention following non-fatal suicidal behavior is relevant to suicide prevention, because the risk of suicide following deliberate self-harm is considerable. In this difficult-to-treat patient population data on therapeutic interventions following non-fatal suicidal behavior are very scant. On the basis of the evidence collected so far it has been highlighted that lithium could have a beneficial effect to prevent deliberate self-harm, but currently there are not randomized clinical trials assessing the efficacy of lithium to reduce deliberate self-harm and suicide in patients with TRD. Objective: The primary aim of the LAST study is to assess whether lithium is effective in reducing the risk of suicidal behavior in subjects with TRD and suicide risk. Secondary aims of the study are to assess whether lithium is effective in improving depressive symptomatology and to evaluate the tolerability profile of lithium. Methods: LAST is a multicentre trial that aims to involve 60-70 Italian psychiatric services. It will include subjects affected by treatment-resistant depression with a history of attempted suicide or deliberate self-harm in the previous 12 months. Patients meeting eligibility criteria will be allocated, through a centralized randomization procedure, to lithium plus usual pharmacological and non pharmacological treatment or to usual pharmacological and non pharmacological treatment. After random allocation subjects will be followed over a period of 12 months and they will be evaluated at baseline and each month on pharmacological therapy, deaths and deliberate self-harm. Additional information about severity of illness will be collected at 3, 6 and 12 months. The composite primary outcome is constituted by suicide completion and acts of deliberate self-harm during the follow-up period. An independent adjudicating committee, blind to treatment allocation, will review all events that might be classified as primary outcome