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The re-emergence (i.e. ‘breakthrough’) of depressive symptoms despite maintenance treatment of depression with antidepressant drugs is a complex clinical phenomenon referred to as tolerance. Herein we critically appraise evidence from both pre-clinical and clinical studies, focusing on putative mechanisms as well as clinical correlates and implications of the emergence tolerance during antidepressant treatment for major depressive disorder (MDD). It is firstly unclear to what extent this phenotype reflects a pharmacological effect of an antidepressant, is driven by non-adherence, is a marker of latent bipolarity or another comorbidity, a marker of neuroprogression of the underlying disorder or the intrusion of the impact of psychosocial variables into the clinical course. The operational definitions of tolerance and its related phenomena have also been largely inconsistent. Several protective clinical indicators have been proposed, including a rapid-cycling course and comorbid chronic anxiety, whilst poor treatment adherence, proneness to emotional blunting and sub-threshold bipolarity have been identified as possible correlates of tolerance to antidepressant treatment in MDD. Putative neurobiological underpinnings include adaptations in the hypothalamic–pituitary–adrenal (HPA) axis and the serotonergic system. Due to the clinical and diagnostic challenges imposed by the emergence of tolerance to antidepressants, there is an urgent need for upcoming international guidelines to reach a consensus on operational definitions for this complex clinical phenomenon, thus enabling a more precise appreciation of the incidence and correlates of tolerance to antidepressants. Taken together, the present review underscores the need to cautiously weight benefits and risks prior to considering long-term antidepressant treatment for patients with MDD as tolerance may emerge in a subset of patients. © 2018 Elsevier Ltd

The prediction of acute and maintenance lithium treatment response carries major clinical and neurobiological implications, warranting systematic review. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant review searched major electronic databases from inception until December 2017 for studies documenting a clinical diagnosis of bipolar disorder (BD) made according to the mainstream diagnostic manuals and confirmed by a structured interview. Eligible studies allowed a quantitative comparison of endpoint vs baseline mean values of a given biomarker, regardless of the mood phase of patients with BD, and the disorder was assessed for severity using validated rating tool(s). Owing to the purposely applied stringent selection criteria, 16 acute and 12 maintenance studies could be included. The anticipated publication bias limited the chances of reportable generalizable findings, hindering a side-by-side comparison of different records across varying biomarkers and subsequent meta-analyses. The PRISMA approach was nonetheless preferred; it aimed at enhancing the homogeneity of the included results and minimizing the chances of “apples and oranges” with respect to the present research theme. The present critical review confirms the need for future research to specifically assess either pretreatment and/or posttreatment putative biomarkers of patients with BD and treated with lithium. © 2018 Elsevier B.V.