Evidence-based pharmacotherapy of treatment-resistant unipolar depression

Treatment resistance to the antidepressive pharmacotherapy represents one of the most important clinical challenges in the pharmacological management of unipolar depression. In this review, we aimed to summarise the evidence for various pharmacological treatment options in therapy-resistant unipolar depression derived from clinical trials, systematic reviews, meta-analyses and treatment guidelines. The first measure in case of insufficient response to the initial antidepressant monotherapy contains the debarment of 'pseudo-resistance', potentially caused by inadequate dose and treatment duration of the antidepressant, insufficient plasma levels, non-compliance of the patient regarding medication intake or relevant psychiatric and/or somatic comorbidities. Applying a dose escalation of the current antidepressant cannot be generally recommended as evidence-based treatment option and the efficacy depends on the class of antidepressants. There is no compelling evidence for a switch to another, new antidepressant compound after insufficient response to a previous antidepressant. The combination of two antidepressants should be preferentially established with antidepressants characterised by different mechanisms of action (e.g. reuptake inhibitors together with presynaptic autoreceptor inhibitors). At present, the most convincing body of evidence exists for the augmentation of antidepressants with second-generation antipsychotic drugs and lithium. Hence, both strategies are consistently advised by treatment guidelines as pharmacological first-line strategy in treatment-resistant depression.