Patients with major depressive episodes require effective treatment to reduce depressive symptoms and improve functional disability. Various alternative treatment strategies have been proposed for non- or partially responsive depressions in unipolar and bipolar disorder. However, achieving an adequate response in patients with MDD continues to be a challenge. Possible treatment strategies for patients with a depressive episode who are non-responsive to an adequate trial of any antidepressant treatment strategy include switching, combination with another antidepressant with a different mechanism of action, or augmentation with a non-antidepressant drug. Augmentation options include lithium, anticonvulsants, and the thyroid hormones, triiodothyronine, T3, and levothyroxine, T4. Add-on lithium as the first-choice augmentation strategy in treating patients with resistant depression is currently the most well-documented augmentation strategy, with more than 30 open-label studies and 10 placebo-controlled studies in the acute treatment of depressive episodes, and has been shown to augment the therapeutic effects of a broad spectrum of antidepressants. More recently, attention has turned to the atypical antipsychotics, e.g. aripiprazole, olanzapine, risperidone and quetiapine. Several controlled studies show favourable outcomes of augmentation treatment with these antipsychotics in unipolar and bipolar depression.