Even the pharmacotherapy is more effective than placebo for the treatment of depression, the outcome of pharmacoltherapy remains unsatisfactory for many patients. Apart from side effects, there are two major limitations of antidepressant therapy. One is the delayed onset of improvement and another is partial response. In order to address these clinical dilemmas, many psychiatrists more commonly employ add-on therapy. In past, the practice of using multiple drugs to enhance treatment response was called polypharamcy, and was disparaged as poor clinical practice. However, with improved understanding of how drugs affects the central nervous system and increased communication in journals and on computer networks about the relative merits of specific combinations, the scientific basis for the combining drugs is being defined. Indeed, the use of multiple medications as a stratege to enhance response has become both acceptable and widespread now a days. It is now referred to more positively as add-on therapy, co-medication, combination therapy, or drug augmentation. Thus, as the methods of practical strategies for treatment of depression, switching classes antidepressant drugs, combination therapy, augmentation strategies and brief treatment algorithm will be presented with items of considerations. However, when combination of drugs being tried, knowledges about the action of mechanism, pharamcokinetics, and pharmacodynamics are essential to cope with the possible adversive reactions and to get the appropriate responses for the treatment of depressive symptoms.