Depression is one of the major challenges facing clinical medicine. Unipolar depression was ranked fifth among the leading causes of disability worldwide in 2000 and projections indicate that by 2020 it will be ranked second only to ischemic heart disease . Recognition and effective treatment of depression is an important concern. Data from the US National Comorbidity Survey indicate that almost half of those who suffer from depression go untreated and that treatment is adequate in only about 41% of cases . Treatment approaches for depression that are supported by evidence from randomized, controlled trials include antidepressant drugs and specific psychotherapeutic approaches based on interpersonal or cognitive-behavioral techniques. The data supporting efficacy of antidepressant drugs are considerable and this modality is the most widely used, for this reason and because it is accessible to clinicians who are not psychiatrists and do not have expertise in psychotherapy. Has the efficacy of antidepressant medication increased appreciably since the first drugs of this type were introduced almost half a century ago? Response rates to active drug and placebo in controlled trials of antidepressants suggest that there has been little change in this regard. While response to active drug and placebo varies, a differential of 20-30% between active drug and placebo remains constant over scores of trials . Since about 40% of responders to active drug in antidepressant trials could well be placebo responders, the true efficacy of currently available medications is a matter of serious concern. These considerations lead to the conclusion that an important challenge facing contemporary psychopharmacology is to develop antidepressant drugs that are effective in the ∼40% of patients who do not respond to current treatment. This will require novel concepts beyond the current templates for drug development that are essentially based on the mechanism of action of existing agents. Whether blockbuster approaches based on the development of "one size fits all" agents are the correct direction is open to serious debate. Progress in the development of new drugs could well depend on phenomenological dissection of clinical subtypes and the identification of core, drug responsive diagnostic entities. Pharmacogenetic approaches could prove pivotal in this regard . A further challenge that is as yet unmet is the delay 2-4 weeks in onset of action of antidepressants and the lengthy period of 6-8 weeks required for drugs to be fully effective. There is very little evidence to suggest that any of the currently available drugs act faster than the others and this latency of effect is a major difficulty facing clinicians who treat depressed patients. On this background, the current issue of explores the pivotally important strategy of supplementation of antidepressant action and is most timely. The concept underlying this collection of papers is that addition of a second therapeutic agent to an antidepressant drug can have augmenting or accelerating effects. Augmentation implies an increase in efficacy i.e. a stronger therapeutic effect, which would convert non- or partial responders to full responders. Accelerating effects imply an earlier onset of action and more rapid achievement of maximal therapeutic action. Both these objectives are fully congruent with the major challenges facing antidepressant drug development. Supplementary treatments currently being explored involve harnessing neurotransmitter systems other than those acted upon by the primary antidepressant drug (such as dopamine), stimulating or blocking mechanistically relevant receptors whose effect is to enhance the action of the primary agent (such as 5-HT1A receptors) or the addition of substances for which there is clinical evidence but whose mechanism of action in depression is not fully understood (such as triiodothyronine). From the point of view of therapeutics two drugs may well be better than one and the current series of papers seeks to explore whether and how this might be so. In the clinic, each additional agent carries with it further risks of adverse effects, the potential for pharmacokinetic interactions and problems with compliance, which are directly related to the number of pills the patient has to take and the frequency with which he needs to take them. Nevertheless, research on strategies for potentiation and facilitation of antidepressant treatment can have very great potential impact, at the clinical level and also as a basis for the development of novel antidepressant drugs based on the mechanisms identified. REFERENCES  Murray, C.J., Lopez, A.D. (1997) Lancet, 349, 1498-1504.  Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E., Wang, P.S. (2003) JAMA, 289, 3095-3105.  Davis, J.M., Wang, Z., Janicak, P.G. (1993) Psychopharmacol. Bull., 29, 175-81.  Lerer, B., Macciardi, F. (2002) Int. J. Neuropsychopharmacol., 5, 255-275.