ear Colleagues,Treatment has always been the ultimate goal of psychiatry. However, truly effective treatments havebeen scarce for most of psychiatrys history. It is only in the last 50 years that drugs acting on the centralnervous system and capable of influencing behavior have been discovered, and often by serendipity. Thediscovery that chemical compounds could influence the brain led to research into the mechanisms of actionof these drugs, and more generally to progress in neuroscience. Thus, indirectly, drug discovery stronglycontributed to our current knowledge of the brains biology.To a large extent, research has elucidated the mechanisms of action of drugs, and we know todaymore or lesswhy treatment works. However, it is also worth asking ourselves why treatment does not workin some cases. Understanding the mechanisms of nonresponse is extremely instructive. However, this questionis complex because of the many factors influencing treatment response. Sources of variation between patientsinclude diagnostic criteria, biological parameters, the heterogeneity of individual responses to dynamic testsor therapeutic models, nutritional or metabolic disturbances, pharmacogenetic polymorphism, andenvironmental factors, to name but a few. Current diagnostic classifications do not identify homogeneousgroups of patients, who respond in a predictable way to a given drug.This calls into question the usefulness ofthese classifications in drug studies. It has been suggested that the diagnosis of a disorder is not sufficient forsuch research.Treatment response or nonresponse should be correlated with additional parameters: underlyingpersonality; quantification of symptoms; neuropsychological tests; laboratory findings derived fromneuroendocrinology or pharmacogenetics; brain imaging, either purely functional (electroencephalography[EEG], quantitative EEG, sleep recordings, or magneto-EEG) or structural and functional (magneticresonance imaging, single-photon emission computed tomography, or positron emission tomography); andthe response to certain models. Patients, disorders, and ad hoc treatments should be characterized underrelatively standardized conditions to ensure a better evaluation of the correlates of nonresponse.Understanding the determinants of nonresponse and poor response is important in order to predictthe prognosis and course of a disorder, as well as to evaluate the social cost of a disease.The current questionsraised by various national health authorities concerning the social and economic aspects of diseases, inparticular mental disorders, cannot be answered without knowing the reasons for nonresponse or poorresponse to treatment.All this explains why this difficult question of nonresponse to treatment is one of the concerns of themembers of the Editorial Board of Dialogues in Clinical Neuroscience. We have therefore contributed to aspecial issue of the journal on this problem, to express our point of view and debate a question of currentimportance.Your sincerely,Jean-Paul Macher, MDMarc-Antoine Crocq, MDE d i t o r i a lD1