A prominent theory of depression focusses on neural plasticity and stress as central issues in seeking to develop a pattern of identifiable biological markers for the depressive disorders. Relative neglect, however, of clinical factors in that theory limits the uncovering of markers and opens to question their methodological approach. A conflicting theory, the ‘opposed neurobehavioral states’, based on dimensional analysis of monoamine neurotransmitter systems and behavioural factors is presented. This perspectives paper contrasts the two approaches viewing the biomarkers theory as premature at this point in the progress of depression research.

Studies developed to support the biomarkers theory and the opposed neurobehavioral states theory are examined for their strengths and limitations in explaining the nature of the disorder and the actions of therapeutic drugs. Reference is made to reviews of the many studies on biomarkers and the recent work that supports the opposed neurobehavioral states theory.

Main issue: the biomarkers theory sets important goals, but despite the many advances in the neural investigations of factors underlying depression, is still not successful in specifying markers. Thus, it is believed to be applying the wrong methodologic approach and premature in its claims. Perspective: the ‘opposed neurobehavioral’ theory is limited in its breadth of research. It applies, however, the dimensional approach to the clinical side of the problem, a methodological approach more likely to be effective in selecting the best clinical treatment and open to a more productive path to understanding of the nature of the disorder in future research.