One of these would be to identify, prior to treatment, the medication that has the highest likelihood of benefitting the patient. Research has sought to indentify “endophenotypes” that could predict response or remission to specific antidepressants for individual patients. As defined by Gottesman and Gould,48 an endophenotype must meet five criteria: The endophenotype is associated with illness in the population. The endophenotype is heritable. The endophenotype is primarily state-independent (manifests in an individual whether or not illness is active). Within families, endophenotype and illness cosegregate. The endophenotype Inhibitors,research,lifescience,medical found in

affected family members is found in nonaffected Inhibitors,research,lifescience,medical family members at a higher rate than in the general population.

Endophenotypes thus are measureable characteristics or physiologic indices that fill “the gap between available descriptors and between the gene and the elusive disease process.”49 Exhaustive studies of clinical features, family history, as well as sleep patterns and neuroendocrine correlates, have identified general prognostic indicators for treatment outcome for depression.50,51 In some cases, the predictors may be useful for groups of patients with certain subtypes Inhibitors,research,lifescience,medical of depression (ie, psychotic depression).52 While some symptomatic and physiologic features in MDD patients demonstrate Inhibitors,research,lifescience,medical promise as

putative endophenotypes, many do not fulfill the actual criteria for an endophenotype or meet the goal of providing greater prognostic specificity than the definition of the illness itself.53 Some brain imaging findings also have demonstrated prognostic significance54-57 and may fulfill the criteria for an endophenotype.58 Part of the challenge in identifying true endophenotypes in MDD is that the physiologic and genetic underpinnings of MDD are complex and poorly understood. As a result, imaging findings Inhibitors,research,lifescience,medical may reflect confounds such as interindividual heterogeneity in brain structure or function unrelated to illness, or the effects of previous or concomitant medication treatment.58 No clinically meaningful endophenotypes predictive of response to specific medications in individual patients prior to the start of treatment yet have been identified.59,60 An alternative to the endophenotypic approach has been to examine genetic polymorphisms as possible outcome NATURE REVIEWS DRUG DISCOVERY predictors. Recent studies have suggested that common genetic variations may be associated with response to specific antidepressant medications.61-63 For example, some common polymorphisms in serotonin system genes have been shown to influence the outcome of SSRI treatment.62,64 Many of these results have not consistently replicated or do not allow the estimation of prediction accuracy in a clinical population.