Discovering Endophenotypes for Major Depression

Abstract

The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness.

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

“…Moreover, reward dependence, a putatively heritable trait associated with maintenance of behavior in response to reward cues, shows trait-like features associated with familiality of depression (Farmer et al, 2003). Collectively, these findings suggest that anhedonia is among the most promising endophenotypes of depression (Hasler et al, 2004). Still, little is know about which aspects of hedonic processing might be dysfunctional in depression.…”

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

“…Anhedonia, the decreased response to pleasurable stimuli, is a defining symptom of the disorder to the extent that MDD may be diagnosed even in the absence of depressed mood if anhedonia and other secondary symptoms are present [1]. Anhedonia is also a central feature of a number of neurobiological theories of depression that posit that deficits in emotional and motivational responses to appetitive stimuli are core features of the disorder [188], and the anhedonic endophenotype of MDD is perhaps the most well supported [10]. …”

Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects

“…The importance of anhedonia in psychopathology has recently been stressed by researchers who demonstrated that this symptom, together with increased stress reactivity, is an important candidate for psychopathological endophenotype of MDD. 9,10 Endophenotypes are subclinical traits that are associated with the expression of an illness and represent the genetic liability of the disorder in non-affected individuals. 1 The neural system underlying reward and pleasure is well defined in humans.…”