Depression, stress, and anhedonia: toward a synthesis and integrated model

Abstract

Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (a) anhedonia, (b) dopamine, and (c) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affects mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research.

Figure 1

Schematic illustration of the heuristic model proposed in the current review. Double-ended arrows denote associations (no causality) between processes. Double lines with dots denote directional inhibitory links (e.g., stress response inhibits mesolimbic DA release). Dotted lines denote causal relations, and the gray boxes denote hypothesized mechanisms (e.g., chronic stress leads to lower DA release and eventually to blunted DA response). The circular arrow denotes long-term DA down-regulation with chronic stress. Letters (A-D) refer to the sections in the text. ↓: decreased, ↑: increased, NAc: nucleus accumbens, PFC: prefrontal cortex. For the sake of simplicity of the illustration, both environmental factors and biological vulnerability are graphically represented as contributing to the clinical syndrome directly; both factors likely affect, however, all of the sub-components of this heuristic model (e.g., decreased reward responsiveness, exaggerated stress responsiveness, blunted mesolimbic DA).

Figure 2

Behavioral findings emerging from a probabilistic reward task involving a differential reinforcement schedule. Response bias toward the more frequently rewarded stimulus was reduced in (a) unmedicated MDD subjects (Pizzagalli et al. 2008b); (b) healthy controls performing the task under acute stressor (Bogdan & Pizzagalli 2006); and (c) healthy controls receiving a single dose of a D2/3 agonist hypothesized to reduce phasic DA signaling to reward outcomes via presynaptic DA autoreceptor activation (Pizzagalli et al. 2008a).

Figure 3

Schematic illustration of mesocortical and mesolimbic DA pathways. The diagram shows DA nuclei within the ventral tegmental area projecting to the nucleus accumbens and prefrontal cortex, and within the substantia nigra projecting to the dorsal striatum (caudate and putamen). Figure adapted with permission from Hyman et al. (2006).