Annu Rev Clin Psychol. 2014 March 28; 10: 393–423. doi:10.1146/annurev-clinpsy-050212-185606. # Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model Diego A. Pizzagalli Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478 ## 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 (1) anhedonia, (2) dopamine, and (3) 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, presenting initial evidence consistent with our model, and discuss directions for future research. ## Keywords Depression; Anhedonia; Stress; Endophenotype; Dopamine ## I NTRODUCTION Despite its “ignominious status as a world leader in burden of disease” (Greden 2001, p. 30) and decades of research, the etiology and pathophysiology of major depressive disorder (MDD) remain largely unknown. This lack of understanding partially stems from issues inherent in current classification systems, which define mental illness based on clusters of symptoms and clinical course rather than etiology or pathophysiology (Hyman 2007). As a consequence, the diagnosis of MDD, although reliable, might lack validity, and encompass a heterogeneous set of disorders with distinct pathophysiologies. To overcome these limitations, a focus on narrowly defined and quantifiable phenotypes, often referred to as “endophenotypes”, has been advocated. According to Gottesman & Gould (2003), “[e]ndophenotypes provide a means for identifying the 'downstream' traits […] of clinical phenotypes, as well as the 'upstream' consequences of genes” (p. 637). In this conceptualization, intermediate phenotypes are assumed to be positioned within the causal chain between genes and disease, and thus represent a more proximal expression of biological and environmental influences than aAnnu Rev Clin Psychol. 2014 March 28; 10: 393–423. doi:10.1146/annurev-clinpsy-050212-185606. # Depression, Stress, and Anhedonia: Toward a Synthesis and Integrated Model Diego A. Pizzagalli Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478 ## 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 (1) anhedonia, (2) dopamine, and (3) 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, presenting initial evidence consistent with our model, and discuss directions for future research. ## Keywords Depression; Anhedonia; Stress; Endophenotype; Dopamine ## I NTRODUCTION Despite its “ignominious status as a world leader in burden of disease” (Greden 2001, p. 30) and decades of research, the etiology and pathophysiology of major depressive disorder (MDD) remain largely unknown. This lack of understanding partially stems from issues inherent in current classification systems, which define mental illness based on clusters of symptoms and clinical course rather than etiology or pathophysiology (Hyman 2007). As a consequence, the diagnosis of MDD, although reliable, might lack validity, and encompass a heterogeneous set of disorders with distinct pathophysiologies. To overcome these limitations, a focus on narrowly defined and quantifiable phenotypes, often referred to as “endophenotypes”, has been advocated. According to Gottesman & Gould (2003), “[e]ndophenotypes provide a means for identifying the 'downstream' traits […] of clinical phenotypes, as well as the 'upstream' consequences of genes” (p. 637). In this conceptualization, intermediate phenotypes are assumed to be positioned within the causal chain between genes and disease, and thus represent a more proximal expression of biological and environmental influences than a