Frontocingulate dysfunction in depression: Toward biomarkers of treatment response Diego A Pizzagalli,¹ ¹ Center for Depression, Anxiety, and Stress Research & Neuroimaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions. Neuropsychopharmacology Reviews (2011) 36, 183–206; doi:10.1038/npp.2010.166; published online 22 September 2010 Keywords: biomarkers; depression; rostral anterior cingulate cortex; rumination; emotional biases; emotion regulation ## INTRODUCTION Major depressive disorder (MDD) is common, recurrent, and disabling. According to the World Health Organization, MDD is the third leading cause of global disease burden and a leading cause of disability worldwide (World Health Organization, 2008). In the United States, 16.6% of individuals will meet criteria for MDD at least once in their life (Kessler et al, 2005). In addition to profound personal suffering, MDD is associated with significant impairments in social and occupational functioning (Lopez et al, 2006) and places a staggering economic burden on society. For example, in the United States alone, workplace-related costs linked to depression have been estimated to exceed 50 billion dollars each year (Greenberg et al, 2003). Despite the availability of a variety of treatments, up to 40–50% of patients fail to respond to antidepressant medication (eg, Trivedi et al, 2006) or psychological treatment (eg, cognitive behavioral therapy; DeRubeis et al, 2005). The likelihood of remission (ie,Frontocingulate dysfunction in depression: Toward biomarkers of treatment response Diego A Pizzagalli,¹ ¹ Center for Depression, Anxiety, and Stress Research & Neuroimaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, USA Increased rostral anterior cingulate cortex (rACC) activity has emerged as a promising predictor of treatment response in depression, but neither the reliability of this relationship nor the mechanisms supporting it have been thoroughly investigated. This review takes a three-pronged approach to these issues. First, I present a meta-analysis demonstrating that the relationship between resting rACC activity and treatment response is robust. Second, I propose that the rACC plays a key role in treatment outcome because of its 'hub' position in the default network. Specifically, I hypothesize that elevated resting rACC activity confers better treatment outcomes by fostering adaptive self-referential processing and by helping to recalibrate relationships between the default network and a 'task-positive network' that comprises dorsolateral prefrontal and dorsal cingulate regions implicated in cognitive control. Third, I support this hypothesis by reviewing neuropsychological, electrophysiological, and neuroimaging data on frontocingulate dysfunction in depression. The review ends with a discussion of the limitations of current work and future directions. Neuropsychopharmacology Reviews (2011) 36, 183–206; doi:10.1038/npp.2010.166; published online 22 September 2010 Keywords: biomarkers; depression; rostral anterior cingulate cortex; rumination; emotional biases; emotion regulation ## INTRODUCTION Major depressive disorder (MDD) is common, recurrent, and disabling. According to the World Health Organization, MDD is the third leading cause of global disease burden and a leading cause of disability worldwide (World Health Organization, 2008). In the United States, 16.6% of individuals will meet criteria for MDD at least once in their life (Kessler et al, 2005). In addition to profound personal suffering, MDD is associated with significant impairments in social and occupational functioning (Lopez et al, 2006) and places a staggering economic burden on society. For example, in the United States alone, workplace-related costs linked to depression have been estimated to exceed 50 billion dollars each year (Greenberg et al, 2003). Despite the availability of a variety of treatments, up to 40–50% of patients fail to respond to antidepressant medication (eg, Trivedi et al, 2006) or psychological treatment (eg, cognitive behavioral therapy; DeRubeis et al, 2005). The likelihood of remission (ie,