Diego A. Pizzagalli, PhD

 

Research Interests

Depression is a major public health problem, but our understanding of this debilitating disorder remains incomplete. This reflects the fact that depression is clinically, etiologically, and pathophysiologically heterogeneous. The aim of Dr. Pizzagalli’s research is to advance our understanding of the psychological, environmental, and neurobiological factors implicated in depression and related disorders (e.g., anxiety). The ultimate goal of this work is to identify novel targets for prevention and treatment.

Dr. Pizzagalli takes a multidisciplinary approach to investigating the causes, consequences, and pathophysiology of depression. For example, studies in his laboratory use:

• Functional and structural magnetic resonance imaging (MRI), high-density electroencephalography (EEG), and positron emission tomography (PET) to identify neural and neurochemical substrates of core depressive symptoms and vulnerabilities, including anhedonia (loss of pleasure), emotion dysregulation, increased stress sensitivity, and executive dysfunction;

• Molecular genetics to investigate the role of particular genes in the emergence of depressive phenotypes (e.g., anhedonia, stress sensitivity) and vulnerability to depression;

• Comprehensive, contextual stress interviews to investigate the role of stress and early adversity in the etiology and maintenance of depression;

• Pharmacological challenges to probe the role of particular neurotransmitters in depression;

• Neurobiologically realistic computational models to investigate the influence of specific neuromodulators on normal and abnormal behavior (in collaboration with Peter Dayan and Quentin Huys, University College London and Michael Frank, Brown University);

• Animal models to more directly test hypotheses about the role of stressors on the emergence of anhedonic behavior (in collaboration with Athina Markou, UCSD).

Anhedonia, the loss of interest in previously pleasurable activities, is a major focus of Dr. Pizzagalli’s work. Several studies from his laboratory have made important conceptual and methodological contributions to the study of anhedonia. For example, in a series of behavioral and neuroimaging studies, depression was characterized by (1) reduced ability to modulate behavior as a function of reward and (2) dysfunction in striatal regions implicated in hedonic coding and reinforcement learning. Similar abnormalities emerged in currently asymptomatic individuals with a history of depression, psychiatrically healthy individuals carrying genetic variants previously linked to depression (particularly when exposed to laboratory or naturalistic stressors), and young adults exposed to childhood adversities two decades earlier. Altogether, these and other findings emerging from Dr. Pizzagalli’s laboratory indicate that anhedonia is an important endophenotype of depression. Furthermore, they suggest that hedonic deficits, including dysfunction in reward-related striatal dopaminergic pathways, constitute a promising candidate mechanism linking stress to depression.

To facilitate tests of his hypotheses and increase translational impact, Dr. Pizzagalli has developed behavioral tests that can objectively assess core symptoms of depression. In particular, Dr. Pizzagalli developed a brief computer task that can be used to measure a key form of hedonic behavior—namely, participants’ ability to modify their choices as a function of differential rewards. More than 65 research groups worldwide are currently using this task to probe reward processing dysfunction across Axis I and II disorders.

In a second line of work, Dr. Pizzagalli is investigating executive dysfunction in depression, especially abnormal reactions to errors and negative feedback. It is clear from several studies that depressed individuals show a catastrophic response to errors, evident in a rapid downward spiral in performance following error commission. Studies from Dr. Pizzagalli’s laboratory were among the first to show that these behavioral impairments are linked to an exaggerated, automatic neural response to errors, along with weak recruitment of brain regions that implement cognitive control. Ongoing studies in the laboratory are testing the hypothesis that these dysfunctions foster the emergence and maintenance of negative processing biases, and thus increase vulnerability to subsequent episodes of depression.

Finally, Dr. Pizzagalli’s laboratory was the first to show that pre-treatment resting EEG activity in the rostral anterior cingulate cortex predicted therapeutic improvement 4-6 months later in depressed individuals. To follow up on this key finding, his laboratory is currently exploring novel behavioral and EEG markers that could be used to examine treatment response prospectively, ultimately leading to improvements in treatment selection. Given that a substantial percentage of depressed individuals do not respond to standard antidepressant treatments, establishing predictors of treatment response could greatly facilitate treatment selection, thus reducing the personal suffering and socio-economic burden associated with the current trial-and-error approach to treatment.

Education and Awards

Dr. Pizzagalli received his M.A. (1995) and Ph.D. (1998) from the University of Zurich, Switzerland and did post-doctoral work at University of Wisconsin, Madison. From 2002-2010 he was a faculty member in the Department of Psychology at Harvard University, where he served as the John and Ruth Hazel Associate Professor of the Social Sciences. In 2010, he was recruited to McLean Hospital to serve as the Founding Director of the newly established Center for Depression, Anxiety and Stress Research (CDASR), as well as the Director of the McLean Imaging Center (MIC). Since September 2015, he also serves as the Director of Research for the Division of Depression and Anxiety. He is currently a Professor of Psychiatry at Harvard Medical School, and the Center Director for a Silvio O. Conte Center for Basic Translational Mental Health Research focused on the neurobiology of and novel treatment targets for depression and anxiety disorders.

The main goals of his research are to improve our understanding of the psychological, environmental, and neurobiological factors associated with mood disorders, particularly major depression. To this end, he integrates behavioral, electrophysiological, neuroimaging, and, more recently, pharmacological approaches to investigate three putative endophenotypes of depression: anhedonia (loss of pleasure), increased stress sensitivity, and executive function deficits.

Dr. Pizzagalli has published over 350 papers and chapters and serves on the editorial board of 13 journals. He is the Editor-In-Chief for the journal Cognitive, Affective and Behavioral Neuroscience, as well as the Principal Editor for Psychopharmacology (Human Psychopharmacology: Experimental).

Among several awards, he received the Distinguished Scientific Award for an Early Career Contribution to Psychophysiology from the Society for Psychophysiological Research (2006), the Early Career Award from the EEG and Clinical Neuroscience Society (2007), the Anne M. Cataldo Excellence in Mentoring Award from McLean Hospital (2015), two MERIT awards from the National Institute of Mental Health (2016, 2022), The Stuart T. Hauser, M.D. PhD. Mentorship Award in Psychiatry from Harvard Medical School (2017), the Joel Elkes Research Award from the American College of Neuropsychopharmacology (2017), a NARSAD Distinguished Investigator Award (2018), and the Anna-Monika-Prize for Research in the Neurobiology and Treatment of Depressive Disorders (2019). Since 2019, he has been a Highly Cited Researcher according to Web of Science.

Selected Publications

Neurobiology of anhedonia

Pizzagalli, D.A. (2014). Depression, stress, and anhedonia: Toward a synthesis and integrated model. Annual Review of Clinical Psychology, 10, 393-423.

Admon, R., Pizzagalli, D.A. (2015). Corticostriatal pathways contribute to the natural time course of positive mood. Nature Communications. 2015 Dec 7;6:10065. doi: 10.1038/ncomms10065.

Pizzagalli, D.A., Berretta, S., Wooten, D., Goer, F., Pilobello, K.T., et al. (2019). Assessment of striatal dopamine transporter binding in individuals with major depressive disorder: In vivo PET and postmortem evidence. JAMA Psychiatry, 76, 854-861.

Krystal, A.D., Pizzagalli, D.A., Smoski, M., Mathew, S.J., Nurnberger, J., Jr., et al. (2020). Application of the “Fast-Fail” approach to evaluating the potential of selective Kappa Opioid Antagonism as a treatment for anhedonia: A Randomized proof of mechanism trial assessing effects on the ventral striatum. Nature Medicine 26:760-768.

Ang, Y-S, Kaiser, R., Deckersbach, T., Almeida, J., Phillips, M.L., et al., Pizzagalli, D.A. (2020). Pretreatment reward sensitivity and frontostriatal resting-state functional connectivity are associated with response to bupropion after sertraline non-response. Biological Psychiatry. 2020 Apr 23;S0006-3223(20)31516-X. doi: 10.1016/j.biopsych.2020.04.009. Online ahead of print.

Kangas, B.D., Wooldridge, L.M., Luc, O.T., Bergman, J., Pizzagalli, D.A. (2020). Empirical validation of a touchscreen probabilistic reward task in rats. Translational Psychiatry, 10, 285. doi.org/10.1038/s41398-020-00969-1

Functional neuroanatomy of depression

Pizzagalli, D.A., Holmes, A.J., Dillon, D.G., Goetz, E.L., Birk, J.L., et al. (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated subjects with Major Depressive Disorder. American Journal of Psychiatry, 166, 702-710.

Kaiser, R.H., Andrews-Hanna, J.R., Wager, T.D., Pizzagalli, D.A. (2015). Large-scale network dysfunction in Major Depressive Disorder: A meta-analysis of resting-state functional connectivity. JAMA Psychiatry, 72, 603-611.

Treadway, M.T., Waskom, M.L., Dillon, D.G., Holmes, A.J., Park, M.T., et al., Pizzagalli DA (2015). Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Biological Psychiatry, 77, 285-294.

Admon, R., Kaiser, R.H., Dillon, D.G., Beltzer, M., Goer. F., et al., Pizzagalli, D.A. (2017). Dopaminergic enhancement of striatal response to reward in major depression. American Journal of  Psychiatry, 174, 378-386.

Ang, Y-S., Frontero, N., Belleau, E., Pizzagalli, D.A. (in press). Disentangling vulnerability, state and trait features of neurocognitive impairments in depression: Bayesian cross-sectional analysis of 9–10 year-old children in the Adolescent Brain Cognitive Development Study. Brain.

Neurobiological Predictors of Treatment Response in Depression

Pizzagalli, D.A. (2011). Frontocingulate dysfunction in depression: Towards biomarkers of treatment response. Neuropsychopharmacology Review, 36, 183-206.

Pizzagalli, D.A.*, Webb, C.A.*, Dillon, D.G., Tenke, C.E., Kayser, J., Goer, F., Fava, M., McGrath, P., Weissman, M., Parsey, R., Adams, P., Trombello, J., Cooper, C., Deldin, P., Oquendo, M.A., McInnis, M.G., Carmody, T., Bruder, G., Trivedi, M.H. Pretreatment Rostral Anterior Cingulate Cortex Theta Activity in Relation to Symptom Improvement in Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Jun 1;75(6):547-554. [*Co-first authors]

Webb, C.A., Trivedi, M.D., Cohen, C., Dillon, D.G., Fournier, F., et al., Pizzagalli, D.A. (2019). Personalized prediction of antidepressant versus placebo response: Evidence from the EMBARC trial. Psychological Medicine, 49, 1118-1127.

Whitton, A.E., Webb, C.A., Dillon, D.G., Kayser, J., Rutherford, A., et al., Pizzagalli. D.A. (2019). Pretreatment rostral anterior cingulate cortex connectivity with salience network predicts depression recovery: Findings from the EMBARC randomized clinical trial.  Biological Psychiatry, 85, 872-880.