Using a multi-modal approach spanning different levels of analyses (e.g., clinical symptoms behavior, brain) as well as studies across species, Dr. Pizzagalli’s Laboratory for Affective and Translational Neuroscience is working towards a better understanding of the causes, pathophysiology and treatment of major depressive disorder (MDD). Often focusing on key depressive phenotypes (e.g. anhedonia, stress responsiveness), we are pursuing three overarching goals:
(1) Improve our understanding of the neurobiology of and risk factors for depression;
(2) Harness this information to develop personalized treatments for depression in order to accelerate symptom reduction and avoid lengthy trial-and-error approaches;
(3) Identify novel treatment and prevention strategies, including in youth at increased risk for this prevalent disorder.
(1) Neurobiology of Anhedonia
Anhedonia—the loss of pleasure or lack of reactivity to reward—is one of the core symptoms of depression, and is poorly addressed by currently available treatments. Surprisingly few studies have utilized laboratory-based measures to objectively characterize anhedonia. The overarching goal of this line of research is to employ a variety of techniques, including electroencephalography (EEG), event-related potentials (ERP), functional magnetic resonance imaging (fMRI), molecular genetics, as well as psychological and pharmacological manipulations to advance our understanding of the neurobiological substrates of anhedonia, and identify novel treatment targets for anhedonia.
Selected publications:
Admon, R.*, Kaiser, R.H.*, Dillon, D.G., Beltzer, M., Goer, F., Olson, D.P., Vitaliano, G., Pizzagalli, D.A. (2017). Dopaminergic enhancement of striatal response to reward in major depression. American Journal of Psychiatry, 174, 378-386. [*Co-first authors]
Kangas, B.D., Short, A.K., Luc, O.T., Stern, H.S., Baram, T.Z., Pizzagalli, D.A. (2022). A cross-species assay demonstrates that reward responsiveness is enduringly impacted by adverse, unpredictable early-life experiences. Neuropsychopharmacology, 47, 767-775.
Pizzagalli, D.A. (2014). Depression, stress, and anhedonia: Toward a synthesis and integrated model. Annual Review of Clinical Psychology, 10, 393-423.
Pizzagalli, D.A. (2022). Anhedonia: Preclinical, Translational, and Clinical Integration. Springer, https://doi.org/10.1007/978-3-031-09682-2.
Pizzagalli, D.A. (2022). Toward a better understanding of the mechanisms and pathophysiology of anhedonia: Are we ready for translation? American Journal of Psychiatry, 179, 458-469.
Pizzagalli, D.A., Smoski, M., Ang, Y-S., Whitton, A.E., Sanacora, G., Mathew, S.J., Nurnberger, J. Jr, Lisanby, S.H., Iosifescu, D.V., Murrough, J.W., Yang, H., Weiner, R.D., Calabrese, J.R., Goodman, W., Potter, W.Z., Krystal, A.D. (2020). Selective kappa opioid antagonism ameliorates anhedonic behavior: Evidence from the Fast-Fail Trial in mood and anxiety spectrum disorders (FAST-MAS). Neuropsychopharmacology, 45, 1656-1663.
(2) Functional Neuroanatomy of Depression
One of lab’s main goals is to improve our understanding of functional, structural, and neurochemical brain abnormalities in depression. This information will be critical for developing better treatments and for identifying individuals at increased risk for depression. Our research has shown that there are specific patterns of brain activation that correspond to individual differences in treatment response, depression severity, anxiety symptoms, and phenotypes of depression. This line of work relies on an integration of various neuroimaging approaches, including electroencephalography (EEG); functional and structural magnetic resonance imaging (fMRI); and positron emission tomography (PET).
Selected publications:
Ironside, M., Duda, J.M., Moser, A.D., Holsen, L.M., Zuo, C.S., Du, F., Perlo, S., Richards, C.E., Chen, X., Nickerson, L.D., Null, K.E., Esfand, S.M., Alexander, M.M., Crowley, D.J., Lauze, M., Misra, M., Goldstein, J.M., Pizzagalli, D.A. (2024). Lower rostral anterior cingulate GABA+ and dysregulated cortisol stress response are associated with altered functional connectivity in young adults with lifetime depression: A multimodal imaging investigation of trait and state effects. American Journal of Psychiatry, 181, 639-650.
Kaiser, R.H., Andrews-Hanna, J.R., Wager, T.D., Pizzagalli, D.A. (2015). Large-scale network dysfunction in Major Depressive Disorder: Meta-analysis of resting-state functional connectivity. JAMA Psychiatry, 72, 603-611.
Krystal, A.D., Pizzagalli, D.A., Smoski, M., Mathew, S.J., Nurnberger, J. Jr, Lisanby, S.H., Iosifescu, D., Murrough, J.W., Yang, H., Weiner, R.D., Calabrese, J.R., Sanacora, G., Hermes, G., Keefe, R.S.E., Song, A., Goodman, W., Szabo, S.T., Whitton, A.E., Gao, K., Potter, W.Z. (2020). A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia. Nature Medicine, 26, 760-768.
Pizzagalli, D.A., Roberts, A.C. (2022). Prefrontal cortex and depression. Neuropsychopharmacology Review, 47, 225-246.
Whitton, A.E., Kumar, P., Treadway, M.T., Rutherford, A.V., Ironside, M.L., Foti, D., Fitzmaurice, G., Du, F., Pizzagalli, D.A. (2023). Distinct profiles of anhedonia and reward processing and their prospective associations with quality of life among individuals with mood disorders. Molecular Psychiatry, 28, 5272-5281.
Zhukovsky, P., Ironside, M., Duda, J.M., Moser, A.D., Null1, K.E., Dhaynaut, M., Normandin, M., Guehl, N.J., El Fakhri, G., Alexander, M., Holsen, L.M., Misra, M., Narendran, R., Hoye, J., Morris, E., Esfand, S.M., Goldstein, J.M., Pizzagalli, D.A. (2024). Acute stress increases striatal connectivity with cortical regions enriched for μ- and κ-opioid receptors. Biological Psychiatry, 96, 717-726.
(3) Toward Personalized Treatments for Depression: Neurobiological Predictors of Treatment Response in Depression
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. Our 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. In more recent studies, we have identified clinical, behavioral and neural markers that specifically predicted response to SSRIs, atypical antidepressants or psychotherapy. We are now using these markers to prospectively assign treatments.
Selected publications:
Ang YS, Kaiser R, Deckersbach T, Almeida J, Phillips ML, Chase HW, Webb CA, Parsey R, Fava M, McGrath P, Weissman M, Adams P, Deldin P, Oquendo MA, McInnis MG, Carmody T, Bruder G, Cooper CM, Chin Fatt CR, Trivedi MH, Pizzagalli DA (2020). Pretreatment reward sensitivity and frontostriatal resting-state functional connectivity are associated with response to bupropion after sertraline nonresponse. Biological Psychiatry, 88, 657-667.
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. (2018). Pretreatment rostral anterior cingulate cortex theta activity in relation to symptom improvement in depression: A randomized clinical trial. JAMA Psychiatry, 75, 547-554. [*Co-first authors]
Webb, C.A., Murray, L., Tierney, A.O., Forbes, E.E., Pizzagalli, D.A. (2023). Reward-related predictors of symptom change in behavioral activation therapy for anhedonic adolescents: A multimodal approach. Neuropsychopharmacology, 48, 623-632.
Webb, C.A., Trivedi, M.H., Cohen, Z.D., Dillon, D.G., Fournier, J.C., Goer, F., Fava, M., McGrath, P.J., Weissman, M., Parsey, R., Adams, P., Trombello, J.M., Cooper, C., Deldin, P., Oquendo, M.A., McInnis, M.G., Huys, Q., Bruder, G., Kurian, B.T., Jha, M., DeRubeis, R.J., Pizzagalli, D.A. (2019). Personalized prediction of antidepressant v. placebo response: evidence from the EMBARC study. Psychological Medicine, 49, 1118-1127.
Zhukovsky, P., Trivedi, M.H., Weissman, M., Parsey, R., Kennedy, S., Pizzagalli, D.A. (in press). Generalizability of treatment outcome prediction across antidepressant treatment trials in depression. JAMA Network Open.