Decoding the Faces of Depression: Anhedonia and Dopamine

Diego Pizzagalli presented the March 2011 Warren Frontiers in Neuroscience Series lecture in Tulsa, Oklahoma on March 1, 2011.  Dr. Pizzagalli works at the Harvard Medical School affiliated Center for Depression, Anxiety and Stress Research & Neuroimaging Center at McLean Hospital in Boston.  He has been involved in research related to brain abnormalities in major depression as well as predictors of treatment response.  I will highlight some of the key points from his lecture and incorporate three recent research manuscripts related to this topic:

• There are over 100 symptom combinations to diagnosis major depression (5 of 9 symptoms required)
• Distinct depressive phenotypes (clinical presentations) are difficult to define--but the phenotype defined by anhedonia (pervasive lack of ability to experience pleasure) has significant research support
• Depression with anhedonia also has a biological component--the brain reward pathways involving dopamine and the striatum.
• Anhedonia has been linked to impaired dopamine function in these brain reward pathways
• Anhedonia appears more heritable than depression and may be related to abnormalities in genes controlling dopamine neurotransmission
• The dopamine reward pathway (substantia nigra-striatum-cingulate/prefrontal cortex) is vulnerable to stress (acute stress increases dopamine, chronic stress reduces it in the rat model)
• He and colleagues developed a heuristic model of the functional neuroanatomy of anhedonia: both environmental and biological factors influence risk of depression: depression includes a decrease in the brains reward response, exaggerated stress responsivity and eventually a blunted mesolimbic dopamine system (and anhedonia)
• Laboratory models and psychometric measures of anhedonia have been developed--studies suggest the ventral striatum (nucleus accumbens) is involved in hedonic coding while the dorsal striatum (caudate) is involved in positive re-inforcement
• Decreased activation of cingulate and caudate with monetary incentive delay task is seen in untreated depression
• Untreated depression (and anhedonia) also linked to decreased size of the caudate
• Early life stress (abuse) may increase depression risk through dysregulation of mesolimbic pathways including left putamen and left pallidum
• Stress even in healthy individuals impairs brains reward processing pathway
• Some genes related to anhedonia may work through stress pathways, i.e. mineralcorticoids, corticotrophin hormone (CRH)
• Future research will focus on further parsing of the heterogeneity associated with depression, developing animal models of reward tasks, using PET to better understand the role of dopamine in depression, using dopaminergic drugs (i.e. pramipexole) in stimulation models of depression and further study of the neurobiology of stress-induced anhedonia

I agree that evaluating the role of dopaminergic drugs in depression accompanied by anhedonia is worthy of basic and clinical research study.  Among typical antidepressants, only bupropion appears to have dopaminergic effects.  Other compounds such as psychostimulants also increase dopamine but carry the risk for abuse.  Several of the dopaminergic drugs used for Parkinson disease are beginning to see more use off-label for the treatment of depression.  I will look at this issue in a future Brain Post. 

Photo of Blake Griffin shooting free throw against Oklahoma City Thunder in 2011 NBA game courtesy of Tim Yates.

Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty DD, Iosifescu DV, Rauch SL, & Fava M (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. The American journal of psychiatry, 166 (6), 702-10 PMID: 19411368

Wacker J, Dillon DG, & Pizzagalli DA (2009). The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques. NeuroImage, 46 (1), 327-37 PMID: 19457367

Pizzagalli DA (2011). Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 36 (1), 183-206 PMID: 20861828