Anhedonia is one of the most important predictors to developing treatment-resistant depression. The ‘interest-activity’ symptom dimension that includes loss of interest, diminished activity, and inability to make decisions has been shown to predict poor outcome of antidepressant treatment in large prospective clinical studies (Uher et al, 2012). Anhedonia symptoms can be induced experimentally in animals and humans by inflammatory cytokines, including interferon-alpha. Cytokines can affect dopamine function in the basal ganglia. Associations between altered dopamine function and impaired cortical-striatal reward circuitry are found in patients with major depression who display increased peripheral inflammatory markers and cytokines that include IL-6, TNF-alpha, and CRP (Felger and Miller, 2012). Anhedonia is not unique to depression. As a trans-diagnostic psychopathological domain that appears in various psychiatric and medical conditions, anhedonia may receive pathogenic contributions from common cellular immunity mechanisms that affect reward systems (Swardfager et al, 2016). SSRIs and other first-line antidepressants fail to alleviate IFN—-induced anxiety and depressive symptoms. Traditional stimulants that increase dopamine release and methylphenidate that blocks its reuptake have minimal effects on fatigue and anhedonia in depressed patients with inflammation-associated medical conditions such as advanced cancer. These findings suggest potential roles for cellular inflammation in mediating the development of treatment resistance to traditional antidepressants and stimulants, specifically when fatigue and anhedonia persist. In Parkinson’s disease, where depression is common and anhedonia is a prominent feature, L-Dopa and other non-receptor specific dopamine agonists display little efficacy in preventing or treating depression. However, pramipexole, a relatively selective D3 dopamine agonist has shown to relieve depression in Parkinson’s disease. Also, in chronic and severe treatment-resistant depressed patients, including bipolar disorder, pramipexole at high doses has shown promising response (Fawcett et al, 2016). The selective expression of D3 receptors in the mesolimbic projection areas including the nucleus accumbens makes this dopamine receptor a promising target to overcome treatment-resistant depression where anhedonia symptoms may be perpetuated by inflammatory cytokines, such as in severe medical conditions with known increased levels of inflammation. The effects of pramipexole on brain immunological mechanisms are not fully understood. However, recent data suggest potentially important roles. Pramipexole attenuates the development of experimental autoimmune encephalomyelitis in mice, an animal model for multiple sclerosis (Lieberknecht et al, 2016). D3 receptors can be found in CD4-positive T cells, which are involved in the modulation of peripheral immune responses and promote neuro-inflammation in a murine model of Parkinson’s disease (Contreras et al, 2016). Future studies in treatment-resistant depression that use D3-preferring and other dopamine agonists should monitor inflammatory markers as well as specific measures of anhedonia to better understand the role of inflammation in anhedonia and treatment resistance.


This article used no funding. Dr Escalona has no disclosures to make. Dr Fawcett has received speaking fees from the American Psychiatric Association and the Nevada Psychiatric Association and serves on a data review board for Amgen, and he has received remuneration as co-principal investigator of an NIMH-funded study.