title: Abnormal temporal difference reward-learning signals in major depression.
abstract: Anhedonia is a core symptom of major depressive disorder (MDD), long thought to be associated with reduced dopaminergic function. However, most antidepressants do not act directly on the dopamine system and all antidepressants have a delayed full therapeutic effect. Recently, it has been proposed that antidepressants fail to alter dopamine function in antidepressant unresponsive MDD. There is compelling evidence that dopamine neurons code a specific phasic (short duration) reward-learning signal, described by temporal difference (TD) theory. There is no current evidence for other neurons coding a TD reward-learning signal, although such evidence may be found in time. The neuronal substrates of the TD signal were not explored in this study. Phasic signals are believed to have quite different properties to tonic (long duration) signals. No studies have investigated phasic reward-learning signals in MDD. Therefore, adults with MDD receiving long-term antidepressant medication, and comparison controls both unmedicated and acutely medicated with the antidepressant citalopram, were scanned using fMRI during a reward-learning task. Three hypotheses were tested: first, patients with MDD have blunted TD reward-learning signals; second, controls given an antidepressant acutely have blunted TD reward-learning signals; third, the extent of alteration in TD signals in major depression correlates with illness severity ratings. The results supported the hypotheses. Patients with MDD had significantly reduced reward-learning signals in many non-brainstem regions: ventral striatum (VS), rostral and dorsal anterior cingulate, retrosplenial cortex (RC), midbrain and hippocampus. However, the TD signal was increased in the brainstem of patients. As predicted, acute antidepressant administration to controls was associated with a blunted TD signal, and the brainstem TD signal was not increased by acute citalopram administration. In a number of regions, the magnitude of the abnormal signals in MDD correlated with illness severity ratings. The findings highlight the importance of phasic reward-learning signals, and are consistent with the hypothesis that antidepressants fail to normalize reward-learning function in antidepressant-unresponsive MDD. Whilst there is evidence that some antidepressants acutely suppress dopamine function, the long-term action of virtually all antidepressants is enhanced dopamine agonist responsiveness. This distinction might help to elucidate the delayed action of antidepressants. Finally, analogous to recent work in schizophrenia, the finding of abnormal phasic reward-learning signals in MDD implies that an integrated understanding of symptoms and treatment mechanisms is possible, spanning physiology, phenomenology and pharmacology.
authors.affiliation: Department of Mental health, University of Aberdeen, Aberdeen AB25 2ZH, UK.
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: G
authors.initials: G
authors.lastname: Waiter
authors.forename: T
authors.initials: T
authors.lastname: Ahearn
authors.forename: M
authors.initials: M
authors.lastname: Milders
authors.forename: I
authors.initials: I
authors.lastname: Reid
authors.forename: J D
authors.initials: JD
authors.lastname: Steele
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use; D001921:Brain / Q000503:physiopathology*; D015283:Citalopram / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000523:psychology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007858:Learning; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012054:Reinforcement, Psychology; D012201:Reward; D013894:Thirst; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram