Anhedonia in depression: the effects of conventional antidepressants and ketamine on reward processing

Thesis

Reward processing involves anticipating rewards and losses, learning from them, experiencing pleasure, and guiding behaviour. These processes are disrupted in depression, particularly in relation to anhedonia, a core feature of depression. However, it remains unclear which components are most affected and how they are modulated by antidepressant treatments. Conventional antidepressants have limited effects on anhedonia. Ketamine produces rapid antidepressant effects and may have anti-anhedonic properties, although its underlying mechanisms remain unclear.

This DPhil thesis investigated reward and loss processing in depression using a probabilistic instrumental learning task with monetary wins and losses and an effort-based decision-making task assessing willingness to exert effort for different reward amounts.

Study 1 used an online observational sample (N=1,917) to examine associations between depressive symptoms, antidepressant use, and reinforcement learning. Greater depressive symptom severity was associated with reduced learning from loss, reflected in lower loss learning rates, with no effects in the reward condition. In individuals with Major Depressive Disorder taking conventional antidepressants (N=124), antidepressant use was associated with higher loss learning rates, reduced choice stability, and poorer optimal choice accuracy on loss trials, with no effects in the reward condition.

Study 2 investigated the effects of ketamine in treatment-resistant depression (N=60) using a placebo-controlled, double-blind design with fMRI, questionnaires, and behavioural tasks. At 24 hours post-infusion, ketamine altered neural responses to win and loss outcomes (monetary feedback) across cortico-striato-limbic circuitry and increased insula responses to loss-related prediction errors, without behavioural changes. Thirty minutes post-infusion, the ketamine group showed a greater decrease in reaction time as reward increased, and changes in reward valuation in offer acceptance were observed at seven days. Depressive symptoms improved over one week, whereas anhedonia and other reward measures did not significantly change. Overall, this thesis applied a reward processing framework to understand mechanisms underlying depression and its treatment.

Authors: Wigg, C

• DOI: 10.5287/ora-do19v6jpe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: anhedonia; reward processing; treatment-resistant depression; ketamine; depression; antidepressants; effort-based decision-making
• Subjects: Experimental Medicine Study