The antidepressant placebo response remains a barrier to the development of novel therapies for depression, despite decades of efforts to identify and methodologically address its clinical correlates. This manuscript reviews recent neuroimaging studies that aim to identify the neural signature of antidepressant placebo response. Data captured in clinical trials have primarily focused on antidepressant efficacy or predicting antidepressant response and have reliably implicated the rostral anterior cingulate cortex (rACC) in antidepressant placebo response, but also in medication response. Imaging and electroencephalography (EEG) experiments specifically interrogating the mechanism of antidepressant placebo response, while few, suggest the reward network, including opiate neurotransmission, is also involved. Therefore, while the rACC is likely involved in the antidepressant placebo response, its observation in isolation is unlikely to prospectively distinguish antidepressant placebo from medication responders. Instead, future studies of antidepressant placebo response should probe the reward network as a whole and incorporate sophisticated computational analytical approaches.
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