Learning and negative outcome expectations can increase pain sensitivity, a phenomenon known as nocebo hyperalgesia. Here, we examined how a targeted pharmacological manipulation of learning would impact nocebo responses and their brain correlates. Participants received either a placebo (n = 27) or a single 80 mg dose of d-cycloserine (a partial NMDA receptor agonist; n = 23) and underwent fMRI. Behavioral conditioning and negative suggestions were used to induce nocebo responses. Participants underwent pre-conditioning outside the scanner. During scanning, we first delivered baseline pain stimulations, followed by nocebo acquisition and extinction phases. During acquisition, high intensity thermal pain was paired with supposed activation of sham electrical stimuli (nocebo trials), whereas moderate pain was administered with inactive electrical stimulation (control trials). Nocebo hyperalgesia was induced in both groups (p < 0.001). Nocebo magnitudes and brain activations did not show significant differences between d-cycloserine and placebo. In acquisition and extinction, there were significantly increased activations bilaterally in the amygdala, ACC, and insula, during nocebo compared to control trials. Nocebo acquisition trials also showed increased vlPFC activation. Increased opercular activation differentiated nocebo-augmented pain aggravation from baseline pain. These results support the involvement of integrative cognitive-emotional processes in nocebo hyperalgesia.

Objective: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. Methods: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. Results: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98–1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84–1.38, P = 0.55). Conclusion: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA ‘deficits’ through supplementation does not seem a promising option to prevent MDD recurrence.