It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder
Authors: R A Koeppe
J-K Zubieta
B J Sanford
D T Hsu
T M Love
B J Mickey
S A Langenecker
K E Hazlett
S J Walker
K K Meyers
Journal: Molecular Psychiatry (2015)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Œº-opioid receptor; social pain; positron emission tomography; endogenous opioid release; major depressive disorder
Affiliations: 1] Department of Psychiatry, Stony Brook University, Stony Brook, NY, USA [2] Department of Psychiatry, The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA., Department of Psychiatry, The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA., Department of Psychology, Wayne State University, Detroit, MI, USA., Department of Psychology, Marquette University, Milwaukee, WI, USA., Department of Psychiatry, Oregon Health & Science University, Portland, OR, USA., Department of Radiology, University of Michigan, Ann Arbor, MI, USA., Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA., 1] Department of Psychiatry, The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA [2] Department of Radiology, University of Michigan, Ann Arbor, MI, USA.

Abstract:  The Œº-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes. 

Retracted: No

PubPeer comments:
 Dear authors, It would be appreciated if you would help us understand some of the analysis methods used in this paper. How many subjects were included in your analyses? The methods section describes 18 HCs and 17 patients with MDD, and and I see no mention of subjects excluded from analyses. This would yield 17 degrees of freedom (HCs), 17 degrees of freedom (MDD), and 33 degrees of freedom (both groups) for the t-tests reported in the results section, but the reported degrees of freedom are 16 and 15, and for both groups there are dfs of 31 and 32, depending on which analysis we check. This is consequential to the reported significance of your results. For example, if only 17 participants were included in the HC analyses (thus giving 16 degrees of freedom for the t-tests), then a Pearson s r correlation of .48 would not be significant like reported. The figures do not help clarify this issue. For example, in Figure 3 d there are 16 HC data points and 17 MDD data points. In figure 4 a, b, and c, there are only 14 HCs and 14 MDDs. I am further confused when evaluating the imaging results. How is the PAG significant with a t-value of 2.3, unless no familywise error corrections were made? Surely the authors corrected their statistics for the statistical tests run on 8 VOIs, further divided hemispherically (yielding 16 VOIs). Table 1 suggests that four different comparisons were made on these 16 individual VOIs, yielding 64 tests (for each of 2 groups). The authors state  VOIs were applied to subtraction images in standardized space and alpha levels were family-wise error (FWE) corrected , which leaves me wondering how a t-value of 2.3 could ever have been significant. Can you please clarify this point? Also, were any direct comparisons made between groups? It seems there are conclusions made in this paper of differences between groups that were not actually tested. I would love to see those results if they are available. Many of these comments were made on your other article, DOI 10.1038 mp.2013.96, but that is because in many places the exact same results on the exact same sample are being reported in both papers. With gratitude, ,