Functional connectivity of the raphe nucleus as a predictor of the response to selective serotonin reuptake inhibitors in obsessive-compulsive disorder

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological agents for treating obsessive-compulsive disorder (OCD). However, because nearly half of patients show insufficient SSRI responses, serotonergic dysfunction in heterogeneous OCD patients should be investigated for precision medicine. We aimed to determine whether functional connectivity (FC) of the raphe nucleus (RN), the major source of most serotonergic neurons, was altered in OCD patients and could predict the SSRI response. A total of 102 medication-free OCD patients and 101 matched healthy control (HC) subjects participated in resting-state functional magnetic resonance imaging. Among them, 54 OCD patients were treated with SSRIs for 16 weeks, resulting in 26 responders and 28 nonresponders. Seed-based whole brain FC with the RN as a seed region was compared between the OCD and HC groups, as well as between SSRI responders and nonresponders. FC cluster values showing significant group differences were used to investigate factors correlated with symptomatic severity before treatment and predictive of SSRI response. Compared to HCs, OCD patients exhibited significantly larger FC between the RN and temporal cortices including the middle temporal gyrus (MTG), paracingulate gyrus, amygdala, hippocampus, putamen, thalamus, and brain stem. Greater RN-left MTG FC was positively correlated with OC symptom severity at baseline. In addition, larger FC of the RN-left MTG was also found in SSRI nonresponders compared to responders, which was a significant predictor of SSRI response after 16 weeks. The FC of RN may reflect the neurobiological underpinning of OCD and could aid future precision medicine as a differential brain-based biomarker.

Fig. 1

Statistical maps of the regions where functional connectivity (FC) with the raphe nucleus (RN) was significantly altered in patients with obsessive-compulsive disorder (OCD) compared to healthy controls. The regions where FC with the RN was greater in OCD are marked in red-yellow and include the a left amygdala/hippocampus/putamen, right putamen/caudate, thalamus, brain stem, and b left and right inferior temporal gyri (ITG)/middle temporal gyri (MTGs). The region where FC with the RN was smaller in OCD is marked in blue-green and contains the c left occipital pole. All the results are displayed at a false discovery rate (FDR)-corrected threshold of p < 0.05. The left hemisphere is depicted on the left in the axial and coronal slices

Fig. 2

a Statistical maps of the regions where functional connectivity (FC) with the raphe nucleus (RN) was significantly larger in patients with obsessive-compulsive disorder (OCD) who did not respond to 16 weeks of selective serotonin reuptake inhibitor (SSRI) treatment (nonresponders) than in patients who showed a sufficient response (responders). The region where FC with the RN was larger in SSRI nonresponders is marked in red-yellow and comprises the left middle temporal gyrus (MTG)/superior temporal gyrus (STG). The results are displayed at a false discovery rate (FDR)-corrected threshold of p < 0.05. The left hemisphere is depicted on the left in the axial and coronal slices. b FC between the RN and the left MTG/STG across SSRI responders and nonresponders. The horizontal lines in the group indicate the means, and the vertical lines in the group indicate the 10th to 90th percentiles. c Correlation between the percent improvement in scores on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after 16 weeks of SSRI treatment and FC between the RN and the left MTG/STG at baseline