In vivo serotonin 1A receptor distribution in treatment-resistant depression

Major depressive disorder (MDD) ranks among the leading causes of disability worldwide. An additional burden arises from treatment-resistance, defined by a lack of response to two or more adequate pharmacotherapeutic treatment trials. Unlike in MDD, where the serotonin 1A receptor subtype (5-HT_1A) has commonly been used to study pathophysiological alterations, treatment-resistant depression (TRD) subjects represent a less investigated cohort. In this cross-sectional study, 5-HT_1A receptor binding was assessed in 33 subjects with TRD with stable medication and 44 healthy control (HC) subjects. Positron emission tomography scans with the radioligand [carbonyl-¹¹C]WAY-100635 were acquired and 5-HT_1A receptor nondisplaceable binding potential (BP_ND) was quantified using the multilinear reference tissue model 2. Regional BP_ND in amygdala, anterior cingulate cortex, hippocampus, insula, orbitofrontal cortex, dorsal raphe nucleus and median raphe nucleus was assessed using a multivariate analysis of covariance (MANCOVA). The MANCOVA showed a significant effect of group (F = 3.349, p < 0.05) and sex (F = 2.428, p < 0.05). The subsequent pairwise comparison revealed a lower BP_ND by 17.45% in the TRD group in the dorsal raphe nucleus (mean difference ± SE = -0.59 ± 0.24, p < 0.05) and by 18.39% in the median raphe nucleus (mean difference ± SE = -0.71 ± 0.30, p < 0.05). Our results extend previously reported alterations of 5-HT_1A receptor distribution in non-resistant depression to TRD. Ultimately, this knowledge may contribute to clarifying the role of serotonin and help to address the urgent issue of treatment resistance in depression.