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-HT1A) has commonly been used to study pathophysiological alterations, treatment-resistant depression (TRD) subjects represent a less investigated cohort. In this cross-sectional study, 5-HT1A 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-HT1A receptor nondisplaceable binding potential (BPND) was quantified using the multilinear reference tissue model 2. Regional BPND 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 BPND 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-HT1A 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.
© 2025. The Author(s).