Neuroprogressive character of sigma-1 receptor pathophysiology in unmedicated patients with acute major depressive disorder as investigated by (-)-[₁₈F]Fluspidine PET

Aim/Introduction:

We have previously shown that the sigma-1 receptor(Sig-1R) availability is increased in unmedicated acute MDD (MDD) using (-)-[18F]Fluspidine PET. In order to assess whether this pathophysiology is progressive, we investigated the relationship between Sig-1R availability and duration of disease (DD), number of depressive episodes (DE) and severity of acute depressive symptoms (Hamilton Depression Rating Scale, HAMD) in this now completed first-in-human (-)-[18F]Fluspidine PET trial.
Materials and Methods:
Patients with moderate to severe MDD (n=18; 32±12 years; 9 females; DD 6±8 years; DE 3±1 years; HAMD: 20±4) were studied using (-)-[18F]Fluspidine PET (300 MBq, ECAT Exact HR+) and compared with sex-/age-matched healthy controls (HC; n=16; 32±13ys [n.s.]; 9 females [n.s.]). VOI analyses were performed and regional distribution volumes (VT) were estimated by kinetic modeling (0-210 min p.i.; 2TCM; metabolite correction).
Results:
In MDD, compared with HC, VT was higher especially within the fronto-temporal, anterior cingulate and insular cortices, amygdala, striatum, thalamus and ncl. raphe (P<0.005). Positive correlations were found between HAMD and VT within the anterior and posterior cingulate and insular cortices, ncl. caudatus and thalamus (r=0.43 to 0.57, P<0.05, adjusted for DD, BMI).Negative correlations were found between DD and VT within the orbitofrontal cortex and hypothalamus (r=-0.40 to -0.47, P<0.05, adjusted for severity of MDD) and between DE and VT within the hypothalamus, orbitofrontal, temporo-parietal and cingulate cortices, striatum, thalamus and cerebellum (r=-0.42 to -0.60, P<0.05, adjusted for severity of MDD).
Conclusion:
Using (-)-[18F]Fluspidine PET, we showed for the first time increased cortico-(para-)limbic Sig-1R availability during the DE of MDD, as compared with HC, that was associated with the severity of acute depressive symptoms (HAMD). Remarkably, in MDD, there is a negative correlation between DE or DD and Sig1-R availability, especially within orbitofrontal cortices and hypothalamus as well as within various (sub)cortical-(para)limbic and cerebellar brain regions. Although verification by longitudinal (-)-[18F]Fluspidine PET studies is needed, our findings suggest a neuroprogressive character of Sig-1R pathophysiology in MDD.