Relationship between sigma-1 receptor availability and depressive or cognitive symptoms in acute early onset unipolar depression: a (S)-(-)-[¹⁸F]Fluspidine PET investigation

Objectives: The sigma-1 receptor (S1R) acts as a neuromodulator and may play an important role for cognitive and behavioral processes in neuropsychiatric disorders. Cognitive dysfunction is common in unipolar major depressive disorder (MDD). Using S1R-specific (S)-(-)-[¹⁸F]Fluspidine PET, the purpose of this study was to investigate the S1R availability and its relationship to depressive and cognitive symptoms in untreated patients with acute early onset MDD (EO-MDD).

Methods: Acute, moderate to severe EO-MDD patients without antidepressive therapy (n = 13; age: 26 ± 6 years; 6 females; age at disease onset: 22 ± 5 years; Hamilton depression rating scale [HAMD-17] 19 ± 4) were investigated and compared with age- and sex-matched healthy controls (HC; n = 12; age: 25 ± 3 years; 6 females [n.s.]) using (S)-(-)-[¹⁸F]Fluspidine PET (300 MBq; 0-90 min p.i.; ECAT Exact HR+). Total distribution volumes (V_T) were determined using kinetic modeling (2TCM, metabolite correction). Regional VOI-analyses were carried out. Cognitive state (memory, attention, executive function and working memory) was evaluated using the Wechsler memory scale (WMS) and the cognitive screening test PANDA.

Results: In EO-MDD, compared with HC, WMS and PANDA scores were significantly lower indicating cognitive dysfunction (P < 0.05) and (S)-(-)-[¹⁸F]Fluspidine V_T values were significantly higher especially within the nucleus caudatus, nucleus accumbens, orbitofronto-temporal, anterior cingulate and insular cortices, nucleus raphe and pons (P < 0.01). In EO-MDD, HAMD-17 correlated positively with V_T, especially within the anterior and posterior cingulate and occipital cortices and midbrain (R ≥ 0.79; P < 0.01; nuisance WMS/PANDA), however, there were no significant correlations between V_T and cognitive dysfunction (P < 0.05; nuisance HAMD-17).

Conclusions: Using (S)-(-)-[¹⁸F]Fluspidine PET, we showed an increase of meso-striato-cortico-limbic and paralimbic S1R availability in untreated patients with acute, moderate to severe EO-MDD which was strongly correlated with the degree of depressive symptoms, but not with the cognitive state. These results provide motivation to apply S1R PET to a larger cohort of depressed patients at different disease stages, potentially also in follow-up after therapy initiation.