839. A new pharmacological strategy against treatment-resistant depression

Abstract

Abstract Background Major depressive disorder (MDD) affects more than 50 million people worldwide and remains a leading cause of disability. Approximately 50% of patients show insufficient response to at least two pharmacological or psychotherapeutic interventions, a condition known as treatment-resistant depression (TRD). In this context, members of the galanin (GAL) neuropeptide family have been implicated in depression, offering a promising opportunity to enhance antidepressant efficacy. The N-terminal fragment GAL(1–15) is particularly active in mood regulation, and our previous studies have explored its potential as an adjunct treatment with selective serotonin reuptake inhibitor (SSRIs) in both naïve and depressive models. In this study, we will investigate whether GAL(1–15) can potentiate the antidepressant effects of Fluoxetine (FLX), a SSRI, in Wistar Kyoto (WKY) rats, a genetic model displaying features of endogenous and treatment-resistant depression. Aims & Objectives The objective was to evaluate the antidepressant potential of combined FLX and GAL(1–15) administration in WKY rats. Specific aims were to: (1) characterize behavioral effects of the combination FLX+GAL(1–15), on despair and anhedonia; (2) determine the role of the GAL receptor subtype GALR2 using the antagonist M871; (3) assess the involvement of 5-HT1A receptor mechanisms through siRNA knockdown and autoradiographic analyses; and (4) examine neuroendocrine regulation by measuring corticosterone levels and performing a dexamethasone-suppressed corticotropin-releasing hormone (CRH) stimulation test. Method Adult male WKY rats were divided into groups receiving vehicle, FLX, GAL(1–15), or FLX+GAL(1–15). Behavioral effects were assessed using the forced swim test and sucrose preference test. GALR2 involvement was examined with M871 pretreatment, and 5-HT1A mechanisms were studied through intracerebral siRNA-mediated knockdown and autoradiographic receptor binding in the prefrontal cortex (PFC) and hippocampus. Plasma corticosterone levels were quantified, and HPA axis regulation was evaluated using dexamethasone/CRH tests to assess feedback sensitivity. Results Neither FLX nor GAL(1–15) alone produced significant antidepressant-like effects in WKY rats. However, co-administration of FLX+GAL(1–15) markedly reduced immobility in the forced swim test and restored sucrose preference, indicating reversal of despair and anhedonia. These effects were abolished by GALR2 blockade with M871, implicating GALR2 receptor involvement. Autoradiographic studies revealed altered 5-HT1A receptor binding in the PFC following combination treatment, suggesting a modulatory effect on serotonergic function. Furthermore, the combination therapy normalized elevated corticosterone levels while not affecting HPA axis feedback induced by the dexamethasone/CRH test. Discussion & Conclusions This study demonstrates that GAL(1–15) significantly enhances FLX’s antidepressant efficacy in a treatment-resistant depression model. The results support a synergistic interaction between galanin and serotonergic systems involving GALR2 and 5-HT1A receptor modulation, particularly within the PFC. Behavioral and neuroendocrine normalization following combination therapy highlights a novel mechanistic pathway for overcoming SSRI resistance. Targeting galanin fragments such as GAL(1–15) may therefore represent a promising augmentation strategy for patients with TRD. These findings open new avenues for translational research exploring galanin-based modulators as adjunctive treatments in refractory depression.