¹Fujita Health University, Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Toyoake, Japan, ²Fujita Health University, International Center for Brain Science (ICBS), Toyoake, Japan, ³Fujita Health University, Advanced Diagnostic System Development, Toyoake, Japan, ⁴Matsunami General Hospital, Matsunami Research Paark, Toba, Japan, ⁵University of Tsukuba, International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba, Japan, ⁶University of Tsukub, Department of Chemistry, Institute of Pure and Applied Sciences, Tsukuba, Japan, ⁷Fujita Health University, Laboratory of Health and Medical Science Innovation, Toyoake, Japan, ⁸NPO, Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan

Background: Major depressive disorder (MDD) has a highly heterogeneous pathophysiology. To optimize outcomes, it is necessary to identify clinically meaningful subtypes and provide treatments tailored to individual patients. Dietary habits have recently emerged as important modifiers of depression risk and treatment response. However, whether dietary habits influence the pathophysiology of MDD remains unclear.

Aims & Objectives: This study investigated how dietary habits, such as excessive sucrose intake, affect the pathophysiology of MDD. Ultimately, we aim to propose tailored therapeutic strategy based on changes in the metabolic axis associated with dietary habits.

Method: We analyzed health checkup data, including depressive and stress indices (CES-D) and dietary habits indices (BDHQ), to identify changes in dietary habits in the depressive group (CES-D ≥ 16). In parallel, mice were exposed to chronic unpredictable mild stress (CUMS) with or without sucrose excessive intake and were evaluated by using behavioral, neurochemical, and metabolic analyses.

Results: Health checkup data showed increased sucrose intake in MDD patients. When mice received sucrose, CUMS-induced hyperactivity and aggression were attenuated, but not social deficits or behavioral despair, although recognition memory was impaired by CUMS. The behavioral changes were associated with dysfunction of the locus coeruleus-prefrontal cortex circuit, through decrease of noradrenaline release by the presynaptic α2-adrenoceptor upregulation, and postsynaptic α1-adrenoceptor and β1-adrenoceptor downregulation. Atipamezole (α2-adrenoceptor antagonist) rescued behavioral changes induced by sucrose excessive intake under CUMS. In contrast, guanfacine (α2-adrenoceptor agonist) administration in CUMS mice reproduced the behavioral changes induced by sucrose excessive intake under CUMS. Among the antidepressants, mirtazapine effectively increased noradrenaline release and rescued behavioral changes induced by excessive sucrose intake under CUMS. Sucrose excessive intake under CUMS induced not only peripheral hyperglycemia, but also dysregulation of central glucose metabolism. Further, phloretin (glucose transporter inhibitor) rescued behavioral changes induced by sucrose excessive intake under CUMS. Both intracerebroventricular and systemic streptozotocin administrations reproduced the behavioral changes through α2-adrenoceptor upregulation.

Discussion & Conclusions: Our findings suggest that the MDD-like behavioral changes are associated with dysfunction of the noradrenergic α2-adrenoceptor system through impaired glucose metabolism. The noradrenergic and metabolic axis may be a promising target for tailored therapeutic strategies in sugar related depression subtypes.