Differentiation between bipolar disorder and major depressive disorder based on AMPA receptor distribution

Sakiko Tsugawa¹Yuichi Kimura²Junichi Chikazoe³Hiroki Abe¹Tetsu Arisawa¹Mai Hatano¹Waki Nakajima¹Hiroyuki Uchida⁴Tomoyuki Miyazaki¹Yuuki Takada¹Akane Sano¹Kotaro Nakano¹Tsuyoshi Eiro¹Akira Suda¹Takeshi Asami¹Akitoyo Hishimoto⁵Hideaki Tani⁴Nobuhiro Nagai⁴Teruki Koizumi⁴Shinichiro Nakajima⁴Shunya Kurokawa⁴Yohei Ohtani⁴Kie Takahashi⁴Yuhei Kikuchi⁴Taisuke Yatomi¹Yoji Hirano⁶Ryo Mitoma⁷Shunsuke Tamura⁶Shingo Baba⁸Osamu Togao⁸Hirotaka Kosaka⁹Hidehiko Okazawa⁹Masaru Mimura⁴Takuya Takahashi^1*

• ¹Yokohama City University, Yokohama, Japan
• ²Kindai University, Higashi-Osaka, Japan
• ³Hiroshima University, Hiroshima, Japan
• ⁴Keio University School of Medicine, Tokyo, Japan
• ⁵Kobe University Graduate School of Medicine, Kobe, Japan
• ⁶University of Miyazaki, Miyazaki, Japan
• ⁷Kyusyu University, Fukuoka, Japan
• ⁸Kyushu University, Fukuoka, Japan
• ⁹University of Fukui, Fukui, Japan

An accurate diagnostic method using biological indicators is critically needed for bipolar disorder (BD) and major depressive disorder (MDD). The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is a crucial regulator of synaptic function, and its dysregulation may play a central role in the pathophysiology of psychiatric disorders. Our recently developed positron emission tomography (PET) tracer, [¹¹C]K-2, enables the quantitative visualization of AMPAR distribution and is considered useful for characterizing synaptic phenotypes in patients with psychiatric disorders. This study aimed to develop a machine learning-based method to differentiate bipolar disorder from major depressive disorder using AMPAR density. Sixteen patients with BD and 27 patients with MDD, all in depressive episodes, underwent PET scans with[¹¹C]K-2 and structural magnetic resonance imaging. AMPAR density was estimated using the standardized uptake value ratio from 30 to 50 minutes after tracer injection, normalized to whole brain radioactivity. A partial least squares model was trained to predict diagnoses based on AMPAR density, and its performance was evaluated using a leave-one-pair-out cross-validation. Significant differences in AMPAR density were observed in the parietal lobe, cerebellum, and frontal lobe, notably the dorsolateral prefrontal cortex between patients with BD and patients with MDD during a depressive episode. The model achieved an area under the curve of 0.80, sensitivity of 75.0%, and specificity of 77.8%. These findings suggest that AMPAR density measured with [¹¹C]K-2 can effectively distinguish BD from MDD and may aid diagnosis, especially in patients with ambiguous symptoms or incomplete clinical presentation.