在臨床精神藥理學的領域裡，我們有幸與一群台灣的專家合作共同形成對於躁鬱症生物治療的共識。更進一步的探索精神藥理由細胞層級延伸到複雜神經迴路的作用，專注於解開情緒穩定劑治療難以捉摸的機制。我們透過動物模型凸顯了神經膠細胞作為藥物干預的整體目標的關鍵角色。在分子層面上，我們揭示了情緒穩定劑對組蛋白尾部進行顯著的乙烯化作用。除了強調了情緒穩定劑作的表觀遺傳調節角色，我們發現神經膠細胞作為精神藥物丙戊酸的關鍵作用標的。以上藥理作用機轉的實驗結果與情緒障礙源於環境刺激與大腦反應之間複雜互動的觀念相符，也強調了這些精神疾病複雜多面的結構，並呼應了在理解和治療這些狀況時採取全人治療方法的必要性。
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Chang, C.C., et al., Mitochondrial DNA Copy Number Is Associated With Treatment Response and Cognitive Function in Euthymic Bipolar Patients Receiving Valproate. Int J Neuropsychopharmacol, 2022. 25(7): p. 525-533.
Hsueh, Y.S., et al., Changes in striatal dopamine transporters in bipolar disorder and valproate treatment. Eur Psychiatry, 2021. 64(1): p. e9.
Chen, P.S., et al., Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry, 2006. 11(12): p. 1116-25.
Peng, G.S., et al., Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Research (Molecular Brain Research) (Brain Res Mol Brain Res), 2005. 134(1): p. 162-9.
Wu, X., et al., Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol, 2008. 11(8): p. 1123-34.
Chen, P.S., et al., Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience, 2007. 149(1): p. 203-12.
Kim, H.J., et al., Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp Ther, 2007. 321(3): p. 892-901.
情緒障礙與代謝紊亂的重疊創造了一個複雜的臨床情境，這個情境以治療挑戰、不良預後和認知衰退的風險增加為特點。我們的研究強調了在嚴重情緒障礙中代謝問題的顯著普遍性，這一問題因情緒障礙藥物對代謝平衡的影響而變得更加複雜。我們深入探討了情緒調節與代謝穩定之間的關係，專注於中腦邊緣系統的獎勵系統以及多巴胺和催產素受體變異對代謝控制的影響。研究顯示，高脂飲食可以導致小鼠出現代謝和抑鬱障礙，這可以通過糖尿病藥物得到緩解。此外，壓力加劇了杏仁體的胰島素抗性，這與情緒障礙患者的認知問題有關。抗憂鬱藥和情緒穩定劑的使用也可能破壞代謝平衡。在憂鬱症和代謝紊亂患者中發現慢性低度炎症的發現強調了需要一種全面治療方法，這種方法應對情緒和代謝健康之間錯綜複雜的關系進行處理。
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Chang, H.H., et al., The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord, 2010. 124(3): p. 319-23.
Lee, C.J., et al., Factors related to metabolic parameters in medicated patients with major depressive disorder--a naturalistic study. Psychiatry Res, 2018. 268: p. 28-33.
Lee, S.Y., et al., Inflammation's Association with Metabolic Profiles before and after a Twelve-Week Clinical Trial in Drug-Naive Patients with Bipolar II Disorder. PLoS One, 2013. 8(6): p. e66847.
Chang, H.H., et al., C825T polymorphism of the GNB3 gene on valproate-related metabolic abnormalities in bipolar disorder patients. J Clin Psychopharmacol, 2010. 30(5): p. 512-7.
Chang, T.T., et al., The DRD3 Ser9Gly Polymorphism Predicted Metabolic Change in Drug-Naive Patients With Bipolar II Disorder. Medicine (Baltimore), 2016. 95(24): p. e3488.
Chang, H.H., et al., The OXTR Polymorphism Stratified the Correlation of Oxytocin and Glucose Homeostasis in Non-Diabetic Subjects. Diabetes Metab Syndr Obes, 2019. 12: p. 2707-2713.
Tsai, S.F., et al., High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens. Mol Psychiatry, 2022. 27(11): p. 4372-4384.
Kuo, Y.Y., et al., Glibenclamide promotes FGF21 secretion in interscapular BAT and attenuates depression-like behaviors in male mice with HFD-induced obesity. Life Sci, 2023. 328: p. 121900.
Tsai, S.F., et al., Stress Aggravates High-Fat-Diet-Induced Insulin Resistance via a Mechanism That Involves the Amygdala and Is Associated with Changes in Neuroplasticity. Neuroendocrinology, 2018. 107(2): p. 147-157.
Tsai, T.H., et al., The relationship between peripheral insulin resistance and social cognitive deficits among euthymic patients with bipolar disorder. J Affect Disord, 2023.
Chang, H.H., et al., Peripheral insulin sensitivity predicting cognitive function in euthymic bipolar disorder patients. CNS Spectr, 2022. 27(5): p. 598-603.
Chang, H.H., et al., The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients. J Affect Disord, 2013. 150(2): p. 295-9.
Chang, H.H., et al., FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate. Int J Neuropsychopharmacol, 2018. 21(4): p. 319-324.
Chang, H.H. and P.S. Chen, Inflammatory Biomarkers for Mood Disorders - A Brief Narrative Review. Curr Pharm Des, 2020. 26(2): p. 236-243.
Chang, H.H., et al., C-reactive protein: A differential biomarker for major depressive disorder and bipolar II disorder. World J Biol Psychiatry, 2017. 18(1): p. 63-70.
Chen, P.S., L.Y. Tang, and H.H. Chang, Roles of C-reactive protein polymorphisms and life event changes on cognitive function in bipolar patients receiving valproate. Int J Immunopathol Pharmacol, 2022. 36: p. 3946320221084835.
Chang, H.H., et al., Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun, 2012. 26(1): p. 90-5.
Wei, S.Y., et al., Associations of leptin and corticostriatal connectivity in bipolar disorder. Sci Rep, 2022. 12(1): p. 21898.
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Chang, H.H., et al., Effect of memantine on C-reactive protein and lipid profiles in bipolar disorder. J Affect Disord, 2017. 221: p. 151-157.
情緒障礙的社會經驗與認知
社會認知包括促進我們理解、感知和解釋社會線索的心理運作，包括他人表現出的情緒、意圖和行為。這個認知領域有助於確定我們的情緒反應和社交活動的品質。在動物實驗中，我們採用自閉症模型來證實杏仁核（情緒腦的核心組成部分）的異常興奮與非典型社會行為之間的關聯。我們先前的臨床研究也強調了情緒障礙患者的社交認知功能明顯受損。此外，創傷性的社會經驗和孤獨感對於塑造社會認知至關重要。尤其是童年創傷，它是深刻影響情緒障礙的發生和演變的重要因素。因此，社交認知能力的增強可以成為增強情緒智商和加強社會連結的重要一步。在合作實驗室中，正在進行實驗來探索各種藥物治療方法，旨在減輕社會認知缺陷，並進而改善相關的情緒和社會挑戰。
Lin, H.C., et al., The amygdala excitatory/inhibitory balance in a valproate-induced rat autism model. PLoS One, 2013. 8(1): p. e55248.
Tsai, Y.T., et al., Social cognitive deficit is associated with visuomotor coordination impairment and dopamine transporter availability in euthymic bipolar disorder. J Psychiatr Res, 2023. 165: p. 158-164.
Liu, Y.C., et al., The social cognitive ability in Han Chinese euthymic patients with bipolar I and bipolar II disorder. J Formos Med Assoc, 2020.
Lee, C.N., et al., Associations of emotion recognition, loneliness, and social functioning in euthymic patients with bipolar disorder. Kaohsiung J Med Sci, 2022. 38(7): p. 703-711.
Tsai, T.Y., et al., The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression. Clin Psychopharmacol Neurosci, 2019. 17(4): p. 487-494.
Hsieh, Y.T., et al., Childhood neglect is associated with corticostriatal circuit dysfunction in bipolar disorder adults. Psychiatry Res, 2021. 295: p. 113550.
Wu, H.F., et al., Alleviation of N-Methyl-D-Aspartate Receptor-Dependent Long-Term Depression via Regulation of the Glycogen Synthase Kinase-3beta Pathway in the Amygdala of a Valproic Acid-Induced Animal Model of Autism. Mol Neurobiol, 2017. 54(7): p. 5264-5276.
Wang, C.C., et al., 5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model. Int J Neuropsychopharmacol, 2013. 16(9): p. 2027-39.
數位醫療與情緒障礙
數位醫療代表了一種對情緒障礙的治療帶來重大改變的創新方法。透過利用可穿戴技術、數據分析、遠程治療平台等技術，它實現了更加個別化和持續的照護模式。遠程監測技術允許實時追蹤情緒指標和生命體徵，提供及時的數位化紀錄。在過去幾年中，研究團隊使用移動裝置記錄了雙相情感障礙病例的數位行為標記。我們嘗試使用機器學習追蹤他們情緒變化的趨勢，並識別與復發相關的行為標記。除了向患者發送提醒消息外，我們還希望通過通知家庭成員和醫療團隊來實現早期介入。精神健康應用程式和線上平台的興起，讓患者有機會接受實證治療，並克服了地理和時間限制。數位醫療結合數位行為表徵，正在轉變情緒障礙的治療方式。這種創新醫療模式將提供患者獨特的個別化治療。
Tseng, Y.C., et al., Associations among smartphone app-based measurements of mood, sleep and activity in bipolar disorder. Psychiatry Res, 2022. 310: p. 114425.
Hsu, J.H., et al., Digital Phenotyping-Based Bipolar Disorder Assessment Using Multiple Correlation Data Imputation and Lasso-MLP. IEEE Transactions on Affective Computing, 2023: p. 1-14.
非侵入性腦刺激術
非侵入性腦刺激（NIBS）指的是一套技術，這些技術可以在不需要手術或植入電極的情況下調節腦部活動。這些方法被用於各種目的，包括治療神經和精神障礙、認知增強，以及研究腦功能。NIBS是一個迅速發展的領域，為理解大腦、治療障礙和增強認知功能提供了有希望的途徑。我以前的和聯合研究以及臨床試驗試圖揭示腦刺激技術的全部潛力和限制，確保它們在精神障礙的各個領域的安全和有效應用。在情緒障礙領域，我們已經展示了高頻率重複經顱磁刺激治療針對左側背外側前額葉皮層是一種有效的抑鬱症干預措施，與躁鬱症相關。這種非侵入性腦刺激技術可以安全地作為藥物治療的輔助手段，增強患有躁鬱症抑鬱的個體的整體治療效果。持續的研究進入個性化治療和優化可能進一步強調其在情緒障礙護理中的潛力。
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Wu, H.F., et al., Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model. Int J Mol Sci, 2018. 19(9).
Lin, S.H., et al., Transcranial direct current stimulation (tDCS) may reduce the expired CO concentration among opioid users who smoke cigarettes: a randomized sham-controlled study. Psychiatry Res, 2021. 299: p. 113874.
Wu, C.L., et al., Comparative efficacy of rTMS add-on treatment for bipolar depression versus unipolar depression. Brain Stimul, 2023. 16(4): p. 1102-1104.