Machado-Vieira Rodrigo, Courtes Alan C, Zarate Carlos A, Henter Ioline D, Manji Husseini K
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX, United States.
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States.
Front Neurosci. 2023 Aug 1;17:1228455. doi: 10.3389/fnins.2023.1228455. eCollection 2023.
Bipolar disorder (BD) is characterized by extreme mood swings ranging from manic/hypomanic to depressive episodes. The severity, duration, and frequency of these episodes can vary widely between individuals, significantly impacting quality of life. Individuals with BD spend almost half their lives experiencing mood symptoms, especially depression, as well as associated clinical dimensions such as anhedonia, fatigue, suicidality, anxiety, and neurovegetative symptoms. Persistent mood symptoms have been associated with premature mortality, accelerated aging, and elevated prevalence of treatment-resistant depression. Recent efforts have expanded our understanding of the neurobiology of BD and the downstream targets that may help track clinical outcomes and drug development. However, as a polygenic disorder, the neurobiology of BD is complex and involves biological changes in several organelles and downstream targets (pre-, post-, and extra-synaptic), including mitochondrial dysfunction, oxidative stress, altered monoaminergic and glutamatergic systems, lower neurotrophic factor levels, and changes in immune-inflammatory systems. The field has thus moved toward identifying more precise neurobiological targets that, in turn, may help develop personalized approaches and more reliable biomarkers for treatment prediction. Diverse pharmacological and non-pharmacological approaches targeting neurobiological pathways other than neurotransmission have also been tested in mood disorders. This article reviews different neurobiological targets and pathophysiological findings in non-canonical pathways in BD that may offer opportunities to support drug development and identify new, clinically relevant biological mechanisms. These include: neuroinflammation; mitochondrial function; calcium channels; oxidative stress; the glycogen synthase kinase-3 (GSK3) pathway; protein kinase C (PKC); brain-derived neurotrophic factor (BDNF); histone deacetylase (HDAC); and the purinergic signaling pathway.
双相情感障碍（BD）的特征是情绪剧烈波动，从躁狂/轻躁狂发作到抑郁发作。这些发作的严重程度、持续时间和频率在个体之间差异很大，对生活质量有重大影响。患有双相情感障碍的人几乎有一半的生命在经历情绪症状，尤其是抑郁，以及相关的临床维度，如快感缺失、疲劳、自杀倾向、焦虑和神经植物性症状。持续的情绪症状与过早死亡、加速衰老以及难治性抑郁症的患病率升高有关。最近的研究努力扩展了我们对双相情感障碍神经生物学以及可能有助于追踪临床结果和药物开发的下游靶点的理解。然而，作为一种多基因疾病，双相情感障碍的神经生物学很复杂，涉及多个细胞器和下游靶点（突触前、突触后和突触外）的生物学变化，包括线粒体功能障碍、氧化应激、单胺能和谷氨酸能系统改变、神经营养因子水平降低以及免疫炎症系统变化。因此，该领域已转向识别更精确的神经生物学靶点，这反过来可能有助于开发个性化方法和更可靠的生物标志物用于治疗预测。针对神经传递以外的神经生物学途径的多种药理学和非药理学方法也已在情绪障碍中进行了测试。本文综述了双相情感障碍中非经典途径中的不同神经生物学靶点和病理生理学发现，这些发现可能为支持药物开发和识别新的临床相关生物学机制提供机会。这些包括：神经炎症；线粒体功能；钙通道；氧化应激；糖原合酶激酶-3（GSK3）途径；蛋白激酶C（PKC）；脑源性神经营养因子（BDNF）；组蛋白脱乙酰酶（HDAC）；以及嘌呤能信号通路。
