Sato Kohji
Department of Organ & Tissue Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, Hamamatsu, Shizuoka 431-3192, Japan.
Med Hypotheses. 2021 Feb;147:110484. doi: 10.1016/j.mehy.2021.110484. Epub 2021 Jan 7.
Bipolar disorder (BD) is a unique disorder where the same patient exhibits depression and mania, states with polar opposite mood symptoms. Lithium is an alkali metal that is widely used for the treatment of BD. However, it is largely unknown why lithium can stabilize mood. Lithium is known to inhibit glycogen synthase kinase-3β (GSK3 β). Interestingly, both in the glutamatergic system and GABAergic system, active GSK3 β decreases neuronal excitability, whereas inhibition of GSK3 β increases neuronal excitability, suggesting that activation of GSK3 β leads to depressive mood, and inhibition of GSK3 β leads to manic mood. The activity of GSK3β is regulated by many kinases and a phosphatase, and they are further controlled by several neurotransmitters and signaling molecules. Thus, these complicated control systems might make the swing of GSK3β activity, the swing of GSK3β activity makes the swing of neuronal excitability and finally resulting in the intrinsic swing of mood, usually observed in healthy human. BD is considered that the amplitude of the mood swing is enhanced by many factors. Lithium can dose-dependently decrease the amplitude of the swing of GSK3β activity. In addition, lithium also inhibits K channel activation, leading to the elongation of refractory period, resulting in the inhibition of neuronal excitability. Therefore, in depressive mood, lithium can increase neuronal activity via the inhibition of neuronal GSK3beta activity, and in manic mood, lithium can inhibit neuronal excitability via inhibiting K channel activation, therefore the amplitude of the mood swing is decreased, i.e. alleviating the depressive state and the manic state, resulting in the normalization of the mood swing.
双相情感障碍（BD）是一种独特的疾病，同一患者会出现抑郁和躁狂，这两种状态具有截然相反的情绪症状。锂是一种碱金属，广泛用于治疗双相情感障碍。然而，锂为何能稳定情绪在很大程度上尚不清楚。已知锂可抑制糖原合酶激酶-3β（GSK3β）。有趣的是，在谷氨酸能系统和γ-氨基丁酸能系统中，活性GSK3β均会降低神经元兴奋性，而抑制GSK3β则会增加神经元兴奋性，这表明激活GSK3β会导致抑郁情绪，抑制GSK3β会导致躁狂情绪。GSK3β的活性受多种激酶和一种磷酸酶调节，它们又进一步受几种神经递质和信号分子控制。因此，这些复杂的控制系统可能导致GSK3β活性的波动，GSK3β活性的波动又导致神经元兴奋性的波动，最终导致情绪的内在波动，这在健康人中也常见。双相情感障碍被认为是情绪波动幅度因多种因素而增强。锂可剂量依赖性地降低GSK3β活性波动的幅度。此外，锂还抑制钾通道激活，导致不应期延长，从而抑制神经元兴奋性。因此，在抑郁情绪中，锂可通过抑制神经元GSK3β活性来增加神经元活性，而在躁狂情绪中，锂可通过抑制钾通道激活来抑制神经元兴奋性，从而降低情绪波动幅度，即缓解抑郁状态和躁狂状态，使情绪波动恢复正常。
