Why is lithium effective in alleviating bipolar disorder?

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.