Little Lithium Does a Whole Lot in Bipolar Patients

Individuals affected by bipolar disorder lead lives that shift from normal to manic states to extreme depressive states. The manic states are noted by extremely happy, excited, irritable, or even grandiose attitudes. In the depressive state, the individual experiences the complete (polar) opposite: inability to concentrate, exhaustion, loss of interest, or possibly suicidal thoughts. Imaginably so, bipolar disorder would be extremely difficult to live with unless treated with an array of options. The focus of this post will be on lithium-the smallest, and what I would argue as most interesting, part of a bipolar treatment option.

A little history on the little lithium: This element was created in the Big Bang. It is the element right under hydrogen on the periodic table, three protons and a whole whopping 6.941 g/mol. Lithium has been used as a treatment option for bipolar since the 1950s.

Figure 1-Malhi et. al.

As pictured above, lithium is well known for its long-term mood stabilization.  Acutely, it helps decrease the manic state by affecting the neurotransmission and cellular levels. The decrease in depression is not evident until about 2 months of a strict regime. Most importantly for the mortality rate of bipolar patients is the decrease in suicide. Individuals with bipolar disorder are ten times as likely to commit suicide than the general population. Those on lithium are six times less likely to follow through with such thoughts. Many meta-analyses have shown that towns with higher amounts of lithium in the water also benefit from this effect, regardless of psychological conditions. The hypothesized mechanism is a lowered amount of aggression, as well as impulsivity.

With autopsies and studies, bipolar disorder has an effect on the brain where it degenerates part of the mass (neurodegenerative).  Lithium works to protect the brain by its long-term actions on the neurotransmitters glutamate and GABA. Glutamate, an excitatory neurotransmitter, works on special receptors in the brain known as NMDA receptors. Longterm, lithium competes with magnesium and downregulates the NMDA receptor, while concurrently increasing the reuptake of glutamate. This reestablishes the glutamate in the brain, preventing over-excitation. The over-excitation that would occur without lithium leads to eventual apoptosis of the neurons, thus degenerating the brain. Lithium’s affect on GABA has a similar result of downregulation of the NMDA receptor. Again, in an individual affected by bipolar disorder, the manic state leads to over-excitation thought to be from the NMDA receptor and too much excitatory glutamate, which eventually leads to the death of neurons.

Within the second messenger system, lithium functions in many places throughout due to competition with magnesium. The ability of lithium to increase CREB activity and inhibition Glycogen Synthase Kinase-3 (GSK3) are both proposed mechanisms in lowering glutamate activity. In lowering this proapoptotic activity, the brain can begin working on promoting neuroplasticity. These two pathways are shown below in the figure as (a) and (c).

Figure 3.-Malhi. et. al.

Sources:

Malhi, G., Tanious, M., Das, P., Coulston, C., & Berk, M. (2013). Potential Mechanisms of Action of Lithium in Bipolar Disorder. CNS Drugs, 27(2), 135-153. doi:10.1007/s40263-013-0039-0

Alda, M. (2015). Lithium in the treatment of bipolar disorder: Pharmacology and pharmacogenetics. Molecular Psychiatry, 20(6), 661-670. doi:10.1038/mp.2015.4