Throughout the week of November 3rd, my neurochemistry class and I learned about and discussed an important treatment that has been utilized to treat bipolar disorder for over half a century. The particular treatment that we explored is lithium. Along with having neuroprotective effects against bipolar disorder, it has also been discovered that lithium reduced cognitive deficits in other neurodegenerative diseases such as, strokes, amyotrophic lateral sclerosis, fragile X syndrome, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, and many others. Within the body, lithium performs a variety of mechanisms which it utilizes in order to reduce the symptoms associated with the many different neurodegenerative diseases that I just mentioned. Throughout this blog, I will try to explain these complex mechanisms as effectively as possibly in order to help you understand them.
Lithium is a monovalent cation that has been the standard pharmacological treatment for bipolar disorder for over 60 years. It is often used in conjunction with mood stabilizers, antidepressants, and antipsychotics in order to reduce the symptoms associated with numerous neurodegenerative diseases. Lithium has a narrow therapeutic range and outside of this range a patient can experience minor to severe side effects, so it is important to monitor the dosage that a patient takes. Several minor side effects occur at lithium levels ranging from 0.6 to 1.2 mEq/L. Symptoms that occur at lithium levels above 1.5 mEq/L are generally mild and include tremor, nausea, diarrhea, vertigo, and confusion. At lithium levels above 2 mEq/L a patient will experience severe symptoms such as, seizures, coma, cardiac dysrhythmia and permanent neurological impairment at lithium levels greater than 2.5 mEq/L.
When a patient is given the correct dosage of litium, it carries out a variety of mechanisms in order to display many neuroprotective effects on the brain. As a class, we came to the conclusion that the inhibition of GSK-3 was the most important pathway that lithium carries out. GSK-3 is a serine/threonine protein kinase that is mediator of signaling pathways and is involved in a variety of cellular functions. GSK-3 activity is regulated by a wide variety of kinases and systems including Akt, protein kinase A, protein kinase C, MAP kinases, and the Wnt pathway. Lithium inhibits GSK-3 by phosphorylating it at the 21/9 serine residue. Another important aspect of the inhibition of GSK-3 is the stabilization of β-catenin. In response to the inhibition of GSK-3, the levels of β-catenin increase, which is a novel therapeutic strategy for treating mood disorders.
The inhibition of NMDA receptor-mediated signaling is another important mechanism that plays a role in the treatment of bipolar disorder by lithium. Glutamate induced excitotoxicity has been found to be an important contributor to bipolar disorder. It has been determined that lithium significantly reduces excitotoxicity, which in turn reduces the symptoms associated with bipolar disorder. Along with reducing excitotoxicity that is induced by glutamate, lithium also reduces excitotoxicity that is induced by calcium by inhibiting the entry of calcium into NMDA receptors.
As you can see, lithium is a very important treatment for bipolar disorder as well as many more neurodegenerative diseases. It affects a variety of different pathways and mechanisms in order to reduce the symptoms that are associated with the disorder. I have very little previously knowledge of bipolar disorder and how it is treated, so it was interesting learning about it and how lithium can be used as a treatment.
The Ups and Downs of Bipolar Disorder
