Before I begin, a big thank you to all of my readers. We are officially well past the 1000 view mark. Not bad for a blog only shared with my friends, family, and their friends!
This week’s question comes from my friend Brock, who asks, “I have Bipolar Disorder. It is currently being treated by use of lithium salts (specifically lithium carbonate), but no one has a straight answer about how it all works. What is known about the lithium’s action in the human brain?”
Before I launch into what I could find on the subject, I would first like to give some background on Bipolar Disorder, especially the symptoms and biological origin. Bipolar Disorder is one of the most well known mental illnesses, and over the years has held many different names. Many of you may recognize it as manic depression/manic depressive disorder or bipolar mania. Generally, people tend to understand it as a radical emotional shift: one moment someone is as happy as they can be and the next they’re in the deepest pit of despair. In fact, the term “bipolar” tends to be used informally to describe someone who is emotionally volatile or erratic.
However, Bipolar Disorder is far more complicated than people realize. The main elements, mania and depression, have tremendous variability and can be punctuated with long bouts of seeming normalcy. Also, its source is often difficult to understand, as symptoms may manifest long before people experience their first “manic break,” or severe bout of psychosis where they break from reality. Distressingly, it is known to have a strong genetic component and heredity is not uncommon.
The grey areas are vast, but generally begin with the concept of hypomania. A hypomanic state makes someone very high energy, restless, erratic, irritable, and easily excited and distracted. Often people in a hypomanic state have reduced inhibitions, an inflated sense of self, and cannot sleep well. These symptoms can progress in severity to the point where the person becomes entirely detached from reality, the aforementioned “manic break.” Though not all of those with Bipolar Disorder present with such severe symptoms, for some even a relatively mild hypomanic state can be life altering and require intervention.
On the other side of the coin, as high as people can get in the manic state is how low they can get in the depressive state. It is almost the polar opposite of the manic state, including lethargy, loss of energy, disinterest in life, problems with concentration and memory, and even suicidal tendencies.
However, it is not even essential to have them discretely or even at all. Some people can experienced mixed symptoms, where elements of one appear in the other type of episode.
The main line treatment for this mental illness is a group of drugs known as “mood stabilizers,” of which lithium carbonate is one. The goal of these drugs is to control in some way the levels and/or use of norepinephrine (NE), a neurotransmitter that has far reaching effects in the brain; it is also deeply tied into the function and release of other neurotransmitters in the brain and around the body. NE especially influences general arousal (including fight or flight mechanisms), attention, and the reward system. Other more common antidepressants (SSRIs, SNRIs, etc.) and antipsychotics (sodium valproate, etc.) can also be used for control of less severe symptoms in either direction of the mood spectrum.
Specifically, it is thought that the manic state is caused by a dramatic increase in NE, and the symtoms seem to correlate well with NE’s function in the brain. The depressive state, then, is the opposite neuro-chemical environment, where there is not enough NE to support normal mood. Unfortunately, it is not known by what exactly mechanism this process works and to what extent the changes in NE alter other neurotransmitter levels–the systems remain too linked to effectively show cause and effect. Even genetic analysis has not provided any greater answers for the biological source of the disease.
Sadly, the reason for lithium’s effect is also not very well understood. For its anti-depressant qualities, two competing theories exist. Both affect signaling pathways far away from the release of neurotransmitters and instead focus on neuroprotective (brain cell protecting) mechanisms. In the first theory, lithium blocks an enzyme pathway responsible for ultimately allowing for the destruction of cells in a region of the brain known as the hippocampus. Damage to the hippocampus (as evidenced by reduced size) is known to be present in depression patients. In the second mechanism, lithium blocks an enzyme responsible for the creation of a cellular messenger known as inositol. Depleting inositol slows down the improper signaling between cells and prevents similar problems with the hippocampus.
The mania is thought to be controlled by lithium’s effects of NE in the brain. Primarily, this is theoretically accomplished by binding to the NE receptor and reducing NE’s ability to bind to it. Secondarily, lithium encourages lithium to be taken back into the cell and stored in elements that are not involved in neurotransmission. Systemically, it is also thought that lithium causes increased release of acetylcholine in the blood, which can have a calming effect generally.
Unfortunately, none of these mechanisms are definitively outlined and proven and thus remain difficult to target more specifically. Things are made much more difficult by the fact that a significant percentage of patients do not respond effectively to lithium. The unreliability makes it just that much harder to definitively prove a mechanism applicable to the disease biology as a whole.
On the whole, it appears that the theories all seem to lay claim to some general alteration of neurotransmitters or signaling pathways, but without further in depth research the mechanisms will remain largely speculative. It certainly appears that Bipolar Disorder is complex disease that involves far more than just NE levels in the brain. Only time will tell exactly what these complexities are and hopefully will yield a more effective treatments.
Hope this helps, Brock! As always, if you have any questions feel free to submit them directly.
Till next time, have a good one!