Bipolar Disorder: The Complexities of the Brain

The 'ups' and 'downs' of bipolar disorder (Source)

Bipolar disorder is fascinating to learn about, as so many details are still unknown. For example, why do some people remain bipolar their whole lives while others go into remission? You may have heard about it as just being mood swings and changes in temper. Bipolar disorder is more than just that, however; it is a chronic illness, in which 25 to 50 percent of those affected attempt suicide and the average life expectancy decreases by around 9 years. 

This is a highly interesting topic to me, as I have always wondered about the specifics of these episodes and why they occur. One of my aunts was diagnosed at a young age with the ailment. She has bipolar II, which is considered less extreme than bipolar I. My mom tells me stories of how one week she was extremely depressed and in bed all day crying, while the next she had episodes of euphoria which included overspending (shopping binges) along with staying up all night. After hearing about her story, and how medications have greatly helped her, I was inspired to delve deeper into the biology behind such an illness. 

There are several treatment options, the main one being lithium, however many patients remain symptomatic. Symptoms include episodes of mania, in which one experiences a sense of euphoria, a dramatically elevated mood, and hyperactivity. There are also parallel depressive episodes-- which are known as the main symptom of bipolar disorder-- where the patient experiences sadness, hopelessness, and anhedonia (the inability to feel pleasure). 

There are actually two different types: bipolar I and bipolar II. Bipolar I involves an alternation between severe mania and depression, while bipolar II involves mild mania and severe depression. Cyclothymia is a related disorder that involves less severe, and more mild episodes than bipolar disorder. 

Comparison of Bipolar I, Bipolar II, and Cyclothymia (Source)

What are the causes of such a complicated disorder? An exact answer is still unknown; the etiology is complex, ranging from several genetic, neurochemical, and environmental factors. Several studies have been made regarding the heritability rate of the disorder (the extent to which the disorder can be explained by genetic factors), which reportedly ranges from 30 to 80 percent. Yet there is no significant sign of Mendelian inheritance, or specific genes involved. This variation shows how epigenetic markers also play a role in gene activity and expression. One example is DNA methylation in promoters which represses gene activation, altering the proteins made in tissues with those affected by bipolar disorder. Early trauma can cause the methylation alterations that continue into adulthood. Methylation (gene repression) can also cause premature aging, and those affected have a faster cognitive decline. 

DNA methylation: the addition of methyl groups to DNA which can prevent binding of transcription factors to a gene, thus inhibiting transcription. (Source)

In the case of bipolar disorder, certain neurotrophic factors are the causes of manic and depressive episodes. These factors regulate the survival and function of cells in the nervous system by binding to a receptor on the cell's surface and causing a certain signal transduction pathway. The neurotrophic factors in the nervous system determine the episodes that a person experiences, and based on this, the brain responds differently to environmental factors/signals. The factors either can signal for cell apoptosis (cell death) or cause differential cell purpose. Bipolar disorder causes a decrease in cell plasticity, which is essentially the ability of cells to change their function in response to external and internal factors. These changes in neurotrophic factors can lead to brain damage, and symptoms such as a deficit in certain functions are seen in those affected.  

Psychological stress can affect the hypothalamic - pituitary - adrenal axis (primary mediator of the response to stress), and this can cause the primary symptoms to occur that are seen in bipolar disorder. Sleeping abnormalities also occur when the circadian rhythms shift due to this increased stress, causing either insomnia or hypersomnia. 

Much of the causes are still just hypotheses. The "mitochondria hypothesis" states that the disorder is triggered by dysfunction of the mitochondria due to impaired oxidative phosphorylation, which is vital to cell metabolism. This is shown through an increase in levels of lactate and a decrease of pH in the cells, signs of less cellular respiration. 

The vast majority of ATP is made during oxidative phosphorylation (34 molecules) where the proton gradient powers the production of ATP. When it's impaired, ATP can only be generated through fermentation, which produces significantly lower levels. (Source)

Another hypothesis states that oxidative stress causes point mutations, thus increasing deletions of mitochondrial DNA. Also, there are calcium ion imbalance and excess cortisol speculations. Nonetheless, all of these hypotheses emphasize how factors work together and can activate receptors, signaling pathways related to changing/activating the immune system (causing brain damage and other bipolar disorder symptoms). 

Lithium is one of the main treatments used to stabilize moods/brain activity. Essentially it enables proper mitochondria function and provides neuroprotection; inhibiting cell apoptosis or the effects of certain neurotrophic factors I previously mentioned, while activating others. It allows for proper gene expression to occur, and doesn't allow brain activity to fluctuate as severely into depressive and manic episodes. 

Lithium activates the transcription factor known as CREB, which then facilitates the production of BDNF and Bcl-2 (neuroprotective factors). (Source)

Another two medications/mood stabilizers commonly used to treat bipolar disorder are Depakote (which successfully worked for my aunt), and Lamictal.

I enjoyed researching this topic, and it made me realize how complex disorders of the brain can be. Bipolar disorder remains much of a mystery, and involves the combination of multiple factors, so there is no easy explanation or solution.