A Summary of Bipolar Disorder

Bipolar disorder is considered to be a “mysterious disorder”, as the National Institute of Health defines it. The main indicators of the disorder include mood swings between states of mania and hypomania (with varying amounts of excitement) alternating with periods of depression. Approximately 1%-4% of people are affected by it worldwide, with 14-59% having thoughts of suicide, 25-50% attempting suicide, and around 20% having committed suicide. There are two main types of bipolar disorder: the traditional “high school textbook” definition of full mania episodes (I) or milder mania periods alternating with depressive stages (II). Although the periods of mania help clarify the disorder as bipolar, the states of depression are longer and more detrimental to the individual. The disorder indirectly affects other functions, such as sleep, energy levels, and speech. Psychotic symptoms such as delusions and hallucinations aren’t rare. The life expectancy of those individuals decreases by an average of 9 years, in addition to increasing the chances for other diseases. Therefore, bipolar disorder has effects that go far beyond its implications for mental health. 

Cognitive impairment provides a challenge in life for those with bipolar disorder. Though symptoms arise during adolescence, most cases are diagnosed during the 20s. There is a consensus that bipolar disorder experiences neuroprogression, where it is split into different stages as one gets older. Each of those stages is caused by a different biological source, and later stages are more resistant to treatment than earlier ones. Generally, bipolar disorder is caused by a combination of genetic, chemical (neurons), and environmental factors. Among these causes, the most prominent one turns out to be genetics; in fact, a child born from a parent with bipolar disorder has 10 times the chance as one born from someone who doesn't. Lithium remains the only verified product to treat the mania stages of bipolar disorders. While other antipsychotics, antidepressants, and antiepileptic drugs such as sodium valproate exist, they result in varying effects–a reflection of the ongoing confusion surrounding the elusive condition. In fact, many of the drugs treating depressive episodes result in an elevation of the mania stages as a common side effect. 

Multiple minor loci (specific genes) are suspected to contribute to bipolar disorder, with at least 19 genes accounted for. Yet none of these genes are pinpointed to specifically cause bipolar disorder, as many are found to be responsible for other similar conditions such as schizophrenia. This suggests that if bipolar disorder can be combated, other disorders can also be tackled. Current research presents much attention on 2 of these genes: the CACNA1C and ANK3 gene.  The ANK3 gene is found to encode ankyrin G, which aids in connecting voltage-gated sodium channels to the cytoskeleton of the cell (a network of protein fibres that supports the structure of the cell). These sodium channels are especially active in electrically charged cells, such as neurons, proving that such strides are significant to the understanding of the disorder.

Researchers are investigating the role of channelopathy in the development of bipolar disorder. They found that the increase in intracellular calcium signalling can be reduced by lithium. Among the many channels, the one most studied for treatment is the L-type voltage-gated calcium channel. However,  it proved difficult to pinpoint which voltage-gated channels are responsible, since the genes that code for such code for other proteins as well. Specifically, the alternative splicing of mRNA during protein synthesis can rearrange the exons, and segments of DNA that code for proteins after removing the non-coding introns. Not all the voltage-gated calcium channels are found in the brain, as some are also found to be coded for in the heart. To further advance the comprehension of bipolar disorder, it is important to know which genes are actually responsible for the disorder. 

Generally, the genes responsible for bipolar disorder hold around a 70-80% heritability rate. These genes include ion channels, neurotransmitter transporters, and proteins, which are responsible for signalling between nerve cells. The single nucleotide polymorphisms, while affecting the splicing variants of introns and exons, provide little to no major change in the DNA sequence of these genes. Rather, a shift towards investigating the role of epigenetics has become more prevalent. DNA methylation, which can be induced by early trauma, is a common way for DNA to coil up together so that it can’t be transcribed. This explains why trauma may be a contributing factor to the disorder. As methylomes methylate DNA, it results in age-related conditions and cognitive decline, accelerating epigenetic aging in the blood and brain. The complicated factors surrounding this phenomenon question the hope that this can be pharmacologically treated. To further expand our avenues of understanding, there is a growing effort to study the role of non-coding mRNA (siRNA). 

Neurosignaling, or signalling between neurons, provides another light into which the causes of bipolar disorder can be confirmed. Specifically, there are proteins called neurotrophic factors whose job is to regulate the many processes regarding neurons, including growth, synapses, and cell specialization in the nervous system. Among the many factors, the most common one studied of bipolar disorder is BDNF (brain-derived neurotrophic factor), in the same family as NGF, NT-3, and NT-4, which binds to tyrosine kinase receptors on neurons to regulate the central nervous system. It was found that the levels of NT-3 and NT-4 were especially prevalent in the depressive stages but lacking during the mania phases. This helps explain the lower cellular plasticity (ability to change and adapt) hypothesis: changes in neuroplasticity result in brain damage that exacerbates mood swings and causes cognitive and functional detriments. Conversely, the levels of BDNF decrease in the blood and brain in individuals with the disorder, resulting in the replacement of a valine amino acid in the protein of a methionine amino acid. Li and UPA can increase the levels of BDNF, making them a possible treatment for this particular underlying cause. 

It is a well-known fact that the mitochondria are responsible for cellular respiration. In the human brain, it also regulates neuronal activity, neural plasticity, and cellular resilience. Derived from the common occurrence of the defunct mitochondria in bipolar disorder patients, the mitochondrial hypothesis states that bipolar disorder is triggered by the dysfunction of the mitochondria in the brain. What causes this occurrence could be blamed on high lactic acid (a byproduct of cellular respiration) levels and lower pH levels, which inhibit cellular respiration, forcing BD patients to rely solely on glycolysis for energy in the brain. When this occurs, the levels of sodium and potassium ATPase activity are unregulated, causing a large amount of calcium to pour in. This not only can bring glutamate excitotoxin deadly to neurons but also cause neuronal apoptosis-neuron degeneration. It also wasn’t surprising to find that certain areas of the bin have lower phosphocreatine and ADP levels that give rapid energy. During the depressive stages, this phenomenon springs up in the left side of the brain, while the right side of the brain experiences in doing mania phases, attributed to regional hypometabolism.

Additionally, the tampering of components of cellular respiration–especially the nonregulation of mRNA and proteins involved in the Krebs cycle, the electron transport chain protein complexes, and creatine kinase–reduces the ability of the cell to successfully oxidize NADH and FADH. Oxidation is important because the high-energy electrons can be transferred to NADH and FADH so the energy can be released. However, due to the failure of such, the electrons are leaked out, allowing free radicals to roam the brain. In other words, the regulation of oxidative stress is altered. 

Evidence of lower levels of inflammatory cytokines, when BD symptoms aren’t apparent, suggests its role in developing the disorder. Though some scientists would like to state that inflammation impairs cognition, more research is needed to make this conclusion valid. The main function of these cytokines (mainly the interferon-gamma and TNF-a) is to activate the kynurenine pathway by signalling the transformation of tryptophan into kynurenine, which is then further converted into hydroxykynurenine, quinolinic acid, and kynurenic acid.  While the latter two are neuroprotective for the most part, the first increases the number of free radicals, which is hyperactivated through inflamed cytokines. Furthermore, the presence of KYNA in higher amounts in the cerebrospinal fluid was found to be a contributor to the psychotic episodes, as more dopamine is released. While the kynurenine pathway can mediate inflammation and neurodegeneration, overactivation of the pathway has the unfortunate side effect of neurotoxicity and the disruption of neurotransmission. 

The hypothalamic-pituitary-adrenal axis, abbreviated as the HPA axis, should not be ignored as a potential cause of BD, with its primary role of mediating the response to stress in the brain. It is believed that the increase in its activity contributed to BD, though it is more prominent in the mania stages. When cortisol levels are elevated in the saliva, it reduces the ex vivo glucocorticoid receptor response and increases levels of FK506 binding protein 51, increasing the methylation of the genes for the proteins responsible for negative feedback of HPA. As a result, the brain develops lower resilience to stress and increases the risk of mood episodes becoming psychotic, since the FK5606 binding protein 51 will desensitize the ability of the glucocorticoid receptor, which signals the pathway to regulate stress. 

Finally, there is reason to believe that circadian rhythm disturbances are also associated with BD. There is a growing consensus that sleep disturbances are a criterion for one to be considered to have BD. While mania episodes limit these disturbances, depressive episodes feature insomnia/hypersomnia as a result of shifting circadian rhythms. The rest-activity cycle is lower in amplitude, meaning during periods of rest there is less received and lower periods of activity performed. Additionally, the variability of the sleep-wake cycle helps predict depressive episodes, with its lower activity levels. For example, one could find themselves awake in the middle of the night or take longer to fall asleep. Many BD patients are found to favor an evening chronotype, correlating with the lower age of rapid-cycling mood switches and lower levels of substances responsible for managing oxidative stress. The mania episodes feature high amounts of melatonin produced (responsible for sleepy feeling) during the day and nighttime but are reduced during the depressive episodes. Cortisol secretion is increased during the entire 24-hour period of the day, suggesting an increase in stress. These disturbances in circadian rhythms feature polygenic heritability, meaning more than one gene is involved in their cause. Scientists believe that the GSK3 𝛽 gene is the candidate gene, as it is expressed more in BD patients than non-patients. Other genes such as the PER3 and the one mentioned in the previous sentence are responsible primarily for the early age of symptoms, and the TIMELESS, CLOCK, CRY2, ARNT2, and other genes play a role in the rapid cycling of such. These findings support the hypothesis that the earlier the age of symptoms, the more severe circadian disturbances that would be present. 

Overall, there is no one biomarker for bipolar disorder. It is the combination of many causes that contributes, and the connectedness of these causes is being increasingly understood. While we may be confident about many findings of BD, very few of them are final conclusions. 

Credits: National Institution of Health