Causes of Bipolar Disorder

Bipolar Disorder [23]
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Individuals with bipolar disorder experience
alternating manic and depressive episodes

The current consensus is that bipolar disorder is a multifactorial disorder and its cause will vary from one afflicted individual to the next. There is evidence to support the widely accepted notion that bipolar disorder appears to arise from a complex interaction of several genetic, neurological, and environmental factors. The strong genetic basis of this disorder stems from family and twin studies showing that individuals with first-degree relatives who are afflicted by bipolar disorder are at an increased risk of developing the disorder themselves, in addition to several genes that have been identified to be potentially implicated in the disease.[1] Neurological causes associated with manic-depressive disorder include abnormalities in the size and activity of various brain structures and irregular signaling of neurotransmitters such as dopamine, serotonin, and glutamate.[1] Additionally, abnormalities associated with neurological circuits that regulate mood and the circadian rhythm have also been shown to play a role in facilitating manic-depressive disorder symptoms.[2] Finally, environmental stressors, such as childhood trauma or major life changes, oftentimes may trigger the onset of bipolar disorder or exacerbate the symptoms associated with the condition in those who are genetically predisposed to bipolar disorder.[1] Knowledge of the various causes of bipolar disorder allows one to form well-informed approaches to treat bipolar disorder.

Genetic

Family studies

Based on numerous studies examining possible genetic components influencing the onset of bipolar disorder, researchers have concluded that the disorder is highly heritable. Genetic influences are estimated to contribute up to 80-85% of the heritability of manic-depressive disorder.[3] The risk of developing bipolar II disorder is also shown to be higher for individuals with relatives afflicted with bipolar II disorder than for individuals related to bipolar I disorder patients, suggesting that genetic differences may underlie the two subtypes of bipolar disorder.[4]

Twin studies

Evidence from twin studies, despite the relatively small sample size used, supports the general consensus that genes play an important role in the implication of bipolar disorder.[1] Concordance rates for bipolar I disorder are 40% for monozygotic twins yet only 5% for dizygotic twins.[5] Bipolar disorder has also been genetically linked, through twin studies, with the development of major depression disorder: the concordance rate for bipolar disorder when a twin is afflicted with unipolar depression is 19% in fraternal twins but rises to 67% in identical twins.[6]

Candidate gene regions

Many candidate regions, such as BDNF, DAOA, DISC1, GRIK4, SLC6A4, TPH2, DGKH, CACNA1C, and ANK3, have been identified to be associated with manic-depressive disorder.[4] However, while the general consensus is that bipolar disorder is highly heritable, with genetic causes attributed to 60-85% of the risk variance of bipolar disorder, the results of many of these candidate gene region studies are inconsistent and are often not replicated.[4] A reason that this occurs is that the disorder may be the result of small accrued effects from many genes, a hypothesis that is currently supported by many researchers in the field.[4] Additionally, research on the genetic causes of bipolar disorder is further complicated by the fact that results from previous studies strongly suggest that the disorder may be heterogeneous, because different genes are often implicated in different families.[7] In 2007, genome-wide association studies (GWAS) have begun to be applied in earnest with regards to bipolar disorder research.[1] These GWAS studies, in summary, provided further evidence to support the notion that bipolar disorder is a highly polygenic disease resulting from the accumulated effects of several genes of small effect.[1]

One example of a candidate gene that has been shown to be possibly implicated in bipolar disorder is the FYN gene, which is associated with the glutamatergic system.[8] Tyrosine kinase FYN is critical for neurotropic factors to interact with the NMDA glutamatergic receptor. Using data collected from almost 1000 subjects, Szczepankiewicz et al. (2009) found that two of the polymorphisms of the FYN gene, rs6916861 T/G and rs3730353 T/C, were associated with increased risk of bipolar disorder, especially in bipolar I disorder and in early onset bipolar disorder.[8]

Neurological

Brain after Stroke [24]
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Strokes can cause brain tissue damage, potentially
resulting in symptoms of bipolar disorder

Structural abnormalities

Structural MRI studies report several structural brain abnormalities associated with bipolar disorder, including increased volume of the lateral ventricles and the globus pallidus and decreased volume of the whole brain and the prefrontal lobe.[9] In addition, although cited as a relatively less common cause of bipolar disorder, physical injury to the brain arising from temporal lobe epilepsy, strokes, traumatic brain injury, and a multitude of other conditions may also affect neurological structures and consequently lead to an increased risk of developing or exacerbating the symptoms of the disorder.[10] Moreover, morphological differences in the neuronal and glial cell size and density between control participants without manic-depressive disorder and those afflicted with the disorder have been observed, suggesting possible metabolic pathway involvement in the implication of bipolar disorder.[11]

Neurotransmitters

Dopamine

Dopamine, a neurotransmitter widely known to enhance mood, is consistently observed to be transmitted in higher levels during the manic phase of bipolar disorder and in lower levels during the depressive phase.[12] Behaviorally, increased dopamine transmission manifests as elevated mood, less need for sleep, and increased drive and overall excitability.[12] The dopamine precursor, L-dopa, can also give rise to symptoms commonly associated with the manic phase of bipolar disorder.[13]

Serotonin

In general, findings with regards to serotonin level differences in the depressive phase are more consistent than findings regarding serotonin levels in the manic phase.[14] Overall, there is a deficiency in serotonin transmission levels during depressive phases of bipolar disorder as well when the patient is in an euthymic (normal) state, indicating that lower serotonin receptor activity may be inherent in bipolar disorder.[14] However, a more recent study emphasizes that the abnormal serotonin transmission levels observed in euthymic states occurs only for patients with bipolar I disorder but not for those with bipolar II disorder.[15]

HPA Axis [25]
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The HPA axis responds to stress

Glutamate

Glutamate is another mood-elevating neurotransmitter that has been found in abnormally high amounts in the left dorsolateral prefrontal cortex, but only during the manic phase.[16] This result has led researchers to postulate that the glutamatergic system in the prefrontal cortex may play a key role during the manic episodes of bipolar disorder.[16]

Neuronal circuitry

Alterations and abnormalities in the functional aspects of the neurological system have been observed to play a role in mediating bipolar disorder. Through functional MRI studies, researchers have found evidence of abnormal signaling between ventral prefrontal and limbic regions, especially in the amygdala, which may be responsible at least in part for the mood swings that feature centrally as part of the symptoms of manic-depressive disorder.[17] Another neurological pathway associated with mood regulation that may play a role in implicating the disorder is abnormalities with the hypothalamic-pituitary-adrenal (HPA) axis, which is often associated with depression-like symptoms, especially in response to stress.[2] There is also strong evidence that bipolar disorder may be affected by disturbances in the circadian rhythm, because disturbances in the neuronal circuits involved in regulating the circadian rhythm often involve sleep disturbances, which is one of the symptoms associated with bipolar disorder.[18] Additionally, circadian rhythm alterations often affect mood, and mood changes are central to the polarized affective episodes observed in someone who is afflicted with bipolar disorder.[18]

Childhood trauma [26]
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Many individuals with bipolar disorder reported more
childhood trauma experiences compared to control sample

Environmental

Childhood trauma

Environmental factors may act in concert with genetic predispositions to affect one’s risk of developing bipolar disorder. Evidence supporting the notion that environmental influences play a role on the onset of bipolar disorder includes studies that have consistently shown that between 33%-50% of adults diagnosed with manic-depressive disorder report childhood trauma and abuse.[19] In addition, compared to the control group whose members are not afflicted with the disease, adult bipolar disorder patients report significantly more stressful childhood events.[20]

Life stressors

There is evidence indicating that a significant proportion of bipolar disorder arises as a result of interactions between genes which confer the risk and environmental stressors which trigger the onset.[21] Consistently, researchers have found that life events and stresses associated with supportive and non-supportive social interactions act as risk factors that may initiate the onset of bipolar disorder or exacerbate its symptoms.[22]

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