Bipolar disorder is a mood disorder characterized by alternating periods of manic (elevated) and depressed mood. While there is some evidence of psychosocial causes and mechanisms of bipolar disorder, there is also ongoing research into the biological parts of its origins. Although no single gene has been identified as the cause, numerous genes are associated with an increased risk of developing the disorder. Gene-environment interactions are also believed to play a role in predisposing individuals to bipolar disorder.Neuroimaging and postmortem studies have identified abnormalities in several brain regions, with the ventral prefrontal cortex and amygdala being most frequently implicated. Dysfunction within the emotional circuits of these regions has been hypothesized as a potential mechanism underlying bipolar disorder. In contrast, some studies have shown increased activation of the anterior prefrontal cortex (aPFC) in patients versus controls, a region associated with executive functioning and attention control. Additionally, evidence points to abnormalities in neurotransmission, intracellular signaling, and cellular functioning as contributing factors.
Research into bipolar disorder, particularly neuroimaging studies, faces challenges such as confounding effects of medication, comorbid conditions, and small sample sizes, which may result in underpowered studies and significant heterogeneity in findings. Further research is needed to consolidate neuroimaging findings, which are often heterogeneous and not consistently reported according to a common standard.
Etiology Genetic
The aetiology of bipolar disorder is unknown. The overall heritability of bipolar is estimated at 79%-93%, and first-degree relatives of bipolar probands have a relative risk of developing bipolar disorder of around 7–10. While the heritability is very high, no specific genes have been conclusively associated with bipolar disorder, and a number of hypotheses have been posited to explain this fact. "The polygenic common rare variant" hypothesis suggests that a large number of risk-conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The "multiple rare variant" model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease. The familial transmission of mania and depression are largely independent of each other. This raises the possibility that bipolar is actually two biologically distinct but highly comorbid conditions.
A number of genome wide associations have been reported, including CACNA1C and ODZ4, and TRANK1. Less consistently reported loci include ANK3 and NCAN, ITIH1, ITIH3 and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa.
In light of associations between bipolar and circadian abnormalities (such as decreased need for sleep and increased sleep latency), polymorphisms in the CLOCK gene have been tested for association, although findings have been inconsistent, and one meta analysis has reported no association with either bipolar or major depressive disorder. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL, RORB, and DEC1. One meta analysis reported a significant association of the short allele of the serotonin transporter, although the study was specific to European populations. Two polymorphisms in the tryptophan hydroxylase 2 gene have been associated with bipolar disorder. NFIA has been linked with seasonal patterns of mania.
One particular SNP located on CACNA1C that confers risk for bipolar disorder is also associated with elevated CACNA1C mRNA expression in the prefrontal cortex, and increased calcium channel expression in neurons made from patient induced pluripotent stem cells.
No significant association exists for the BDNF Val66Met allele and bipolar disorder, except possibly in a subgroup of bipolar II cases, and suicide.
Due to the inconsistent findings in GWAS, multiple studies have undertaken the approach of analyzing SNPs in biological pathways. Signaling pathways traditionally associated with bipolar disorder that have been supported by these studies include CRH signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, cardiac hypertrophy signaling, Wnt signaling, notch signaling, and endothelin 1 signaling. Of the 16 genes identified in these pathways, three were found to be dysregulated in the dorsolateral prefrontal cortex portion of the brain in post-mortem studies, CACNA1C, GNG2, and ITPR2.
Advanced paternal age has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new genetic mutations.
A meta-analysis was performed to determine the association between bipolar disorder and oxidative DNA damage measured by 8-hydroxy-2'-8-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG). Levels of 8-OHdG and 8-oxodG are widely used as measures of oxidative stress in mental illnesses. It was determined from this meta-analysis that oxidative DNA damage was significantly increased in bipolar disorder.
Environmental Manic episodes can be produced by sleep deprivation in around 30% of people with bipolar. While not all people with bipolar demonstrate seasonality of affective symptoms, it is a consistently reported feature that supports theories of circadian dysfunction in bipolars.
Risk factors for bipolar include obstetric complications, abuse, drug use, and major life stressors.
The "kindling model" of mood disorders suggests that major environmental stressors trigger initial mood episodes, but as mood episodes occur, weaker and weaker triggers can precipitate an affective episode. This model was initially created for epilepsy, to explain why weaker and weaker electrical stimulation was necessary to elicit a seizure as the disease progressed. While parallels have been drawn between bipolar disorder and epilepsy, supporting the kindling hypothesis, this model is generally not supported by studies directly assessing it in bipolar subjects.
Neurological disorders Mania occurs secondary to neurological conditions between a rate of 2% to 30%. Mania is most commonly seen in right sided lesions, lesions that disconnect the prefrontal cortex, or excitatory lesions in the left hemisphere.
Diseases associated with "secondary mania" include Cushing's disease, dementia, delirium, meningitis, hyperparathyroidism, hypoparathyroidism, thyrotoxicosis, multiple sclerosis, Huntington's disease, epilepsy, neurosyphillis, HIV dementia, uremia, as well as traumatic brain injury and vitamin B12 deficiency.
Pathophysiology Neurobiological and neuroanatomical models The main loci of neuroimaging and neuropathological findings in bipolar have been proposed to constitute dysfunction in a "visceromotor" network, composed of the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), hippocampus, amygdala, hypothalamus, striatum and thalamus.
A model of functional neuroanatomy produced by a workgroup led by Stephen M. Strakowski concluded that bipolar was characterized by reduced connectivity, due to abnormal pruning or development, in the prefrontal-striatal-pallidal-thalamic-limbic network leading to dysregulated emotional responses. This model was supported by a number of common neuroimaging findings. Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. While amygdala hyperactivity is not a uniform finding, a number of methodological challenges could explain discrepancies. As most studies utilize fMRI to measure blood-oxygen-level dependent signal, excess baseline activity could result in null findings due to subtraction analysis. Furthermore, heterogenous study design could mask consistent hyperactivity to specific stimuli. Regardless of directionality of amygdala abnormalities, as the amygdala plays a central role in emotional systems, these findings support dysfunctional emotional circuits in bipolar. A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. The dorsal ACC is commonly under-activated in bipolar, and is generally implicated in cognitive functions, while the ventral ACC is hyperactive and implicated in emotional functions. Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder. Strakowski, along with DelBello and Adler have put forward a model of "anterior limbic" dysfunction in bipolar disorder in a number of papers.
Green et al. 2007 suggested a model of bipolar disorder based on the convergence of cognitive and emotional processing on certain structures. For example, the dACC and sgACC were cognitively associated with impairment of inhibition of emotional responses and self monitoring, which could translate to emotional stimuli having excessive impact on mood. Deficits in working memory associated with abnormal dlPFC function could also translate to impaired ability to represent emotional stimuli, and therefore the impaired ability to reappraise emotional stimuli. Dysfunction in the amygdala and striatum has been associated with attentional biases, and may represent a bottom up mechanism of dysfunctional emotional processing.
Blond et al. proposed a model centered on dysfunction in an "amygdala-anterior paralimbic" system. This model was based on the consistent functional and structural abnormalities in the ventral prefrontal cortex and amygdala. The model also proposes a developmental component of bipolar disorder, wherein limbic abnormalities are present early on, but rostral prefrontal abnormalities develop later in the course. The importance of limbic dysfunction early in development is highlighted by the observation that amygdala lesions early in adulthood produce emotional abnormalities that are not present in people who develop amygdala damage in adulthood.
Lateralized seizure sequelae similar to bipolar has been reported in people with mesial temporal lobe seizures, and provides support for kindling hypotheses about bipolar. This observation led to the first experiments with anticonvulsants in bipolar, which are effective in stabilizing mood. Studies reporting reduced markers of inhibitory interneurons post-mortem link the analogy with epilepsy to a possible reduction in inhibitory activity in emotional circuits. Overlap with epilepsy extends to include abnormalities in intracellular signaling, biochemistry in the hippocampus and prefrontal cortex, and structure and function of the amygdala.