exerting a mild to moderate effect. the risk of bipolar disorder is nearly ten-fold higher in first-degree relatives of those with bipolar disorder than in the general population; similarly, the risk of major depressive disorder is three times higher in relatives of those with bipolar disorder than in the general population. although the first genetic linkage finding for mania was in 1969, linkage studies have been inconsistent. findings point strongly to heterogeneity, with different genes implicated in different families. robust and replicable genome-wide significant associations showed several common single-nucleotide polymorphisms (snps) are associated with bipolar disorder, including variants within the genes cacna1c, odz4, and ncan. the largest and most recent genome-wide association study failed to find any locus that exerts a large effect, reinforcing the idea that no single gene is responsible for bipolar disorder in most cases. polymorphisms in bdnf, drd4, dao, and tph1 have been frequently associated with bipolar disorder and were initially associated in a meta-analysis, but this association disappeared after correction for multiple testing. on the other hand, two polymorphisms in tph2 were identified as being associated with bipolar disorder. due to the inconsistent findings in a genome-wide association study, 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 corticotropin-releasing hormone 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. bipolar disorder is associated with reduced expression of specific dna repair enzymes and increased levels of oxidative dna damages. environmental psychosocial factors play a significant role in the development and course of bipolar disorder, and individual psychosocial variables may interact with genetic dispositions. recent life events and interpersonal relationships likely contribute to the onset and recurrence of bipolar mood episodes, just as they do for unipolar depression. in surveys, 30–50% of adults diagnosed with bipolar disorder report traumatic/abusive experiences in childhood, which is associated with earlier onset, a higher rate of suicide attempts, and more co-occurring disorders such as post-traumatic stress disorder. the number of reported stressful events in childhood is higher in those with an adult diagnosis of bipolar spectrum disorder than in those without, particularly events stemming from a harsh environment rather than from the child's own behavior. acutely, mania can be induced by sleep deprivation in around 30% of people with bipolar disorder. neurological less commonly, bipolar disorder or a bipolar-like disorder may occur as a result of or in association with a neurological condition or injury including stroke, traumatic brain injury, hiv infection, multiple sclerosis, porphyria, and rarely temporal lobe epilepsy. proposed mechanisms brain imaging studies have revealed differences in the volume of various brain regions between patients with bipolar disorder and healthy control subjects. the precise mechanisms that cause bipolar disorder are not well understood. bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions. a neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts. the ventral system (regulates emotional perception) includes brain structures such as the amygdala, insula, ventral striatum, ventral anterior cingulate cortex, and the prefrontal cortex. the dorsal system (responsible for emotional regulation) includes the hippocampus, dorsal anterior cingulate cortex, and other parts of the prefrontal cortex. the model hypothesizes that bipolar disorder may occur when the ventral system is overactivated and the dorsal system is underactivated. other models suggest the ability to regulate emotions is disrupted in people with bipolar disorder and that dysfunction of the ventricular prefrontal cortex is crucial to this disruption. meta-analyses of structural mri studies have shown that certain brain regions (e.g., the left rostral anterior cingulate cortex, fronto-insular cortex, ventral prefrontal cortex, and claustrum) are smaller in people with bipolar disorder, whereas other regions are larger (lateral ventricles, globus pallidus, subgenual anterior cingulate, and the amygdala). additionally, these meta-analyses found that people with bipolar disorder have higher rates of deep white matter hyperintensities. functional mri findings suggest that the ventricular prefrontal cortex regulates the limbic system, especially the amygdala. in people with bipolar disorder, decreased ventricular prefrontal cortex activity allows for the dysregulated activity of the amygdala, which likely contributes to labile mood and poor emotional regulation. consistent with this, pharmacological treatment of mania returns ventricular prefrontal cortex activity to the levels in non-manic people, suggesting that ventricular prefrontal cortex activity is an indicator of mood state. however, while pharmacological treatment of mania reduces amygdala hyperactivity, it remains more active than the amygdala of those without bipolar disorder, suggesting amygdala activity may be a marker of the disorder rather than the current mood state. manic and depressive episodes tend to be characterized by dysfunction in different regions of the ventricular prefrontal cortex. manic episodes appear to be associated with decreased activation of the right ventricular prefrontal cortex whereas depressive episodes are associated with decreased activation of the left ventricular prefrontal cortex. these disruptions often occur during development linked with synaptic pruning dysfunction. people with bipolar disorder who are in a euthymic mood state show decreased activity in the lingual gyrus compared to people without bipolar disorder. in contrast, they demonstrate decreased activity in the inferior frontal cortex during manic episodes compared to people without the disorder. similar studies examining the differences in brain activity between people with bipolar disorder and those without did not find a consistent area in the brain that was more or less active when comparing these two groups. people with bipolar have increased activation of left hemisphere ventral limbic areas—which mediate emotional experiences and generation of emotional responses—and decreased activation of right hemisphere cortical structures related to cognition—structures associated with the regulation of emotions. neuroscientists have proposed additional models to try to explain the cause of bipolar disorder. one proposed model for bipolar disorder suggests that hypersensitivity of reward circuits consisting of frontostriatal circuits causes mania, and decreased sensitivity of these circuits causes depression. according to the "kindling" hypothesis, when people who are genetically predisposed toward bipolar disorder experience stressful events, the stress threshold at which mood changes occur becomes progressively lower, until the episodes eventually start (and recur) spontaneously. there is evidence supporting an association between early-life stress and dysfunction of the hypothalamic-pituitary-adrenal axis leading to its overactivation, which may play a role in the pathogenesis of bipolar disorder. other brain components that have been proposed to play a role in bipolar disorder are the mitochondria and a sodium atpase pump. circadian rhythms and regulation of the hormone melatonin also seem to be altered. dopamine, a neurotransmitter responsible for mood cycling, has increased transmission during the manic phase. the dopamine hypothesis states that the increase in dopamine results in secondary homeostatic downregulation of key system elements and receptors such as lower sensitivity of dopaminergic receptors. this results in decreased dopamine transmission characteristic of the depressive phase. the depressive phase ends with homeostatic upregulation potentially restarting the cycle over again. glutamate is significantly increased within the left dorsolateral prefrontal cortex during the manic phase of bipolar disorder, and returns to normal levels once the phase is over. medications used to treat bipolar may exert their effect by modulating intracellular signaling, such as through depleting myo-inositol levels, inhibition of camp signaling, and through altering subunits of the dopamine-associated g-protein. consistent with this, elevated levels of gαi, gαs, and gαq/11 have been reported in brain and blood samples, along with increased protein kinase a (pka) expression and sensitivity; typically, pka activates as part of the intracellular signalling cascade downstream from the detachment of gαs subunit from the g protein complex. decreased levels of 5-hydroxyindoleacetic acid, a byproduct of serotonin, are present in the cerebrospinal fluid of persons with bipolar disorder during both the depressed and manic phases. increased dopaminergic activity has been hypothesized in manic states due to the ability of dopamine agonists to stimulate mania in people with bipolar disorder. decreased sensitivity of regulatory α2 adrenergic receptors as well as increased cell counts in the locus coeruleus indicated increased noradrenergic activity in manic people. low plasma gaba levels on both sides of the mood spectrum have been found. one review found no difference in monoamine levels, but found abnormal norepinephrine turnover in people with bipolar disorder. tyrosine depletion was found to reduce the effects of methamphetamine in people with bipolar disorder as well as symptoms of mania, implicating dopamine in mania. vmat2 binding was found to be increased in one study of people with bipolar mania. diagnosis bipolar disorder is commonly diagnosed during adolescence or early adulthood, but onset can occur throughout life. its diagnosis is based on the self-reported experiences of the individual, abnormal behavior reported by family members, friends or co-workers, observable signs of illness as assessed by a clinician, and ideally a medical work-up to rule out other causes. caregiver-scored rating scales, specifically from the mother, have shown to be more accurate than teacher and youth-scored reports in identifying youths with bipolar disorder. assessment is usually done on an outpatient basis; admission to an inpatient facility is considered if there is a risk to oneself or others. the most widely used criteria for diagnosing bipolar disorder are from the american psychiatric association's (apa) diagnostic and statistical manual of mental disorders, fifth edition (dsm-5) and the world health organization's (who) international statistical classification of diseases and related health problems, 10th edition (icd-10). the icd-10 criteria are used more often in clinical settings outside of the u.s. while the dsm criteria are used within the u.s. and are the prevailing criteria used internationally in research studies. the dsm-5, published in 2013, includes further and more accurate specifiers compared to its predecessor, the dsm-iv-tr. this work has influenced the upcoming eleventh revision of the icd, which includes the various diagnoses within the bipolar spectrum of the dsm-v. several rating scales for the screening and evaluation of bipolar disorder exist, including the bipolar spectrum diagnostic scale, mood disorder questionnaire, the general behavior inventory and the hypomania checklist. the use of evaluation scales cannot substitute a full clinical interview but they serve to systematize the recollection of symptoms. on the other hand, instruments for screening bipolar disorder tend to have lower sensitivity. differential diagnosis bipolar disorder is classified by the international classification of diseases as a mental and behavioural disorder. mental disorders that can have symptoms similar to those seen in bipolar disorder include schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (adhd), and certain personality disorders, such as borderline personality disorder. a key difference between bipolar disorder and borderline personality disorder is the nature of the mood swings; in contrast to the sustained changes to mood over days to weeks or longer, those of the latter condition (more accurately called emotional dysregulation) are sudden and often short-lived, and secondary to social stressors. although there are no biological tests that are diagnostic of bipolar disorder, blood tests and/or imaging are carried out to investigate whether medical illnesses with clinical presentations similar to that of bipolar disorder are present before making a definitive diagnosis. neurologic diseases such as multiple sclerosis, complex partial seizures, strokes, brain tumors, wilson's disease, traumatic brain injury, huntington's disease, and complex migraines can mimic features of bipolar disorder. an eeg may be used to exclude neurological disorders such as epilepsy, and a ct scan or mri of the head may be used to exclude brain lesions. additionally, disorders of the endocrine system such as hypothyroidism, hyperthyroidism, and cushing's disease are in the differential as is the connective tissue disease systemic lupus erythematosus. infectious causes of mania that may appear similar to bipolar mania include herpes encephalitis, hiv, influenza, or neurosyphilis. certain vitamin deficiencies such as pellagra (niacin deficiency), vitamin b12 deficiency, folate deficiency, and wernicke korsakoff syndrome (thiamine deficiency) can also lead to mania. common medications that can cause manic symptoms include antidepressants, prednisone, parkinson's disease medications, thyroid hormone, stimulants (including cocaine and methamphetamine), and certain antibiotics. bipolar spectrum since emil kraepelin's distinction between bipolar disorder and schizophrenia in the 19th century, researchers have defined a spectrum of