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==Overview==
==Overview==
According to the U.S. government's [[National Institute of Mental Health]] (NIMH), "There is no single cause for bipolar disorder—rather, many factors act together to produce the illness." "Because bipolar disorder tends to run in families, researchers have been searching for specific [[gene]]s passed down through generations that may increase a person's chance of developing the illness." "In addition, findings from gene research suggest that bipolar disorder, like other mental illnesses, does not occur because of a single gene.".<ref>{{cite web |url=http://www.nimh.nih.gov/publicat/bipolar.cfm#bp5 |title=What Causes Bipolar Disorder? |accessdate= |format= |work= |author=NIMH}}</ref> Psychological factors also play a strong role in the psychopathology of the disease, and the development of mania may depend on the occurrence of strssful life events, and the individuals ability to handle stress.
According to the U.S. government's [[National Institute of Mental Health]] (NIMH), "There is no single cause for bipolar disorder—rather, many factors act together to produce the illness." "Because bipolar disorder tends to run in families, researchers have been searching for specific [[gene]]s passed down through generations that may increase a person's chance of developing the illness." "In addition, findings from gene research suggest that bipolar disorder, like other mental illnesses, does not occur because of a single gene.".<ref>{{cite web |url=http://www.nimh.nih.gov/publicat/bipolar.cfm#bp5 |title=What Causes Bipolar Disorder? |accessdate= |format= |work= |author=NIMH}}</ref> Psychological factors also play a strong role in the psychopathology of the disease, and the development of mania may depend on the occurrence of stressful life events, and the individuals ability to handle stress.


==Causes==
==Causes==


It is well established that bipolar disorder is a genetically influenced condition which can respond very well to medication (Johnson & Leahy, 2004; Miklowitz & Goldstein, 1997; Frank, 2005).  
* Abnormalities in brain function have been related to feelings of [[anxiety]] and lower stress resilience. When faced with a very stressful, negative major life event, such as a failure in an important area, an individual may have his first major depression. Conversely, when an individual accomplishes a major achievement he may experience his first [[hypomanic]] or [[manic]] episode. Individuals with bipolar disorder tend to experience episode triggers involving either [[interpersonal]] or achievement-related life events. An example of interpersonal-life events include [[falling in love]] or, conversely, the death of a close friend. Achievement-related life events include acceptance into an elite graduate school or by contrast, being fired from work (Miklowitz & Goldstein, 1997). [[Childbirth]] can also trigger a postpartum psychosis for bipolar women, which can lead in the worse cases to infanticide.
(See [[treatment of bipolar disorder]] for a more detailed discussion of treatment.)


Psychological factors also play a strong role in both the [[psychopathology]] of the disorder and the [[psychotherapeutic]] factors aimed at alleviating core symptoms, recognizing episode triggers, reducing negative expressed emotion in relationships, recognizing [[prodromal]] symptoms before full-blown recurrence, and, practising the factors that lead to maintenance of [[remission (medicine)|remission]] (Lam et al, 1999; Johnson & Leahy, 2004; Basco & Rush, 2005; Miklowitz & Goldstein, 1997; Frank, 2005). Modern [[evidence based medicine|evidence based]] psychotherapies designed specifically for bipolar disorder when used in combination with standard medication treatment increase the time the individual stays well significantly longer than medications alone (Frank, 2005). These psychotherapies are [[interpersonal and social rhythm therapy]] for bipolar disorder, family focused therapy for bipolar disorder, psychoeducation, [[cognitive therapy]] for bipolar disorder, and [[prodrome]] detection. All except psychoeducation and prodrome detection are available as books.
* The "kindling" theory<ref name="kindling">[http://www.bpinfo.net/kindling_theory.htm Link and reference involving kindling theory]</ref> asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events, each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and becomes recurrent) by itself. Not all individuals experience subsequent mood episodes in the absence of positive or negative life events, however.  
Abnormalities in brain function have been related to feelings of [[anxiety]] and lower stress resilience. When faced with a very stressful, negative major life event, such as a failure in an important area, an individual may have his first major depression. Conversely, when an individual accomplishes a major achievement he may experience his first [[hypomanic]] or [[manic]] episode. Individuals with bipolar disorder tend to experience episode triggers involving either [[interpersonal]] or achievement-related life events. An example of interpersonal-life events include [[falling in love]] or, conversely, the death of a close friend. Achievement-related life events include acceptance into an elite graduate school or by contrast, being fired from work (Miklowitz & Goldstein, 1997). [[Childbirth]] can also trigger a postpartum psychosis for bipolar women, which can lead in the worse cases to infanticide.


The "kindling" theory<ref name=kindling>[http://www.bpinfo.net/kindling_theory.htm Link and reference involving kindling theory]</ref> asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events, each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and becomes recurrent) by itself. Not all individuals experience subsequent mood episodes in the absence of positive or negative life events, however.
=== Psychosocial factors ===


Individuals with late-[[adolescent]]/early [[adult]] onset of the disorder will very likely have experienced [[childhood]] anxiety and depression. Some argue that childhood-onset bipolar disorder should be treated early.
* paternal age increase the risk of bipolar disorder in one’s offspring that could be due to increased genetic mutations during spermatogenesis.  As an example, a national registry study found that the risk of bipolar disorder in offspring of fathers 45 years and older was six times greater.<ref name="pmid24499422">{{cite journal| author=Chudal R, Gissler M, Sucksdorff D, Lehti V, Suominen A, Hinkka-Yli-Salomäki S | display-authors=etal| title=Parental age and the risk of bipolar disorders. | journal=Bipolar Disord | year= 2014 | volume= 16 | issue= 6 | pages= 624-32 | pmid=24499422 | doi=10.1111/bdi.12182 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24499422  }}</ref>


A [[family history (medicine)|family history]] of [[bipolar spectrum]] disorders can impart a genetic predisposition towards developing a bipolar spectrum disorder.<ref name=Genetic_Likelihood>[http://www.psycheducation.org/depression/risk.htm Genetics and Risk] PsychEducation.org</ref> Since bipolar disorders are [[polygenic]] (involving many genes), there are apt to be many unipolar and bipolar disordered individuals in the same family pedigree. This is very often the case (Barondes, 1998). [[Anxiety disorders]], clinical depression, [[eating disorders]], [[premenstrual dysphoric disorder]], [[postpartum depression]], postpartum psychosis and/or [[schizophrenia]] may be part of the patient's family history and reflects a term called "genetic loading."
* Stressful life events may be associated with onset of bipolar disorder and a more severe course of illness. It is more common among individuals who reported a history of childhood physical abuse.<ref name="pmid22806701">{{cite journal| author=Sugaya L, Hasin DS, Olfson M, Lin KH, Grant BF, Blanco C| title=Child physical abuse and adult mental health: a national study. | journal=J Trauma Stress | year= 2012 | volume= 25 | issue= 4 | pages= 384-92 | pmid=22806701 | doi=10.1002/jts.21719 | pmc=3805363 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22806701  }}</ref><ref name="pmid25597794">{{cite journal| author=Janiri D, Sani G, Danese E, Simonetti A, Ambrosi E, Angeletti G | display-authors=etal| title=Childhood traumatic experiences of patients with bipolar disorder type I and type II. | journal=J Affect Disord | year= 2015 | volume= 175 | issue=  | pages= 92-7 | pmid=25597794 | doi=10.1016/j.jad.2014.12.055 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25597794  }}</ref>


Bipolar disorder is not either environmental or physiological, it is multifactorial; that is, many genes and [[environmental factors]] conspire to create the disorder (Johnson & Leahy, 2004). Since bipolar disorder is so [[heterogeneous]], it is likely that people experience different pathways towards the illness (Miklowitz & Goldstein, 1997). Recent research done in Japan indicates a hypothesis of dysfunctional mitochondria in the brain (Stork & Renshaw, 2005)''
<br />
===Heritability or inheritance===


 
* The disorder runs in families.<ref>
 
===Heritability or inheritance===
The disorder runs in families.<ref>
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</ref> More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.
</ref> More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.
* Genes that are involved in bipolar disorder have been studied, but no single gene has been identified.<ref name="pmid23663951">{{cite journal| author=Craddock N, Sklar P| title=Genetics of bipolar disorder. | journal=Lancet | year= 2013 | volume= 381 | issue= 9878 | pages= 1654-62 | pmid=23663951 | doi=10.1016/S0140-6736(13)60855-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23663951  }}</ref> it may involve many genes with small effects.<ref name="pmid16603476">{{cite journal| author=Finn CT, Smoller JW| title=Genetic counseling in psychiatry. | journal=Harv Rev Psychiatry | year= 2006 | volume= 14 | issue= 2 | pages= 109-21 | pmid=16603476 | doi=10.1080/10673220600655723 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16603476  }}</ref>
* Studies have found that several genetic variants are associated with bipolar disorder. One possible locus is CACNA1C, which codes for a calcium channel that is involved in channel gating.<ref name="pmid236639512">Craddock N, Sklar P (2013) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=23663951 Genetics of bipolar disorder.] ''Lancet'' 381 (9878):1654-62. [http://dx.doi.org/10.1016/S0140-6736(13)60855-7 DOI:10.1016/S0140-6736(13)60855-7] PMID: [https://pubmed.gov/23663951 23663951]</ref><ref name="pmid18711365">{{cite journal| author=Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L | display-authors=etal| title=Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. | journal=Nat Genet | year= 2008 | volume= 40 | issue= 9 | pages= 1056-8 | pmid=18711365 | doi=10.1038/ng.209 | pmc=2703780 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18711365  }}</ref>
* A meta-analysis of genetic studies of bipolar disorder suggests that other biologic pathways are cardiac β-adrenergic signaling, cardiac hypertrophy signaling, corticotropin releasing hormone signaling, endothelin 1 signaling, glutamate signaling, and phospholipase C signaling.<ref name="pmid24718920">{{cite journal| author=Nurnberger JI, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I | display-authors=etal| title=Identification of pathways for bipolar disorder: a meta-analysis. | journal=JAMA Psychiatry | year= 2014 | volume= 71 | issue= 6 | pages= 657-64 | pmid=24718920 | doi=10.1001/jamapsychiatry.2014.176 | pmc=4523227 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24718920  }}</ref>
* In addition, a meta-analysis of genome-wide association studies identified three single-nucleotide polymorphisms on chromosomes 3 and 10. One of the polymorphisms was located on a brain expressed gene that encodes calcium channel subunits; calcium signaling regulates neuronal growth and development.<ref name="pmid23453886">{{cite journal| author=Serretti A, Fabbri C| title=Shared genetics among major psychiatric disorders. | journal=Lancet | year= 2013 | volume= 381 | issue= 9875 | pages= 1339-1341 | pmid=23453886 | doi=10.1016/S0140-6736(13)60223-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23453886  }}</ref><ref name="pmid23453885">{{cite journal| author=Cross-Disorder Group of the Psychiatric Genomics Consortium| title=Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. | journal=Lancet | year= 2013 | volume= 381 | issue= 9875 | pages= 1371-1379 | pmid=23453885 | doi=10.1016/S0140-6736(12)62129-1 | pmc=3714010 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23453885  }}</ref>
=== Inflammation ===


Studies seeking to identify the genetic basis of bipolar disorder indicate that susceptibility stems from multiple genes. Scientists are continuing their search for these genes, using advanced genetic analytic methods and large samples of families affected by the illness. The researchers are hopeful that identification of susceptibility genes for bipolar disorder, and the brain proteins they code for, will make it possible to develop better treatments and preventive interventions targeted at the underlying illness process.
* Bipolar disorder is associated with immune system dysregulation. Separate meta-analyses have each found that cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) and cytokine receptors are elevated in patients with bipolar disorder<ref name="pmid23419545">{{cite journal| author=Modabbernia A, Taslimi S, Brietzke E, Ashrafi M| title=Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. | journal=Biol Psychiatry | year= 2013 | volume= 74 | issue= 1 | pages= 15-25 | pmid=23419545 | doi=10.1016/j.biopsych.2013.01.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419545  }}</ref>
* A meta-analysis of 11 studies found that levels of C reactive protein were higher in patients than controls, and the difference was small to moderate.<ref name="pmid25742201">{{cite journal| author=Dargél AA, Godin O, Kapczinski F, Kupfer DJ, Leboyer M| title=C-reactive protein alterations in bipolar disorder: a meta-analysis. | journal=J Clin Psychiatry | year= 2015 | volume= 76 | issue= 2 | pages= 142-50 | pmid=25742201 | doi=10.4088/JCP.14r09007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25742201  }}</ref>


==References==
==References==

Revision as of 11:09, 23 July 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

According to the U.S. government's National Institute of Mental Health (NIMH), "There is no single cause for bipolar disorder—rather, many factors act together to produce the illness." "Because bipolar disorder tends to run in families, researchers have been searching for specific genes passed down through generations that may increase a person's chance of developing the illness." "In addition, findings from gene research suggest that bipolar disorder, like other mental illnesses, does not occur because of a single gene.".[1] Psychological factors also play a strong role in the psychopathology of the disease, and the development of mania may depend on the occurrence of stressful life events, and the individuals ability to handle stress.

Causes

  • Abnormalities in brain function have been related to feelings of anxiety and lower stress resilience. When faced with a very stressful, negative major life event, such as a failure in an important area, an individual may have his first major depression. Conversely, when an individual accomplishes a major achievement he may experience his first hypomanic or manic episode. Individuals with bipolar disorder tend to experience episode triggers involving either interpersonal or achievement-related life events. An example of interpersonal-life events include falling in love or, conversely, the death of a close friend. Achievement-related life events include acceptance into an elite graduate school or by contrast, being fired from work (Miklowitz & Goldstein, 1997). Childbirth can also trigger a postpartum psychosis for bipolar women, which can lead in the worse cases to infanticide.
  • The "kindling" theory[2] asserts that people who are genetically predisposed toward bipolar disorder can experience a series of stressful events, each of which lowers the threshold at which mood changes occur. Eventually, a mood episode can start (and becomes recurrent) by itself. Not all individuals experience subsequent mood episodes in the absence of positive or negative life events, however.

Psychosocial factors

  • paternal age increase the risk of bipolar disorder in one’s offspring that could be due to increased genetic mutations during spermatogenesis. As an example, a national registry study found that the risk of bipolar disorder in offspring of fathers 45 years and older was six times greater.[3]
  • Stressful life events may be associated with onset of bipolar disorder and a more severe course of illness. It is more common among individuals who reported a history of childhood physical abuse.[4][5]


Heritability or inheritance

  • The disorder runs in families.[6] More than two-thirds of people with bipolar disorder have at least one close relative with the disorder or with unipolar major depression.
  • Genes that are involved in bipolar disorder have been studied, but no single gene has been identified.[7] it may involve many genes with small effects.[8]
  • Studies have found that several genetic variants are associated with bipolar disorder. One possible locus is CACNA1C, which codes for a calcium channel that is involved in channel gating.[9][10]
  • A meta-analysis of genetic studies of bipolar disorder suggests that other biologic pathways are cardiac β-adrenergic signaling, cardiac hypertrophy signaling, corticotropin releasing hormone signaling, endothelin 1 signaling, glutamate signaling, and phospholipase C signaling.[11]
  • In addition, a meta-analysis of genome-wide association studies identified three single-nucleotide polymorphisms on chromosomes 3 and 10. One of the polymorphisms was located on a brain expressed gene that encodes calcium channel subunits; calcium signaling regulates neuronal growth and development.[12][13]

Inflammation

  • Bipolar disorder is associated with immune system dysregulation. Separate meta-analyses have each found that cytokines (eg, interleukin-4 and tumor necrosis factor-alpha) and cytokine receptors are elevated in patients with bipolar disorder[14]
  • A meta-analysis of 11 studies found that levels of C reactive protein were higher in patients than controls, and the difference was small to moderate.[15]

References

  1. NIMH. "What Causes Bipolar Disorder?".
  2. Link and reference involving kindling theory
  3. Chudal R, Gissler M, Sucksdorff D, Lehti V, Suominen A, Hinkka-Yli-Salomäki S; et al. (2014). "Parental age and the risk of bipolar disorders". Bipolar Disord. 16 (6): 624–32. doi:10.1111/bdi.12182. PMID 24499422.
  4. Sugaya L, Hasin DS, Olfson M, Lin KH, Grant BF, Blanco C (2012). "Child physical abuse and adult mental health: a national study". J Trauma Stress. 25 (4): 384–92. doi:10.1002/jts.21719. PMC 3805363. PMID 22806701.
  5. Janiri D, Sani G, Danese E, Simonetti A, Ambrosi E, Angeletti G; et al. (2015). "Childhood traumatic experiences of patients with bipolar disorder type I and type II". J Affect Disord. 175: 92–7. doi:10.1016/j.jad.2014.12.055. PMID 25597794.
  6. McGuffin, P; Rijsdijk, F; Andrew, M; Sham, P; Katz, R; Cardno, A (2003), "The Heritability of Bipolar Affective Disorder and the Genetic Relationship to Unipolar Depression", Archives of General Psychiatry, 60 (5): 497–502
  7. Craddock N, Sklar P (2013). "Genetics of bipolar disorder". Lancet. 381 (9878): 1654–62. doi:10.1016/S0140-6736(13)60855-7. PMID 23663951.
  8. Finn CT, Smoller JW (2006). "Genetic counseling in psychiatry". Harv Rev Psychiatry. 14 (2): 109–21. doi:10.1080/10673220600655723. PMID 16603476.
  9. Craddock N, Sklar P (2013) Genetics of bipolar disorder. Lancet 381 (9878):1654-62. DOI:10.1016/S0140-6736(13)60855-7 PMID: 23663951
  10. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L; et al. (2008). "Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder". Nat Genet. 40 (9): 1056–8. doi:10.1038/ng.209. PMC 2703780. PMID 18711365.
  11. Nurnberger JI, Koller DL, Jung J, Edenberg HJ, Foroud T, Guella I; et al. (2014). "Identification of pathways for bipolar disorder: a meta-analysis". JAMA Psychiatry. 71 (6): 657–64. doi:10.1001/jamapsychiatry.2014.176. PMC 4523227. PMID 24718920.
  12. Serretti A, Fabbri C (2013). "Shared genetics among major psychiatric disorders". Lancet. 381 (9875): 1339–1341. doi:10.1016/S0140-6736(13)60223-8. PMID 23453886.
  13. Cross-Disorder Group of the Psychiatric Genomics Consortium (2013). "Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis". Lancet. 381 (9875): 1371–1379. doi:10.1016/S0140-6736(12)62129-1. PMC 3714010. PMID 23453885.
  14. Modabbernia A, Taslimi S, Brietzke E, Ashrafi M (2013). "Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies". Biol Psychiatry. 74 (1): 15–25. doi:10.1016/j.biopsych.2013.01.007. PMID 23419545.
  15. Dargél AA, Godin O, Kapczinski F, Kupfer DJ, Leboyer M (2015). "C-reactive protein alterations in bipolar disorder: a meta-analysis". J Clin Psychiatry. 76 (2): 142–50. doi:10.4088/JCP.14r09007. PMID 25742201.

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