Is Response to Prophylactic Lithium a Familial Trait?

Grof, Paul; Duffy, Anne; Cavazzoni, Patrizia; Grof, Eva; Garnham, Julie; MacDougall, Marsha; O′Donovan, Claire; Alda, Martin

doi:10.4088/jcp.v63n1013

Cited by 381 publications

(323 citation statements)

References 19 publications

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“…In addition, relatives with ADHD were at increased risk of BPD; this is consistent with other studies suggesting that comorbid BPD and ADHD is a familial phenotype (Faraone et al, 2003). In addition to age of onset, other phenotypic features of BPD that have been reported to aggegate in families include polarity of illness onset (mania vs. depression) (Kassem et al, 2006), mood episode frequency (Fisfalen et al, 2005), psychosis (Potash et al, 2003, Saunders et al, 2007 and lithium-responsiveness (Grof et al, 2002), suicidality (Saunders et al, 2007), rapid-cycling (Saunders et al, 2007), and comorbid alcohol use disorders and panic disorder (Saunders et al, 2007).The familial nature of BPD does not in itself establish that genes contribute since both genes and environmental factors could cause familial aggregation. Two methods which do allow genetic effects to be teased apart from environmental ones are adoption studies and twin studies.…”

supporting

confidence: 87%

Genetics of bipolar disorder

Smoller

Gardner-Schuster²

2007

Curr Psychiatry Rep

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Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) has raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.Bipolar disorder (BPD) is a common and serious mental disorder characterized by severe mood symptoms, including episodes of mania or hypomania and depression, occurring with a typically cyclical course. Lifetime risk for BPD has typically been reported to be approximately 1%, though recent estimates are as high as 4%. (Kessler et al., 2005). The personal and societal costs of BPD are enormous: even among adequately-treated individuals, relapse is common and the disorder can be profoundly disabling, resulting in serious economic burden (Kessler et al., 2006) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production pr...

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supporting

confidence: 87%

Genetics of bipolar disorder

Smoller

Gardner-Schuster²

2007

Curr Psychiatry Rep

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“…26,[122][123][124][125] Most family studies support the association of lithium response and family history of BD, 102,[126][127][128][129][130][131] and the response to lithium prophylaxis itself appears to have a familial component. 132 In studies of three independent populations, we found that lithium responders were a more homogeneous subgroup of BD, characterized by a stronger genetic loading for BD, and with a familial transmission compatible with a major-gene effect. 102,103,133,134 Similar support for a major-gene effect was found in other study of lithium responders 131 and in typical BD.…”

Section: Response To Long-term Treatmentmentioning

confidence: 78%

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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The search for susceptibility genes for bipolar disorder (BD) depends on appropriate definitions of the phenotype. In this paper, we review data on diagnosis and clinical features of BD that could be used in genetic studies to better characterize patients or to define homogeneous subgroups. Clinical symptoms, long-term course, comorbid conditions, and response to prophylactic treatment may define groups associated with more or less specific loci. One such group is characterized by symptoms of psychosis and linkage to 13q and 22q. A second group includes mainly bipolar II patients with comorbid panic disorder, rapid mood switching, and evidence of chromosome 18 linkage. A third group comprises typical BD with an episodic course and favourable response to lithium prophylaxis. Reproducibility of cognitive deficits across studies raises the possibility of using cognitive profiles as endophenotypes of BD, with deficits in verbal explicit memory and executive function commonly reported. Brain imaging provides a more ambiguous data set consistent with heterogeneity of the illness. Keywords: bipolar disorder; genetics; endophenotype; neurocognitive function; brain imaging Bipolar disorder (BD) has a genetic basis with heritability of at least 80%. 1 A number of studies have attempted to map the susceptibility loci giving evidence of linkage in multiple genomic regions. In particular, findings in 4p, 4q, 8q, 10p, 12q24, 13q, 18p, 18q, 21q, and 22q have been supported by more than one study. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, these studies have not identified any specific genes, and a recent metaanalysis of available genome scans showed no regions with a conclusive evidence of linkage. 20 The relatively slow progress of gene-mapping efforts is often explained by the 'complex' nature of the illness and of the genotype-phenotype relation. The complexity most likely includes heterogeneity, interactions of multiple loci, incomplete penetrance, as well as phenotypes resulting from environmental effects-either alone or in interaction with the genetic predisposition. The goal of psychiatric genetic research is identification of (heritable) variations in DNA sequence or function that influence behaviour or give rise to mental illness. By definition, in complex (multifactorial) traits, this link is not unique and specific. That is, a particular change in gene sequence does not necessarily lead to a specific behaviour, and similar behaviours (symptoms) may be due to distinct (sets of) genes. Moreover, we must consider the possibility that the path between the genotype and behaviour is not unidirectional. Emerging examples point not only to general effects of environment, for instance stress, on behaviour, but also to specific behaviours influencing gene function that can be transmitted onto the next generation. 21 No single method is considered clearly superior in identifying susceptibility genes for complex traits such as BD. Most researchers agree that a combination of strategies is most lik...

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“…Studies have found abnormal membrane phospholipid metabolism in first-degree relatives of patients with schizophrenia [80,81] suggesting heightened PLA 2 activity in relatives of schizophrenia. Response to lithium has been shown to follow familial patterns [82]. Given that lithium asserts its action on PLA 2 [83,84], this may suggest a possible relation between aberrant PLA 2 activity and bipolar relatives.…”

Section: Pla 2 Activity In Psychosesmentioning

confidence: 99%

Psychoses and creativity: is the missing link a biological mechanism related to phospholipids turnover?

Folley

Doop

Park

2003

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Recent evidence suggests that genetic and biochemical factors associated with psychoses may also provide an increased propensity to think creatively. The evolutionary theories linking brain growth and diet to the appearance of creative endeavors have been made recently, but they lack a direct link to research on the biological correlates of divergent and creative thought. Expanding upon Horrobin's theory that changes in brain size and in neural microconnectivity came about as a result of changes in dietary fat and phospholipid incorporation of highly unsaturated fatty acids, we propose a theory relating phospholipase A 2 (PLA 2 ) activity to the neuromodulatory effects of the noradrenergic system. This theory offers probable links between attention, divergent thinking, and arousal through a mechanism that emphasizes optimal individual functioning of the PLA 2 and NE systems as they interact with structural and biochemical states of the brain. We hope that this theory will stimulate new research in the neural basis of creativity and its connection to psychoses.

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Is Response to Prophylactic Lithium a Familial Trait?

Cited by 381 publications

References 19 publications

Genetics of bipolar disorder

Genetics of bipolar disorder

The phenotypes of bipolar disorder: relevance for genetic investigations

Psychoses and creativity: is the missing link a biological mechanism related to phospholipids turnover?

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