Lithium response and genetics of affective disorders

Grof, Paul; Alda, Martin; Gror, Eva; Zvolský, P; Walsh, Mary Louise

doi:10.1016/0165-0327(94)90066-3

Cited by 146 publications

(109 citation statements)

References 22 publications

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“…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. 135 Nonaffective psychiatric disorders among relatives of lithium responders are uncommon.…”

Section: Response To Long-term Treatmentsupporting

confidence: 85%

“…In family studies of lithium-responsive probands, we found little evidence of linkage to chromosome 18 markers, 100,101 which is consistent with the observation of very low rates of comorbid conditions and mood lability among responders to lithium. 102 Such traits, on the other hand, are common among responders to the anticonvulsant lamotrigine. 103 Substance abuse also occurs at high rates in BD.…”

Section: Psychiatric Comorbiditymentioning

confidence: 99%

“…Their clinical features correspond to the BD 'core phenotype', with an episodic course of the illness, low rates of comorbid conditions, and absence of rapid cycling. 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.…”

Section: Response To Long-term Treatmentmentioning

confidence: 99%

“…135 Nonaffective psychiatric disorders among relatives of lithium responders are uncommon. [101][102][103] Treatment outcome findings in BD also define lithium responders as a distinct, more uniform subgroup. Responders to lithium differ from responders to other mood stabilizers and the treatment response appears to be specific; 103,[136][137][138][139] the antimanic responses to valproate and lithium are present in different patient groups.…”

Section: Response To Long-term Treatmentmentioning

confidence: 99%

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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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Section: Response To Long-term Treatmentsupporting

confidence: 85%

Section: Psychiatric Comorbiditymentioning

confidence: 99%

Section: Response To Long-term Treatmentmentioning

confidence: 99%

Section: Response To Long-term Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

The phenotypes of bipolar disorder: relevance for genetic investigations

2005

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“…Clinical predictors account for less than half of the variance, [1][2][3][4][5][6][7][8] and there are evidences suggesting that genetic factors play a substantial role in lithium prophylaxis effectiveness. [9][10][11][12][13][14][15][16][17][18][19][20] A large number of studies reported an association between prophylactic lithium response and a family history of bipolar disorder, 10,[12][13][14]17 although not unequivocally confirmed. [21][22][23][24][25] Recently, Grof et al 26 reported that lithium response in a sample of relatives of responder probands was 67% compared to 30% in the comparison group.…”

Section: Introductionmentioning

confidence: 99%

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

et al. 2004

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We previously reported an association between the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR) and the prophylactic efficacy of lithium in a sample of 201 Italian subjects affected by Mood disorders. The aim of the present study was to replicate analyses on an independent sample. In total, 83 subjects affected by Bipolar disorder were recruited in the Mood Disorders Clinic of the Eginition Hospital of the Athens University, Medical School Department of Psychiatry. All patients were administered with lithium as prophylactic therapy and they were prospectively observed for at least 3 years. Subjects were typed for their SERTPR variant using polymerase chain reaction techniques. SERTPR variants were associated with lithium outcome among those subjects who had few manic episodes before lithium treatment and, as a trend, among subjects who received a high daily dose of lithium (X1200 mg/die). In both cases, subjects with the l/l variant showed a higher probability to develop an illness episode within 3 years of prophylactic treatment with lithium. The present study confirmed our previous observation of a better response of SERTPR*l/s carriers, but could not confirm a poor efficacy in subjects with the SERTPR*s/s genotype. Notwithstanding the conflicting results, SERTPR variants are a possible liability factor for lithium long-term efficacy in mood disorders. Further studies on independent and large samples are required to determine the reliability and direction of the possible association between SERTPR variants and lithium outcome. INTRODUCTIONLithium is an effective prophylactic agent in mood disorders but not all patients equally respond to lithium therapy. Clinical predictors account for less than half of the variance, 1-8 and there are evidences suggesting that genetic factors play a substantial role in lithium prophylaxis effectiveness. [9][10][11][12][13][14][15][16][17][18][19][20] A large number of studies reported an association between prophylactic lithium response and a family history of bipolar disorder, 10,[12][13][14]17 although not unequivocally confirmed. [21][22][23][24][25] Recently, Grof et al 26 reported that lithium response in a sample of relatives of responder probands was 67% compared to 30% in the comparison group.

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