Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy

Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Journal of Psychopharmacology (Impact Factor: 3.59). 09/2011; 26(3):368-73. DOI: 10.1177/0269881111415736
Source: PubMed


A number of candidate genes for lithium prophylactic efficacy have been proposed, some of them being also associated with a predisposition to bipolar illness. The aim of the present study was to investigate a possible association between polymorphisms of 14 common genes with the quality of prophylactic lithium response in patients with bipolar mood disorder, in relation to the putative role of these genes in the pathogenesis of this disorder. Some association with lithium prophylactic efficacy was found for the polymorphisms of 5HTT, DRD1, COMT, BDNF and FYN genes, but not for 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GSK-3, NTRK2, GRIN2B and MMP-9. Possible aspects of these genes with regard to the mechanism of lithium activity and pathogenesis of bipolar mood disorder are discussed.

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    • "A paradigm of " excellent lithium responders " (ELR) has been used in molecular-genetic, cognitive and neurobiological studies, performed by our research group in recent years. A number of polymorphisms of common genes was shown to differentiate ELR from lithium partial-or non-responders (Rybakowski et al. 2012). In other studies, we have demonstrated that the preservation, or even improvement , of cognitive functions may be connected with a quality lithium prophylaxis. "
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    ABSTRACT: Objectives. The aim of the study was to assess neurobiological and temperamental correlates in offspring of lithium-treated patients, related to parental lithium response. Methods. The study comprised 27 female and 23 male subjects, aged 17-54 years, the offspring of 36 bipolar patients receiving lithium for 5-38 years. Thirteen subjects were offspring of excellent lithium responders (ELR), 25 of partial lithium responders and 12 of lithium non-responders. In all subjects, serum brain-derived neurotrophic factor (BDNF), matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were measured, and the subjects were assessed by the Temperament Scale of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) and the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE) scale. Results. In offspring of the ELR, the percentage of persons treated for mood disorder was higher (46 vs. 16%), and higher mean BDNF and MMP-9 levels and lower IL-6 levels were found, compared with the remaining subjects. There were also differences between the ELR and the remaining patients on the TEMPS-A and O-LIFE scale, and within the ELR, between subjects treated for mood disorders and the healthy ones. Conclusions. The offspring of ELR show distinct neurobiological and temperamental profiles compared to other lithium-treated patients.
    Full-text · Article · May 2014 · The World Journal of Biological Psychiatry
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    • "In addition, the G allele is more common in persons with bipolar disorder [80], [81], and has also been implicated in traits such as compulsive eating, shopping, and gambling [82]–each of which is linked to increased brain dopaminergic tone [83]. The GG genotype is associated with an increased susceptibility for antipsychotic-induced tardive dyskinesia [84] along with treatment resistance in schizophrenia [85] and bipolar disorder [86]. For these reasons, presence of the G allele was classified as having increased dopamine neurotransmission (score = 1); A/A, score = 0. "
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    ABSTRACT: Dopamine is important to learning and plasticity. Dopaminergic drugs are the focus of many therapies targeting the motor system, where high inter-individual differences in response are common. The current study examined the hypothesis that genetic variation in the dopamine system is associated with significant differences in motor learning, brain plasticity, and the effects of the dopamine precursor L-Dopa. Skilled motor learning and motor cortex plasticity were assessed using a randomized, double-blind, placebo-controlled, crossover design in 50 healthy adults during two study weeks, one with placebo and one with L-Dopa. The influence of five polymorphisms with established effects on dopamine neurotransmission was summed using a gene score, with higher scores corresponding to higher dopaminergic neurotransmission. Secondary hypotheses examined each polymorphism individually. While training on placebo, higher gene scores were associated with greater motor learning (p = .03). The effect of L-Dopa on learning varied with the gene score (gene score*drug interaction, p = .008): participants with lower gene scores, and thus lower endogenous dopaminergic neurotransmission, showed the largest learning improvement with L-Dopa relative to placebo (p<.0001), while L-Dopa had a detrimental effect in participants with higher gene scores (p = .01). Motor cortex plasticity, assessed via transcranial magnetic stimulation (TMS), also showed a gene score*drug interaction (p = .02). Individually, DRD2/ANKK1 genotype was significantly associated with motor learning (p = .02) and its modulation by L-Dopa (p<.0001), but not with any TMS measures. However, none of the individual polymorphisms explained the full constellation of findings associated with the gene score. These results suggest that genetic variation in the dopamine system influences learning and its modulation by L-Dopa. A polygene score explains differences in L-Dopa effects on learning and plasticity most robustly, thus identifying distinct biological phenotypes with respect to L-Dopa effects on learning and plasticity. These findings may have clinical applications in post-stroke rehabilitation or the treatment of Parkinson's disease.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "In our recent study [78] we investigated an association between the polymorphism of 14 common genes with the quality of prophylactic lithium response, in relation to the putative role of these genes in the pathogenesis of bipolar disorder and found some association with five of them; namely, 5-HTT, DRD1, COMT, BDNF and FYN. "
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    ABSTRACT: Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0-10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.
    Full-text · Article · Feb 2013 · CNS Drugs
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