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Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study., Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling., Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders)., Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Background: The adverse renal effects of lithium have long been known, but glomerular insufficiency had been considered an unlikely event until recently, when new studies have raised concern regarding very long-term treatment. In this cross-sectional study, we examined glomerular function in a cohort of patients treated with lithium for up to 33 years and a control group of lithium-naïve patients treated with other mood-stabilizers., Methods: Patients with a diagnosis of recurrent or persistent affective disorders, examined between 1 October 2007 and 31 December 2009, were screened. Demographic and clinical data were extracted from clinical charts regarding two study groups: one for patients treated with lithium for at least 12 months and the other for patients never exposed to lithium. Multivariate regression analysis was applied: the dependent variable was the estimated glomerular filtration rate (eGFR) calculated from the last available serum creatinine value using the Modification of Diet in Renal Disease Study Group equation; the following independent variables, potentially associated with renal dysfunction, were included: gender, current age, duration of lithium treatment, cigarette smoking, hypertension, diabetes and dyslipidemia., Results: eGFRs lower than 60 ml/min were significantly more frequent in the group treated with lithium (38/139 = 27.3%) compared to lithium-naïve patients (4/70 = 5.7%) (P = 0.0002; Fisher's test). Regression analysis showed a significant effect on eGFR of age, gender and duration of lithium treatment but no effect of cigarette smoking, hypertension, diabetes or dyslipidemia. eGFR was estimated to decrease by 0.64 ml/min (95% confidence interval = 0.38 to 0.90; P = 0.00) for each year of lithium treatment., Conclusions: The duration of lithium treatment is a risk factor for glomerular failure, in addition to advancing age. For example, all patients aged 60 years or older may be estimated to undergo Stage 3 or more severe chronic kidney disease (namely an eGFR less than 60 ml/min) if treated with lithium for 30 years. These data may be added to the current debate on the balance between the protective effects of lithium on recurrent affective disorders and suicide and the risk of renal disease.See related commentary article here http://www.biomedcentral.com/1741-7015/11/34.

Aims: Bipolar disorder (BD) is a lifelong psychiatric illness characterized by manic and depressive episodes affecting 1-5% of the general population. Among mood-stabilizing treatments, lithium represents the mainstay in the therapeutic management of BD. However, besides the relatively high rate of excellent responders, a significant fraction of patients present patterns of partial or nonresponse to lithium. This variability might be influenced by genetic factors, even though findings have so far been inconclusive. Here, we present the results of an exploratory genome-wide scan followed by extended genotyping carried out on a sample of 204 Sardinian BD patients characterized for lithium response., Materials & Methods: Phenotypic assessment of lithium response was made using the retrospective criteria of long-term treatment response scale. Using Affymetrix(®) 6.0 SNP arrays, we genotyped a subsample of 52 BD patients evenly distributed at the extreme ends of the treatment response scale. The associated SNPs were then prioritized and selected for validation and extended genotyping in the whole sample of BD patients characterized for lithium response. Association was also tested using the scale for a quantitative trait analysis., Results: Our findings showed that several SNPs were nominally associated (p ≤ 10(-5)) with lithium response in the subgroup of 52 BD subjects. Some association signals were then confirmed in the extended sample. The strongest association, also supported by the quantitative trait analysis, was shown for a SNP located in intron 1 of the ACCN1 gene, encoding for a cation channel with high affinity for sodium and permeable to lithium., Conclusion: Our results indicate that ACCN1 gene is a potential candidate for response to lithium treatment that would serve as a genetic marker of lithium efficacy for BD patients.

The discovery of the genetic factors implicated in the predisposition to complex diseases may greatly profit from genetic studies in isolated populations. In this perspective, we performed a genome-wide scan using 507 microsatellite markers, with an average interval size of 7.6 cM, on a sample of 88 nuclear families with at least two affected sibs with bipolar disorder recruited in the Sardinian population. An initial analysis yielded non-parametric linkage exceeding 3.4 with P-values <0.0003 at two adjacent markers, D1S206 and D1S435 in the 1p22-p21 chromosomal region. Moreover, positive linkage ranging between 2.0 and 3.0 was obtained for other loci in several cases in regions that have already been linked to predisposition to bipolar disorder, such as 5p15.33, 8q24.13, and 11q14.3. A subsequent analysis of the 1p22-p21 region using the same set of families and a dense panel of 20 new microsatellite markers, spaced at 1.2 cM on average, reinforced the finding of suggestive linkage for this region. Interestingly, NPL values above 2.1 and P-values <0.02 were obtained for a cluster of 10 markers comprising D1S435. Thus, this study suggests that the 1p22-p21 region may contain a new locus participating to the genetic susceptibility to bipolar disorder and reproduces positive linkage for several other loci already implicated in this pathology. Since the Sardinian population presents a peculiar genetic homogeneity, these results may pave the way to further studies for replication in this population contributing to the rapid discovery of the genetic factors predisposing to bipolar disorder., ((c) 2010 Wiley-Liss, Inc.)

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts., (Copyright 2010 S. Karger AG, Basel.)

Lithium represents the first-choice and most effective drug in the treatment of bipolar disorder (BD). While its mechanism of action is far from being totally understood, a large amount of evidence pointed to a role of second messengers mediated pathways and elements of the circadian system in modulating its mood stabilizing effect. In the present paper, we tested the possible association and interaction effect of the nuclear receptor subfamily 1, group D, member 1 (NR1D1) gene and the Diacylglycerol kinase eta (DGKH) gene with the therapeutic response to lithium prophylaxis. Single nucleotide polymorphisms (SNPs) rs12941497 and rs939347 at NR1D1 gene and SNPs rs9315885, rs1012053 and rs1170191 at DGKH gene were genotyped in a sample of 199 Sardinian BD patients characterized for the response to lithium therapy. Genotype and allele frequency distributions did not differ significantly between groups of patients Full Responders and partial/not responders to lithium prophylaxis. Moreover, no significant differences were identified between groups of patients when divided considering the improvement in symptoms after lithium treatment. The interaction analysis did not show a significant effect on these outcomes. While negative, our findings do not exclude an involvement of DGKH and NR1D1 in lithium prophylaxis. Moreover, the lack of statistic interaction might not necessarily correspond to a lack of biologic interaction between the genes studied.

Polymorphisms within the DRD1, DRD2, DRD3, DAT1, 5-HTTLPR and HTR2A genes are being studied for association with lithium prophylaxis in a sample of 155 Sardinian unrelated probands affected by bipolar disorder (BP). No significant association was shown between the polymorphisms of the genes studied and response to lithium treatment.

Objective: The aim of our study was to investigate the association between REV-ERBalpha gene (NR1D1) single nucleotide polymorphisms (SNPs) and bipolar disorder (BP) in a case-control sample of Sardinian ancestry and evaluate its effect on age at onset (AAO) of BP., Methods: We genotyped SNPs rs12941497 (SNP1) and rs939347 (SNP2), located, respectively, in the first intron and in the 5'UTR region of the gene, in a sample comprised of 300 bipolar patients and 300 healthy controls of Sardinian ancestry. We also studied AAO by means of admixture analysis, obtaining a cutoff point of age 22 and then carrying out association analysis between the two AAO groups., Results: In the case-control comparison, single marker analysis showed no association for any of the SNPs tested. Haplotype analysis showed a nominally significant association for two haplotypes of SNPs 1-2. Comparing the early- and later-onset groups, nominal association was found for SNP1. Haplotype analysis showed that one haplotype was nominally associated with the later-onset group., Conclusions: Our results, indicating a nominal association of the REV-ERBalpha gene with BP, suggest a possible role of REV-ERBalpha in the pathogenesis of BP. Further investigation of larger independent samples and different populations is warranted.

Aim: Bipolar disorder (BP) is a mood disorder with a prevalence of 1-2% in the general population. Lithium is the most widely used and best characterized long-term treatment for BP. The aim of this study is the evaluation of the effectiveness of lithium treatment in a naturalistic setting. Moreover we investigated if a number of clinical markers were positively or negatively associated with treatment response., Methods: We evaluated 199 outpatients affected by BP (according to DSM-IV criteria), who had continuously received lithium for at least one year. Life course of illness in each patient was graphically depicted with the NIMH Life Chart method which allowed us to apply the Retrospective Evaluation of Prophylactic Treatment Response Scale in order to assess the treatment outcome. This scale rates the degree of improvement in the course of treatment weighted by the likelihood of response being attributable to the treatment, rather than other factors., Results: Full Responders to lithium were 29% of the sample. Bipolar II (BPII) patients were significantly overrepresented in the Full Responders group (p = 0.035). In addition, psychotic symptoms were significantly associated to a poorer treatment outcome (p = 0.0197)., Conclusions: This study supports the effectiveness of lithium treatment in a naturalistic setting, suggesting that BPII patients could also benefit from lithium treatment. Finally, it suggests that the use of another mood stabilizer or of a combination treatment could represent a valuable therapeutic choice in the management of bipolar patients with psychotic symptoms.

Objectives: PDLIM5 (ENH, LIM protein) [Postsynaptic Density-95/discs large/Zone occludens-1 (PDZ) and Lin-11, Isl-1, Mec-3 (LIM) domain 5;] is an adaptor protein that selectively binds protein kinase C-epsilon (PKC epsilon) to N-type Ca channels in brain neurons. As it has been suggested that alterations in protein kinase C activity might be involved in the pathophysiology of bipolar disorder (BD), PDLIM5 might play an important role in modulating susceptibility to the disease. Earlier investigations have reported altered expression of the PDLIM5 gene in postmortem brains and leukocytes of patients with BD. In a recent study, positive association for PDLIM5 single nucleotide polymorphisms (SNPs) was shown in a Japanese bipolar sample. The aim of our study was to investigate the association between PDLIM5 SNPs and BD in a case-control sample., Methods: We genotyped SNPs rs10008257 (SNP1), rs2433320 (SNP2) and rs2433322 (SNP3) located within the 5' region of the gene in a sample that comprises of 300 bipolar patients and 300 healthy controls of Sardinian ancestry., Results: In single-marker analysis, no association was found for any of the SNPs tested. After correction for multiple testing, haplotype analysis showed slight statistically significant association for a rare haplotype of SNPs 1 and 2. Although the findings presented in this paper do not provide strong evidence that the PDLIM5 gene significantly affects the pathophysiology of BD, they suggest that rare variants within the promoter region of the gene may have a marginal effect on the disorder. Further investigation on independent samples and different populations is warranted.

Objective: We studied age at onset (AAO) in order to assess the presence of different subgroups in a homogeneous genetic population, such as the Sardinian population., Methods: Admixture analysis was applied in order to identify a model of separate normal distribution of AAO characterized by different means, variances and population proportions to allow for evaluation of different subgroups in a sample of 181 unrelated patients of Sardinian origin with bipolar disorder (BP) type I. The Mann-Whitney test was used to compare the means of AAO between subjects with a history of suicide attempts and subjects with no such history., Results: The best-fitting model had three components with means (SD) of 18.1 (2.3), 24.3 (5.3) and 41 (11.5) years, comprising 36%, 39% and 25% of the sample, respectively. We obtained two cut-off points at 21 and 33 years, enabling the sample to be divided into three subgroups. The Mann-Whitney test revealed a difference between the mean AAO of subjects with a positive history of suicide attempts and that of subjects with no such history (p = 0.041)., Conclusions: We found three AAO sub-groups in our sample of BP I patients of Sardinian origin. Our findings add further support to the hypothesis whereby AAO acts as a clinical marker of biological heterogeneity in BP.

Objective: To report the case of a patient affected by gastrointestinal stromal tumors (GIST) who developed cutaneous adverse drug reactions during treatment with imatinib and lansoprazole., Case Summary: After 2 months of treatment with imatinib 400 mg/day, a 60-year-old white female affected by GIST developed bilateral palpebral edema with hyperemic conjunctivae and labial edema when lansoprazole 15 mg/day was introduced to treat dyspeptic symptomatology. Treatment was discontinued, and on reintroduction of both drugs, the patient developed Stevens-Johnson syndrome. Two months later, generalized cutaneous reactions appeared immediately following reintroduction of low-dose imatinib with corticosteroid plus lansoprazole treatment. After discontinuation of all drugs, with the exception of the corticosteroid, the progression of cutaneous lesions stopped., Discussion: The use of imatinib is commonly associated with a high dose-dependent rate of rash and edema. Several cases of Stevens-Johnson syndrome have also been described, although not in patients affected by GIST. Severe skin reactions have been reported for lansoprazole including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Applying Naranjo's algorithm, the adverse events were considered possible due to imatinib and probable due to lansoprazole., Conclusions: On the basis of the data reported, we conclude that the adverse reactions described may be attributed to either drug alone. However, combined use of drugs may increase the risk of onset of these adverse reactions due to a potential drug interaction involving CYP3A4.

Association studies with candidate genes may contribute towards the understanding of the etiopathogenesis of bipolar disorder. Candidate genes in bipolar disorders are those related to aminergic neurotransmission, which is the target of the effects of antipsychotics and antidepressants, as well as genes related to signal transduction pathways, reporting the target for the mood-stabilizing effects of lithium. Association with such candidate genes may provide clues towards the understanding of the biological components of bipolar disorder. An association study was performed between the 5' regulatory region of the serotonin transporter gene (5-HTTLPR), the inositol polyphosphate 1-phosphatase gene (INPP1) and bipolar disorder using our sample of proband/parent trios. A total of 101 bipolar probands were considered eligible for the study. Since both parents had to be available, mean age at onset of bipolar disorder in probands was relatively young. However, the mean duration of illness and the number of episodes were consistent with a stable diagnosis. In our trios sample, the transmission disequilibrium test revealed no preferential transmission of alleles of the 5-HTTLPR and INPP1 from heterozygous parents to probands. Therefore, additional family-based data are warranted, possibly with a more complete subdivision of 5-HTTLPR alleles, since short and long alleles have recently been divided into four and six kinds of allelic variant, respectively, with significant ethnic differences in allele and genotype distributions.

One hundred patients who had attempted suicide before commencing lithium prophylaxis were followed up. Outcome was analyzed in terms of attempted or completed suicide after a mean of 10 years since admission to the lithium clinics. Of 10 patients who committed suicide, 9 had discontinued adequate lithium prophylaxis for a period ranging from 2 weeks to 7 years before death. Having discontinued lithium therapy was associated with suicide also in the subgroup of patients for whom lithium had not completely prevented episodes during lithium treatment. Suicide risk was 24 times as high during periods off compared with periods on adequate lithium prophylaxis. Incidence of attempting suicide was similar during the periods before receiving or after discontinuing lithium treatment, whereas it was 5 to 6 times lower during prophylaxis. Continuous and adequate lithium prophylaxis should be considered in the presence of high suicide risk, even if the prophylactic effect on the underlying mood disorder may be incomplete.

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.