Caterina Chillotti

The International Consortium on Lithium Genetics (ConLiGen): An Initiative by the NIMH and IGSLI to Study the Genetic Basis of Response to Lithium Treatment

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.

Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

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.

Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder.

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.

Age at onset in Sardinian bipolar I patients: evidence for three subgroups

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.

Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients

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.

A48G polymorphism in the D1 receptor genes associated with bipolar I disorder

Several lines of evidence point to a role for dopamine in mood disorders and, in particular, in bipolar disorders. In line with a considerable amount of evidence, the dopamine D1 receptor gene (DRD1) is considered to be a good candidate gene for bipolar disorders. Several studies did not find any association between bipolar 1 patients and DRD1. In this study, we investigate a possible association between BP disorder and −48A/G polymorphism of the DRD1. We genotyped 107 bipolar 1 patients and 129 healthy control subjects of exclusively Sardinian descent. A statistically significant difference in genotype (χ2 = 6.29, df = 2, P = 0.042) and allele (χ2 = 5.46, df=1, P = 0.019; OR = 1.53, 95% CI = 1.08–2.16) frequencies was found, suggesting an association between the DRD1 gene and bipolar I disorder (BP I) in the Sardinian population.

Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in sardinia

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power.

Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts

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.

Association of personal and familial suicide risk with low serum cholesterol concentration in male lithium patients

Objective:  We sought to establish whether low cholesterol concentration may be associated with a personal history of attempted suicide or a family history of completed suicide in psychiatric out‐patients on maintenance lithium treatment, who represent a population at risk for suicide.

Interacting genes in lithium prophylaxis: preliminary results of an exploratory analysis on the role of DGKH and NR1D1 gene polymorphisms in 199 Sardinian bipolar patients.

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.