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Bipolar disorder (BD) is a chronic and often severe psychiatric illness characterized by manic and depressive episodes. Among the most effective treatments, mood stabilizers represent the keystone in acute mania, depression, and maintenance treatment of BD. However, treatment response is a highly heterogeneous trait, thus emphasizing the need for a structured informational framework of phenotypic and genetic predictors. In this paper, we present the current state of pharmacogenomic research on long-term treatment in BD, specifically focusing on mood stabilizers. While the results provided so far support the key role of genetic factors in modulating the response phenotype, strong evidence for genetic predictors is still lacking. In order to facilitate implementation of pharmacogenomics into clinical settings (i.e., the creation of personalized therapy), further research efforts are needed.

The implementation of genetic data for a better prediction of response to medications and adverse drug reactions is becoming a reality in some clinical fields. However, to be successful, personalized medicine should take advantage of an informational structured framework of genetic, phenotypic and environmental factors in order to provide the healthcare system with useful tools that can optimize the effectiveness of specific treatment. The impact of personalized medicine is potentially enormous, but the results that have so far been gathered are often difficult to translate into clinical practice. In this article we have summarized the most relevant applications of pharmacogenomics on diseases to which they have already been applied and fields in which they are currently emerging. The article provides an overview of the opportunities and shortcomings of the implementation of genetic information into personalized medicine and its full adoption in the clinic. In the second instance, it provides readers from different fields of expertise with an accessible interpretation to the barriers and opportunities in the use/adoption of pharmacogenomic testing between the different clinical areas.

Adults with ADHD smoke cigarettes at a higher rate than normal subjects. Nicotine has been shown to significantly improve clinical ADHD symptoms as measured by the Clinical Global Impression scale (CGI) as well as by measures of attention, vigour and arousal in ADHD subjects. In this study we hypothesized that the allele 113bp in D15S1360 marker at CHRNA7 and the 2 bp deletion allele at CHRFAM7A are associated with increased smoking in a sample of 90 DSM-IV patients affected by Adult ADHD. Temperament and Character Inventory (TCI) scores were included as covariates in the analysis to distinguish the contribution of personality traits from the contribution of the nicotinic genes under investigation. Smoking status was determined from the medical history questionnaire, and there were 35 current smokers and 55 non-smokers. Single marker associations and the CHRNA7-CHRFAM7A interaction were calculated by logistic regression, considering the 113 bp and the -2 bp deletion in a dominant model. No association of these genes with smoking was observed. Similarly, no significant interaction between the genes was observed in the logistic model. However, Persistence score of the TCI was significantly associated with smoking status. Further investigation on the hypothesis of the molecular interaction between CHRNA7 and CHRFAM7A genes is warranted.

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.

To assess the possibility of an association between TNF gene polymorphisms and migraine without aura, a case-control study was performed in a Sardinian sample. Migraine without aura is a complex genetic disease in which susceptibility and environmental factors contribute towards its development. Several studies suggest that tumour necrosis factors (TNF) (TNF-alpha and lymphotoxin-alpha or TNF-ss) may be involved in the pathophysiology of migraine. The TNF-alpha and TNF-ss genes are located on chromosome 6p21.3 in the human leukocyte antigene (HLA) class III region. We evaluated 299 patients affected by migraine without aura (I.H.S. criteria 2004) and 278 migraine-free controls. The polymorphisms G308A of the TNF- alpha gene, and G252A of TNF-beta gene were determined by NcoI restriction fragment length polymorphism analysis. We found a statistically significant difference in allele (p = 0.018; OR = 1.46 95 % CI: 1.066 to 2.023) and genotype (trend chi2 = 5.46, df = 1, p = 0.019) frequencies of TNF-beta gene, between cases and controls. Allele and genotype frequencies of TNF-alpha polymorphism did not differ significantly between the two groups. These data suggest that subjects with the TNFB2 allele have a low risk of developing migraine without aura and/or that the polymorphism of the TNF-beta gene is in linkage disequilibrium with other migraine responsible genes in the HLA region.

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.

A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score