Maria Del Zompo

Realities and expectations of pharmacogenomics and personalized medicine: impact of translating genetic knowledge into clinical practice

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.

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.

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimers disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.

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.

Induction of fos-like-immunoreactivity in the central extended amygdala by antidepressant drugs

The induction of the early gene c‐fos was evaluated through Fos immunohistochemistry in areas belonging to the extended amygdala after acute administration of two antidepressants, citalopram and imipramine. Both citalopram and imipramine at the dose of 5 and 20 mg/kg, respectively, induced Fos‐like immunoreactivity (FLI) in the central amygdaloid nucleus, lateral division of the bed nucleus of the stria terminalis (BSTL), and interstitial nucleus of the posterior limb of the anterior commissure (IPAC). The shell of the nucleus accumbens, which forms a continuum with the central extended amygdala, showed a decrease of FLI after administration of either citalopram or imipramine. The mechanism of action and the brain areas affected by antidepressants are still a matter of debate. By showing that the central extended amygdala is a common site of action for two different antidepressant types, these results provide new insight into the mechanism of action of antidepressants. Synapse 31:1–4, 1999.

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.

A double-blind study of l-sulpiride versus amitriptyline in lithium-maintained bipolar depressives

A double‐blind group comparison study of L‐sulpiride and amitriptyline was carried out in 30 bipolar outpatients on maintenance treatment with lithium suffering from a major depressive recurrence. L‐sulpiride showed equivalent antidepressant activity to amitriptyline at 4 weeks using the Hamilton Rating Scale for Depression. However, the onset of action was faster in the L‐sulpiride group, showing a significant improvement at 1 week in both anxiety‐somatization and specific depression items, including depressed mood, feelings of guilt, work & activities and retardation. The incidence of anticholinergic side effects was significantly higher in the amitriptyline treatment group.

Catechol-O-Methyltransferase Val158Met Polymorphism in Schizophrenia: Associations with Cognitive and Motor Impairment

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val158Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val158Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.

COMT Val158Met and BDNF C270T polymorphisms in schizophrenia: a case-control study

Abstract In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol- O -methyl transferase (COMT) Val 158 Met and/or the brain-derived neurotrophic factor (BDNF) C 270 T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val 158 Met or BDNF C 270 T gene polymorphisms are associated with liability to schizophrenia.