Claudia Pisanu

Pharmacogenomics of bipolar disorder

Bipolar disorder (BD) is a lifelong severe psychiatric condition with high morbidity, disability and excess mortality. The longitudinal clinical trajectory of BD is significantly modified by pharmacological treatment(s), both in acute and in long-term stages. However, a large proportion of BD patients have inadequate response to pharmacological treatments. Pharmacogenomic research may lead to the identification of molecular predictors of treatment response. When integrated with clinical information, pharmacogenomic findings may be used in the future to determine the probability of response/nonresponse to treatment on an individual basis. Here we present a selective review of pharmacogenomic findings in BD. In light of the evidence suggesting a genetic effect of lithium reponse in BD, we focused particularly on the pharmacogenomic literature relevant to this trait. The article contributes a detailed overview of the current status of pharmacogenomics in BD and offers a perspective on the challenges that can hinder its transition to personalized healthcare.

Assessment of the Pharmacogenomics Educational Environment in Southeast Europe

Background/Aims: Pharmacogenomics aims to use the information derived from an individuals genomic profile in the context of individualizing medical treatment modalities. However, currently, pharmacogenomics education is not uniformly provided to health care professionals. This study investigates the status of pharmacogenomics education in Southeast Europe. Methods: University websites served as information sources in order to investigate the discrepancies in pharmacogenomics education in Southeast Europe. In parallel, a survey was conducted at the University of Cagliari (Italy) to test pharmacogenomics knowledge and understanding among specialists, residents and undergraduate students. Results: Our study shows that pharmacogenomics knowledge is not uniformly spread in universities in Southeast Europe and provides the basis for the harmonization of pharmacogenomics education that would directly impact on a smoother integration of pharmacogenomics into mainstream medical practice. Also, a considerable gap in pharmacogenomics education was obvious between the group of specialists and the groups of residents and undergraduate students. Conclusions: Pharmacogenomics education as well as the continuous enrichment of pharmacogenomics knowledge for health care professionals are fundamental approaches toward personalized medicine. Ideally, pharmacogenomics should be taught as a stand-alone course or at least in the context of genetics courses that already exist in universities in Southeast Europe.

Leukocyte telomere length positively correlates with duration of lithium treatment in bipolar disorder patients.

Bipolar disorder (BD) has been suggested to be associated with accelerated aging and premature cell senescence. While findings on shorter telomeres in BD are controversial, a recent study showed that long-term lithium treatment correlates with longer telomeres in BD. In our study, we sought to investigate the correlation between leukocyte telomere length (LTL) and long-term lithium treatment in a sample of 200 BD patients characterized for lithium response. We also compared data from two different methods commonly used to measure telomere length, quantitative PCR (qPCR) and quantitative fluorescence in situ hybridization (Q-FISH). We also measured, for the first time, the effect of lithium in vitro on the expression of the telomerase gene in human-derived neural progenitor cells (NPCs). Our findings showed that LTL correlated negatively with age (p=0.0002) and was independent of sex, diagnosis, age at onset, suicidal behavior, number of mood episodes, response to lithium and use of other psychotropic medications. After correcting for age, LTL was positively correlated with lithium treatment duration in patients treated for more than two years (n=150, R=0.17, p=0.037). There was a significant correlation between data measured with qPCR and Q-FISH (p=0.012, R=0.826). Lithium treatment increased telomerase expression in NPCs, though this effect was not statistically significant. Our data support previous findings showing that long-term lithium treatment associates with longer telomeres in BD, though this effect appeared to be independent from clinical response to the treatment. Moreover, we suggested for the first time that lithium increases the expression of telomerase gene in human neural progenitor cells.

Preliminary Transcriptome Analysis in Lymphoblasts from Cluster Headache and Bipolar Disorder Patients Implicates Dysregulation of Circadian and Serotonergic Genes

Bipolar disorder (BD) and cluster headache (CH) are distinct conditions with important similarities such as a temporal pattern of disturbances, dysregulation of the sleep–wake cycle, and response to lithium treatment in a proportion of patients. Aiming to identify common transcription signatures in these two disorders, we carried out an exploratory microarray gene expression analysis in lymphoblasts from 8 CH and 10 BD I patients selected for positive response to lithium and 10 healthy controls (CO). Gene expression levels of BD and CH were compared with CO to create two lists of differentially expressed genes. We then matched the two lists and focus on genes showing statistically significant difference and same change direction in both disorders. RNA binding motif protein 3 (RBM3) was the most significantly altered gene in the list (3.17 × 10−13 in BD, 9.44 × 10−14 in CH). Pathway analysis identified protein processing in endoplasmic reticulum as the most significantly enriched. For validation with quantitative reverse transcription PCR (qRT-PCR) using the same samples, we selected seven genes. Among these, we were able to validate the RBM3, nuclear receptor subfamily 1, group D, member 1 (NR1D1), and tryptophan hydroxylase 1 (TPH1). These genes encode for elements involved in circadian rhythm regulation (RBM3 and NR1D1) and in serotonin synthesis (TPH1), processes previously involved in both disorders, and in the mechanism of action of lithium.

Sex differences in substance use disorders: focus on side effects

Although sex differences in several aspects of substance use disorders (SUDs) have been identified, less is known about the importance of possible sex differences in side effects induced by substances of abuse or by medications used to treat SUDs. In the SUD field, the perception of certain subjective effects are actively sought, while all other manifestations might operationally be considered side effects. This article was aimed at reviewing sex differences in side effects induced by alcohol, nicotine, heroin, marijuana and cocaine and by medications approved for alcohol, nicotine and heroin use disorders. A large body of evidence suggests that women are at higher risk of alcohol‐induced injury, liver disease, cardiomyopathy, myopathy, brain damages and mortality. The risk of tobacco‐induced coronary heart disease, lung disease and health problems is higher for women than for men. Women also experience greater exposure to side effects induced by heroin, marijuana and cocaine. In addition, women appear to be more vulnerable to the side effects induced by medications used to treat SUDs. Patients with SUDs should be advised that the risk of developing health problems may be higher for women than for men after consumption of the same amount of substances of abuse. Doses of medications for SUD women should be adjusted at least according to body weight. The sex differences observed also indicate an urgent need to recruit adequate numbers of female subjects in pre‐clinical and clinical studies to improve our knowledge about SUDs in women.

Telomere length in bipolar disorder and lithium response

Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are thought to be the consequence of allostatic load, consisting in the overactivation of allostatic systems due to chronic exposure to severe medical conditions and failure to adapt to chronic stressful stimuli. Most of the studies on telomere length in psychiatry have focused on major depressive disorder, but recent findings have shown shorter leukocyte telomere length in bipolar disorder patients and suggested that lithium may counteract telomeres shortening. These findings provided new insights into the pathophysiology of bipolar disorder and the mechanism of action of lithium. In this review we will present findings from the literature on telomere length in bipolar disorder, with a specific focus on lithium. We will also discuss advances and limitations of published work as well as methodological issues and potential confounding factors that should be taken into account when designing research protocols to study telomere length.

Understanding the molecular mechanisms underlying mood stabilizer treatments in bipolar disorder: Potential involvement of epigenetics.

Mood stabilizers are a category of medications used in the management of mood disorders. The mood stabilizing properties of lithium were first reported in 1949 by John Cade, and since then it has been considered the first line treatment for bipolar disorder. Despite presenting more differences than similarities, mood stabilizers are all characterized by high variability in response in treated patients. This feature has stimulated a vast body of research on potential predictive markers of clinical response, with promising but often inconclusive findings. Pharmacogenetics of mood stabilizers has provided valuable hints toward the involvement of genes and pathways in modulating response. However, with the exception of lithium, the number of studies is still too sparse to draw definite conclusions. Moreover, the mechanism of action of these drugs has yet to be completely elucidated. A growing body of research has explored the effect of mood stabilizers on a family of molecular players responsible for the regulation of gene expression without interfering with the DNA sequence. These processes belong to the epigenetic machinery and represent the mechanisms through which our biological systems interact with environmental factors, including drug treatments. In this review we focused on findings from preclinical and clinical studies suggesting that mood stabilizers may interfere with epigenetic mechanisms, providing an intriguing perspective that may help us filling the gap between molecular functions and clinical efficacy of mood stabilizers.

High leptin levels are associated with migraine with aura

Background Migraine is a prevalent disorder characterised by recurrent headache attacks preceded or accompanied by aura in a subgroup of patients. Migraine often occurs together with major depressive disorder (MDD). Alterations of adipokine levels have been reported both in migraine and in MDD. In this cross-sectional study, we aimed to assess the associations between serum leptin and adiponectin levels and migraine or migraine subtypes. Analyses were adjusted for a lifetime history of MDD in order to investigate the association between adipokines and migraine under consideration of depression status. Methods We included 3025 participants from the CoLaus/PsyCoLaus study. The impact of leptin and adiponectin levels on a diagnosis of migraine was analysed by binary regression analyses, adjusting for variables known to influence adipokine levels. Subgroup analyses were conducted based on the presence of aura. Results Crude leptin levels were significantly higher in subjects with migraine than controls (Mann–Whitney U = 515,102, p = 6 × 10−7). When performing adjusted analyses, leptin levels were found to be significantly higher in subjects with migraine (odds ratio = 1.22, p = 0.024) and migraine with aura (odds ratio = 1.34, p = 0.004). Conclusion High leptin levels might play a role in the pathogenesis of migraine and migraine with aura.

Lithium Pharmacogenetics: Where Do We Stand?

Preclinical Research

HDAC3 role in medication consumption in medication overuse headache patients: a pilot study

BackgroundMedication overuse headache (MOH) is a common and debilitating disorder characterized by generation, perpetuation, and persistence of intense chronic migraine, caused by overuse of analgesics, triptans, or other acute headache compounds. It has been suggested that MOH could share some pathogenetic mechanisms with other kinds of drug addiction. In this regard, histone deacetylases 3 (HDAC3) seems to have a role in the memory processes involved in extinction of drug-seeking behavior in animal models. HDAC3 is inhibited by sodium valproate, a drug with proven efficacy in MOH. Recent evidence suggests an involvement of genetic factors in predisposition to medication overuse.ResultsIn this association study, we sequenced all exons, intron/exon junctions, and 3′-5′UTR regions of HDAC3 in 23 MOH patients to investigate its role in medication overuse. Associations between genotypes with continuous and dichotomous clinical characteristics were tested by multivariate analysis and Fisher’s exact test, respectively.Sequencing of HDAC3 revealed six single-nucleotide polymorphisms. The G allele of rs2530223 was significantly associated with the number of acute medications/month used and with the number of days/month in which medications were used (p = 0.006 and p = 0.007, respectively), but neither with headache frequency or intensity. None of the single-nucleotide polymorphisms (SNPs) was associated with clinical characteristics or response to sodium valproate.ConclusionsHDAC3 could be implicated in excessive medication consumption in MOH patients. Our preliminary findings provide support for the need of further investigation on larger independent samples to confirm and extend the role of HDAC3 in medication overuse headache.