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Biomedical subjects

J Licinio

Publications and source records attributed to J Licinio.

At least 19 recordsLinked to original sources
PubMed2006

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene-environment interactions.

Obesity and depression are serious public health problems and also constitute cardiovascular disease risk factors. Research organizations have called for efforts to explore the interrelationship between obesity and depression. A useful starting point is the fact that in both disorders there is dysregulation of stress systems. We review molecular and clinical evidence indicating that the mediators of the stress response are a key locus for gene-environment interactions in the shared biology of depression and obesity. Scientific milestones include translational paradigms such as mice knockouts, imaging and pharmacogenomic approaches that can identify new therapeutic strategies for those burdened by these two afflictions of contemporary civilization. Perspectives for the future are promising. Our ability to dissect the underpinnings of common and complex diseases with shared substrates will be greatly enhanced by the Genes and Environment Initiative, the emerging Large Scale Studies of Genes and Environment in Common Disease, and the UK Biobank Project.

Adaptation, Physiological↗
PubMed2006

150 years of Sigmund Freud: What would Freud have said about the obesity epidemic?

The 150th birthday of Sigmund Freud has triggered widespread interest and media coverage on his unique contribution and impact on society. Recent evidence from neuroscience and advanced imaging technology has provided support for some of his major concepts including the unconscious and the key role of early life events. In this perspective, we attempt to write on his behalf an updated version of a Freudian way of thinking focused on the current high rates of obesity and depression.

Depression↗
PubMed2005

The evolution of signaling complexity suggests a mechanism for reducing the genomic search space in human association studies.

The size complexity of the human genome has been traditionally viewed as an obstacle that frustrates efforts aimed at identifying the genetic correlates of complex human phenotypes. As such complex phenotypes are attributed to the combined action of numerous genomic loci, attempts to identify the underlying multi-locus interactions may produce a combinatorial sum of false positives that drown out the real signal. Faced with such grim prospects for successfully identifying the genetic basis of complex phenotypes, many geneticists simply disregard epistatic interactions altogether. However, the emerging picture from systems biology is that the cellular programs encoded by the genome utilize nested signaling hierarchies to integrate a number of loosely coupled, semiautonomous, and functionally distinct genetic networks. The current view of these modules is that connections encoding inter-module signaling are relatively sparse, while the gene-to-gene (protein-to-protein) interactions within a particular module are typically denser. We believe that each of these modules is encoded by a finite set of discontinuous, sequence-specific, genomic intervals that are functionally linked to association rules, which correlate directly to features in the environment. Furthermore, because these environmental association rules have evolved incrementally over time, we explore theoretical models of cellular evolution to better understand the role of evolution in genomic complexity. Specifically, we present a conceptual framework for (1) reducing genomic complexity by partitioning the genome into subsets composed of functionally distinct genetic modules and (2) improving the selection of coding region SNPs, which results in an increased probability of identifying functionally relevant SNPs. Additionally, we introduce the notion of 'genomic closure,' which provides a quantitative measure of how functionally insulated a specific genetic module might be from the influence of the rest of the genome. We suggest that the development and use of theoretical models can provide insight into the nature of biological systems and may lead to significant improvements in computational algorithms designed to reduce the complexity of the human genome.

Epistasis, Genetic↗
PubMed2005

The experience of bipolar disorder: a personal perspective on the impact of mood disorder symptoms.

This is a personal perspective on bipolar disorder, entirely written by a well-informed patient who is a successful mental heath professional. The patient prefers to remain anonymous; therefore, I am listed here as the contact person to whom queries to the author can be referred. We believe that her insights are particularly important for those working in the field. As we investigate the molecular substrates of psychiatric disorders, it is crucial to keep in mind the clinical entities that are addressed in our research. The patient's words provide a deep understanding of real suffering that is overcome by effective treatment in the context of a highly supportive social structure. In her own words, 'I was terrified that I could feel so wrecked inside, terrified that something was horribly wrong with me and terrified that I didn't know how to tell anyone that I was slipping into a dark place. My struggle with bipolar disorder forced me to leave an Ivy League university and endure six hospitalizations during my early adulthood. After countless medication trials, I was successful on clozapine and graduated from college and then graduate school. My medications remind me each day of my struggle with mental illness but also of my recovery. I am relishing my life as a happily married woman, a beloved daughter and sister, and as a psychologist.' One important item illustrated in this narrative is that clinical symptoms can be worsened by some treatments and positively affected by others. While some in the field erroneously believe that better treatment approaches depend exclusively on new drugs, this perspective shows how important it is to optimize the use of existing compounds. For some diseases like acute lymphoblastic leukemia (ALL) of childhood, rates of remission and cure have been constantly advancing through better use of existing compounds. In the last 20 years, without the advent of new drugs for that disease, new protocols for ALL have solely optimized the use of existing drugs. It is likewise crucial to advance the optimization of psychiatric treatments by identifying predictors of treatment response, possibly by pharmacogenomic approaches, which have the potential to individualize the use of existing treatments. This could rapidly decrease the enormous burden of psychiatric disorders, which is eloquently described in this perspective article.

Adult↗
PubMed2005

Pharmacogenomics education: International Society of Pharmacogenomics recommendations for medical, pharmaceutical, and health schools deans of education.

Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a 'Pharmacogenomics Education Forum' was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of 'Background Statement' and 'Recommendations and Call for Action' addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.

Curriculum↗
PubMed2004

St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response.

Both the prototypic tricyclic antidepressant imipramine (IMI) and the herbal product St John's wort (SJW) can be effective in the treatment of major depressive disorder. We studied hypothalamic gene expression in rats treated with SJW or IMI to test the hypothesis that chronic antidepressant treatment by various classes of drugs results in shared patterns of gene expression that may underlie their therapeutic effects. Individual hypothalami were hybridized to individual Affymetrix chips; we studied three arrays per group treatment. We constructed 95% confidence intervals for expression fold change for genes present in at least one treatment condition and we considered genes to be differentially expressed if they had a confidence interval excluding 1 (or -1) and had absolute difference in expression value of 10 or greater. SJW treatment differentially regulated 66 genes and expression sequence tags (ESTs) and IMI treatment differentially regulated 74 genes and ESTs. We found six common transcripts in response to both treatments. The likelihood of this occurring by chance is 1.14 x 10(-23). These transcripts are relevant to two molecular machines, namely the ribosomes and microtubules, and one cellular organelle, the mitochondria. Both treatments also affected different genes that are part of the same cell function processes, such as glycolytic pathways and synaptic function. We identified single-nucleotide polymorphisms in the human orthologs of genes regulated both treatments, as those genes may be novel candidates for pharmacogenetic studies. Our data support the hypothesis that chronic antidepressant treatment by drugs of various classes may result in a common, final pathway of changes in gene expression in a discrete brain region.

Antidepressive Agents↗
PubMed2004

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.

Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases (1970-2003) on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

Alleles↗
PubMed2004

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans.

There are well-replicated, independent lines of evidence supporting a role for corticotropin-releasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n=54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.1+/-4.5 vs 37.1+/-6.9%, respectively, P=0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.3+/-4.3 vs 51.2+/-6.0%, respectively, P=0.03). In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb.org.

Adult↗