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Biomedical subjects

Julio Licinio

Publications and source records attributed to Julio Licinio.

At least 19 recordsLinked to original sources
PubMed2006

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.

Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are down-regulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)/cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Modeling of the temporal patterns of fluoxetine prescriptions and suicide rates in the United States.

BACKGROUND: To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960-2002. METHODS AND FINDINGS: Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (r(s) = -0.92; p < 0.001). Mathematical modeling of what suicide rates would have been during the 1988-2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400-45,000). CONCLUSIONS: The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988-2002.

Antidepressive Agents, Second-Generation↗
PubMed2006

Relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function.

OBJECTIVES: We sought to evaluate effects of obesity, insulin resistance, and inflammation on coronary circulatory function and its relationship to leptin plasma levels. BACKGROUND: It is not known whether obesity, commonly paralleled by insulin resistance, inflammation, and leptin, is independently associated with coronary circulatory dysfunction. METHODS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and pharmacologic vasodilation was measured with positron emission tomography and 13N-ammonia. Study participants were divided into three groups based on their body mass index (BMI, kg/m2): control, 20 < or = BMI <25 (n = 19); overweight, 25 < or = BMI <30 (n = 21); and obese, BMI >30 (n = 32). RESULTS: Body mass index was significantly correlated to the Homeostasis Model Assessment Index of insulin resistance and C-reactive protein levels (r = 0.60 and r = 0.47, p < 0.0001). Compared with control subjects, endothelium-related change in MBF (DeltaMBF) to CPT progressively declined in overweight and obese groups (0.32 +/- 0.09 vs. 0.21 +/- 0.19 and 0.07 +/- 0.16 ml/g/min; p < 0.03 and p < 0.0001). The dipyridamole-induced total vasodilator capacity was significantly lower in obese than in control subjects (1.77 +/- 0.51 vs. 2.04 +/- 0.37 ml/g/min, p < 0.02). On multivariate analysis, BMI (p < 0.012) and age (p < 0.035) were significant independent predictors of DeltaMBF. Finally, only in the obese group leptin plasma levels significantly correlated with DeltaMBF (r = 0.37, p < 0.036). CONCLUSIONS: Increased body weight is independently associated with abnormal coronary circulatory function that progresses from an impairment in endothelium-related coronary vasomotion in overweight individuals to an impairment of the total vasodilator capacity in obese individuals. The findings that elevated leptin plasma levels in patients that are obese might exert beneficial effects on the coronary endothelium to counterbalance the adverse effects of increases in body weight on coronary circulatory function should be tested.

Adult↗
PubMed2005

Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia.

The mortality of chronic heart failure (CHF) doubles either when CHF patients are depressed or when their plasma norepinephrine (NE) level exceeds those of controls by approximately 40%. We hypothesized that patients with major depression had centrally driven, sustained, stress-related, and treatment-reversible increases in plasma NE capable of increasing mortality in CHF patients with depression. We studied 23 controls and 22 medication-free patients with melancholic depression. In severely depressed patients before and after electroconvulsive therapy (ECT), we measured cerebrospinal fluid (CSF) NE, plasma NE, plasma epinephrine (EPI), and plasma cortisol hourly for 30 h. In mildly-to-moderately depressed melancholic patients, we assessed basal and stress-mediated arterial NE appearance. Severely depressed patients had significant increases in mean around-the-clock levels of CSF NE (P < 0.02), plasma NE (P < 0.02), plasma EPI (P < 0.02), and plasma cortisol (P < 0.02). CSF NE, plasma NE, and cortisol all rose together throughout the night and peaked in the morning. Each fell to control values after ECT. Mildly-to-moderately melancholic patients also had increased basal (P < 0.05) and stress-related (P < 0.03) arterial NE-appearance rates. Severely melancholic depressed, medication-free patients had around-the-clock increases in plasma NE levels capable of increasing mortality in CHF. Twenty-four-hour indices of central noradrenergic, adrenomedullary, and adrenocortical secretion were also elevated. Concurrent diurnal rhythms of these secretions could potentiate their cardiotoxicity. Even mildly-to-moderately depressed melancholic patients had clinically relevant increases in the arterial NE-appearance rate. These findings will not apply to all clinical subtypes of major depression.

Adult↗
PubMed2005

Effect of leptin replacement on brain structure in genetically leptin-deficient adults.

The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.

Adult↗
PubMed2005

Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications.

BACKGROUND: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS: We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS: MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.

Adult↗
PubMed2005

Microanalysis of eating behavior of three leptin deficient adults treated with leptin therapy.

Leptin deficiency has been associated with extreme obesity and hyperphagia in rodents and humans. A rare genetic disorder in humans yields the absence of the hormone leptin, extreme obesity, and a ravenous appetite. Reports on these rare cases have indicated that therapy using leptin injections can yield significant weight loss and changes in appetite. The aim of this report on acute leptin therapy in three leptin deficient adults was to provide a microanalysis of changes in eating behavior and ratings of hunger and satiety. In addition to substantial weight loss, 15 weeks of leptin therapy was associated with approximately 50% reduction in food intake and substantial changes in ratings of hunger and satiety before most meals. After short-term leptin therapy, the three participants ate until ratings indicated they were satiated, which was comparable to the ratings before leptin therapy. These findings suggest that one of the primary effects of acute leptin therapy may be to reduce the ravenous hunger associated with leptin deficiency, resulting in reduced food intake and significant weight loss. These results are discussed in the context of the scientific literature pertaining to leptin and its effects on appetite and obesity.

Adult↗
PubMed2005

Depression, antidepressants and suicidality: a critical appraisal.

Regulatory agencies in the United Kingdom and United States have been critically examining the possible link between suicidality and antidepressant use in children and adults, which has resulted in an FDA directive to the manufacturers of all antidepressant medications to add a 'black box' warning that describes the increased risk of suicidal behaviour in children and adolescents who take antidepressants. A crucial issue in this debate, as we discuss here, is the assessment of the capacity of antidepressants to increase suicidality over and above what is caused by the underlying disorder, major depression, which is itself the principal cause of suicide.

Antidepressive Agents↗
PubMed2005

Development of a PCR-based strategy for CYP2D6 genotyping including gene multiplication of worldwide potential use.

There is growing consensus on the potential use of pharmacogenetics in clinical practice, and hopes have been expressed for application to the improvement of global health. However, two major challenges may lead to widening the "biotechnological gap" between the developing and the industrial world;first the unaffordability of some current technologies for poorer countries, and second the necessity of analyzing all described alleles for every clinical case due to the inability to predict the ethnic group of a given patient. Because of its role in the metabolism of a number of drugs, cytochrome P450 2D6 (CYP2D6) is an excellent candidate for use in the optimization of drug therapy. CYP2D6 is a highly polymorphic gene locus with more than 50 variant alleles, and subjects can be classified as poor metabolizers (PM), extensive metabolizers (EM), or ultrarapid metabolizers (UM) of a given CYP2D6 substrate. Several strategies and methods for CYP2D6 genotyping exist. Some, however, are expensive and laborious. The aim of this study was to design a PCR-based genotyping methodology to allow rapid, straightforward, and inexpensive identification of 90%-95% of CYP2D6 PM or UM genotypes for routine clinical use, independent of the individual's ethnic group. CYP2D6 is amplified in initial extra long PCRs (XL-PCRs), which subsequently undergo fragment-length polymorphism analysis for the determination of carriers of CYP2D6 allelic variants. The same XL-PCRs are also used for the determination of CYP2D6 multiplication and 2D6*5 allele (abolished activity). The application of this new strategy for the detection of CYP2D6 mutated alleles and multiplications to routine clinical analysis will enable the PM and UM phenotypes to be predicted and identified at a reasonable cost in a large number of individuals at most locations.

Alleles↗
PubMed2004

Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity.

Ghrelin plays a key role in the regulation of growth hormone secretion and energy homeostasis. Adiponectin is exclusively secreted by adipose tissue and is abundantly present in the circulation, with important effects on metabolism. We studied five lean and five obese young men [ages: 24.2 +/- 1.0 (lean) and 21.8 +/- 1.6 (obese) years (difference not significant); body mass indexes: 35.0 +/- 1.3 and 23.0 +/- 0.3 kg/m2 (P = 0.01)], sampled blood every 7 min over 24 h, and measured ghrelin, adiponectin, and leptin in 2,070 samples for a total of 6,210 data points. Circulating 24-h ghrelin showed significant ultradian fluctuations and an orderly pattern of release in lean and obese subjects with similar pulsatility characteristics. Plasma adiponectin concentrations were significantly lower in the obese group, with lower pulse height. In contrast to leptin, which is secreted in an orderly manner, the 24-h patterns of adiponectin were not significantly different from random in both the lean and obese groups. We show here that adipocytes can simultaneously secrete certain hormones, such as leptin, in patterns that are orderly, whereas other hormones, such as adiponectin, are secreted in patterns that appear to be random. The cross-approximate entropy statistic revealed pattern synchrony among ghrelin-leptin, ghrelin-adiponectin, and leptin-adiponectin hormone time series in the lean and obese subjects. Plasma ghrelin concentrations showed a nocturnal rise that exceeded the meal-associated increases in lean subjects, and this newly identified nocturnal rise was blunted in the obese. We suggest that the blunting of the nocturnal rise of ghrelin is a biological feature of human obesity.

Adipocytes↗
PubMed2004

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults.

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01-0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 +/- 2.5 (mean +/- SEM) at baseline to 26.9 +/- 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

Adult↗
PubMed2004

From monoamines to genomic targets: a paradigm shift for drug discovery in depression.

Depression, a complex psychiatric disorder that affects approximately 15% of the population, has an enormous social cost. Although the disorder is thought to be the outcome of gene-environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. All the antidepressant drugs now in use--the forerunner of which was discovered serendipitously 50 years ago--modulate monoamine neurotransmission, and take six to eight weeks to exert their effects, but each drug is efficacious in only 60-70% of patients. A conceptually novel antidepressant that acted rapidly and safely in a high proportion of patients would almost certainly become the world's bestselling drug. Yet such a drug is not on the horizon. Here, we cover the different phases of antidepressant drug discovery in the past, present and future, and comment on the challenges and opportunities for antidepressant research.

Animals↗
PubMed2004

Simultaneous and continuous 24-hour plasma and cerebrospinal fluid leptin measurements: dissociation of concentrations in central and peripheral compartments.

The entrance of leptin into the central nervous system is of physiological relevance to the regulation of food intake, energy balance, and neuroendocrine function. To our knowledge, the relation between plasma and lumbar cerebrospinal fluid (CSF) leptin has not been examined across the 24-h period. To evaluate the relation between plasma and CSF leptin across the 24-h period, we studied simultaneous and continuous plasma and CSF leptin in nine subjects. We measured plasma and lumbar CSF leptin every 30 min for 24 h. All subjects had diurnal periodicity in 24-h plasma leptin levels, but not in CSF levels, as assessed by analysis of covariance and cosinor analysis. Plasma leptin had a significant 24-h pattern (P = 0.001), but CSF leptin did not. A 25-fold range of plasma leptin concentrations was reflected by a less-than-2-fold range in lumbar CSF leptin concentrations. Nocturnal increases in plasma leptin concentrations were not accompanied by commensurate changes in CSF values. It appears that leptin enters the brain by a mechanism that is highly saturable at physiological leptin concentrations and that the dynamics of plasma leptin is not accompanied by similar dynamics in CSF leptin measured at the lumbar spinal level. Therefore, it is not possible to use plasma leptin levels to predict lumbar CSF leptin concentrations. Although we acknowledge that lumbar CSF concentrations do not fully reflect the dynamics of leptin in the brain, we suggest that the nocturnal saturability of leptin transport into the central nervous system might help explain the lack of responsiveness to the central physiologic effects of leptin in states of hyperleptinemia, such as obesity.

Adult↗