Erika Fernández

Polymorphisms of the LEP- and LEPR genes, metabolic profile after prolonged clozapine administration and response to the antidiabetic metformin

BACKGROUND The role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes. METHODS Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs. RESULTS Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo. CONCLUSIONS BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.

Association of obesity with leukocyte count in obese individuals without metabolic syndrome

AIMS Inflammation in obesity is associated to insulin resistance (IR), hyperglycemia, hypertension and hyperlipidemia. Leukocytes play an important role in obesity associated inflammation. The initial factors that generate the inflammatory events in the obesity remain unclear. Therefore, the aim of this study was to determine the association of circulating leukocytes with clinical and biochemical parameters in obese individuals with clinical and biochemical parameters in normal range and with or without IR. METHODS Nineteen obese non-diabetic and 9 lean subjects were studied for serum levels of insulin, lipids, glycated hemoglobin, glycemia, for clinical parameters as HOMA-IR, arterial pressure and anthropometric parameters, and for leukocyte counts. Neutrophil/lymphocyte ratio (N/L) was calculated using the loge of leukocyte counts. Association between leukocytes and studied parameters was determined by Pearsons correlation. RESULTS Two groups of obese individuals were observed: with high levels of insulin (with IR) and with normal levels (without IR). Positive correlations were observed between leukocyte and lymphocyte counts with body mass index and HOMA-IR and negative correlation with decreased HDL levels. Lymphocytes correlated with increased levels of insulin. Leukocytes and neutrophils correlated positively with increased visceral fat and liver steatosis. These associations were absent in the obese group without IR. N/L ratio did not show correlations with studied parameters. The leukocyte associations were mainly observed in obese individuals with IR. CONCLUSIONS These data may represent initial leukocyte associations with morbidity features and define two different obese individuals that may evolve to the chronic inflammation observed in the obesity.

Colonic transit diagnostic test shows significant gastrointestinal hypomotility in clozapine-treated patients in comparison with subjects treated with other antipsychotics

BACKGROUND Constipation occurs in 25-60% of the subjects during administration of the antipsychotic drug (AP) clozapine (CLZ). METHODS We used a colonic transit diagnostic test that quantifies in a single abdominal X-ray the number of silver O-ring markers out of 25 units ingested five days before. The quantity of markers is directly proportional to the degree of gastrointestinal hypomotility, and elimination of over 80% of the markers is considered normal. The test was applied to three groups of AP-treated subjects for at least three consecutive months: CLZ alone (n=45), CLZ+Other APs (n=28), and Other APs (n=64). RESULTS The number of remaining markers at day 5 (mean±S.D.) was significantly higher in the CLZ alone (10.8±10.6) and in the CLZ+Other APs (9.7±9.7) groups than in the Other AP group (4.5±6.7), Kruskal-Wallis test: p=0.004. No significant associations were found between the number of markers, age, AP dose and treatment duration. All subjects who passed <80% of markers - which approximately corresponds to the 60th percentile of marker elimination - showed a scattered marker distribution along the colon, thus suggesting colon inertia. In subjects with hypomotility, 38.5% of the CLZ group, 25% of the CLZ+Other APs group, and 25% of the Other APs group were negative for the Rome III clinical criteria of constipation, thus showing objective, not subjective, hypomotility. CONCLUSIONS This study objectively confirms significant gastrointestinal hypomotility associated with CLZ administration.

Pro12Ala polymorphism of the PPAR-γ2 gene, metabolic syndrome and response to metformin in clozapine-treated patients.

The peroxisome proliferator-activated receptor gamma (PPAR-γ, PPARG or glitazone receptor) encoded by the PPAR-γ gene is implicated in obesity, diabetes, atherosclerosis and cancer (Costa et al., 2010). The Pro12Ala polymorphism of the PPAR-γ2 gene determines three genotypes. The Ala substitution is associated with a favorable metabolic profile in non-psychiatric populations (Fernández et al., 2009; Costa et al., 2010); however, results are conflicting (Tönjes

Abnormal correlation between serum leptin levels and body mass index may predict metabolic dysfunction irrespective of the psychopharmacological treatment.

In an earlier study, we found a similar frequency of individuals with an abnormal correlation between serum leptin levels and body mass index (BMI) (outliers above or below the 95% confidence interval in the regression line) during treatment with antipsychotic drugs (n=301), other psychotropic drugs (n=65), and drug-free individuals (n=229). In this secondary analysis, we compare the frequency of the metabolic syndrome (International Diabetes Federation), its constituting variables, obesity, (BMI>30 kg/m2), leptin and insulin serum levels, and an insulin-resistance index (homeostatic model assessment-insulin resistance) in outliers, nonoutliers distributed in their original treatment groups, and all the nonoutliers controlled by age, sex, and BMI. We identified 28 outliers, 24 above and four below the 95% confidence interval limits. Nine individuals were under antipsychotic treatment, four under other drug treatment, and 15 were drug-free. The outliers had a significantly higher frequency of metabolic syndrome and obesity, and higher values of waist circumference, triglycerides, insulin, and blood diastolic pressure. The outliers in the correlation between leptin and BMI may represent a population at high risk of metabolic dysfunction, irrespective of the specific psychotropic drug treatment administered.

Safety of long-term clozapine administration. Frequency of cardiomyopathy and hyponatraemia: Two cross-sectional, naturalistic studies:

Background: The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available. Methods: Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36). Results: Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; –0.7, 7.1); other atypical APDs (4.9%; –0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; –7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy. Conclusions: Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation.

Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder

Objective: Evidence points to a high prevalence of metabolic dysfunction in bipolar disorder (BD), but few studies have evaluated the relatives of subjects with BD. We conducted a cross-sectional study in an extended family of patients with BD type I. Methods: The available relatives of the same family were interviewed (DSM-IV-R) and assessed in fasting conditions for body mass index, constituent variables of the metabolic syndrome (MS), leptin levels, insulin resistance index, and single nucleotide polymorphisms (SNPs) for the leptin receptor and promoter and PPAR-γ2 genes. The frequency of MS was compared with that recorded in the local general population. Results: Ninety-three relatives of three adults with BD were evaluated (30 aged < 18 years, 63 aged > 18 years). The frequency of MS was similar to that of the general population. Significantly higher frequencies of abnormal glucose, total and low density cholesterol (LDL-c) levels (all p < 0.05), waist circumference (p = 0.057), and leptin and insulin resistance values (in adults only) were observed in the family. Adults with the QQ genotype of the leptin receptor displayed higher LDL-c levels than carriers of the R allele. Conclusions: The associations among BD consanguinity, familial hypercholesterolemia, and leptin receptor SNPs reported herein should be replicated and extended in other pedigrees.

Increased proinflammatory markers and lipoperoxidation in obese individuals: Inicial inflammatory events?

BACKGROUND Chronic inflammation associated to obesity increases the risk for developing insulin resistance (IR), hyperglycemia, hypertension and hyperlipidemia. The initial factors involved in generating the inflammatory events in the obesity remain unclear. Therefore, this study was aimed to determine inflammatory and oxidative markers in the blood of obese individuals with normal clinical and biochemical parameters and with or without IR. METHODS Nineteen obese non-diabetic and nine lean subjects were studied for serum levels of TNF-α, IL-1β, adiponectin, angiotensin II, insulin, malondialdehyde (MDA) and the expressions of RAGE (advanced glycation end product receptor), AT1 (Ang II receptor), s100A12 protein (RAGE ligand) and nuclear factor-κB (NF-κB) in circulating mononuclear cells (CMC) by available antibodies and commercial kits. CMC were also cultured to determine pro-inflammatory mediators. RESULTS Insulin was increased in obese subjects with IR. Decreased serum adiponectin in obese individuals and increased TNF-α, IL-1β and CMC bearing RAGE, AT1 and s100A12 in obese individuals without IR were found. High values of serum MDA in obese subjects were observed. Similar TNF-content in cultures from obese and controls, increased cellular IL-1β content in cultures from obese individuals without IR and high content of MDA in supernatants from obese individual cultures were observed. CONCLUSIONS The inflammatory events were mainly observed in obese individuals without IR. The absent of inflammatory events and high levels of insulin in obese subjects with IR, suggest a protector role of insulin for developing inflammatory events. These data can represent initial aspects of the chronic inflammation observed in the obesity.

Increased C-reactive protein and decreased Interleukin-2 content in serum from obese individuals with or without insulin resistance: Associations with leukocyte count and insulin and adiponectin content.

AIMS Chronic inflammation in obesity is associated with co-morbidities such as, hyperglycemia, hypertension and hyperlipidemia. Leukocytes play an important role in this inflammation and C-reactive protein (CRP) and Interleukin-2 (IL-2) can be important effectors during the immune response in obesity; however, the initial inflammatory events in obesity remain unclear. The aim of this study was to determine the circulating levels of CRP, IL-2, insulin and adiponectin, their association and the association with leukocyte count in obese individuals without co-morbidities and with or without insulin resistance (IR). MATERIALS AND METHODS Nineteen obese non-diabetic and 9 lean subjects were studied for serum levels of CRP, IL-2, insulin, adiponectin, lipids, glycated hemoglobin, glycemia, for homeostasis model assessment of insulin resistance (HOMA-IR), arterial pressure and anthropometric parameters, and for leukocyte counts. Neutrophil/lymphocyte ratio (N/L) was calculated using the loge of leukocyte counts. Associations were determined by Pearsons correlation. RESULTS None of the studied groups presented co-morbidities and two groups of obese individuals with normal or high levels of insulin (IR) were found. Increased CRP concentration and decreased IL-2 and adiponectin concentrations in obese were observed. Positive correlation between leukocyte type counts with CRP in obese with IR was found; however, no correlations with IL-2 in obese were observed. Insulin in obese were positively correlated with CRP and negatively correlated with IL-2 in IR obese individuals. Adiponectin in obese was negatively correlated with CRP. CONCLUSION CRP and IL-2 may represent two important effectors in the early inflammatory events in obese individuals without co-morbidities. Adiponectin and insulin may be involved in anti-inflammatory events.