Clozapine-induced myocarditis in observational cross-sectional and follow-up evaluations: comparison with other antipsychotics in naturalistic settings / Miocarditis inducida por clozapina durante la evaluación observacional, transversal y longitudinal: comparación con otros antipsicóticos en ambientes naturalísticos

Myocarditis occurs more frequently during clozapine (CLZ) administration than during treatment with other antipsychotic drugs (APs). In this observational study, we transversally screened outpatients for myocarditis by comparing a CLZ group of 132 subjects, with a non-CLZ group taking other APs (n = 371) only, and in 21 CLZ-treated patients and 18 subjects treated with other APs who had been followed for more than one year. The protocol included a) assessment of symptoms such as dyspnea, tachycardia, chest discomfort, fever, cough, and edema, b) blood pressure and heart auscultation; c) a standard electrocardiogram after a 5-minute rest, d) white cell count, and qualitative determination of troponin I, creatine-kinase-MB and myoglobin, and e) a cardiologist evaluation of subjects with suspected myocarditis. Only one case of myocarditis was detected, providing an approximation of the frequency of myocarditis of 1.6% in the first month of treatment. This was a 30-year-old man with schizophrenia who developed symptoms at day 6 after starting a treatment with 200 mg of CLZ a day without titration. Myocarditis was not observed during prolonged CLZ or other AP administration. These results support the proposal of starting CLZ treatment with a low dose and the feasibility of a simple protocol for myocarditis detection in psychiatry primary care.

El desarrollo de miocarditis ocurre con más frecuencia durante el tratamiento con clozapina (CLZ) que durante el uso de otros antipsicóticos (APs). En el presente estudio observacional evaluamos la presencia de miocarditis mediante un protocolo transversal comparando 132 sujetos tratados con CLZ con 371 pacientes tratados con otro AP, y en 21 sujetos tratados con CLZ y 18 pacientes tratados con otro AP en un protocolo longitudinal mayor 1 año de duración. La evaluación incluyó: a) detección de síntomas como disnea, taquicardia, malestar torácico, fiebre, tos y edema; b) presión arterial y auscultación cardiaca; c) electrocardiograma estándar luego de un reposo de 5 minutos; d) contaje de glóbulos blancos y determinación cualitativa de troponina I, creatin-kinasa-MB y mioglobina, y e) evaluación por un cardiólogo en sujetos sospechosos para miocarditis. Detectamos un solo caso de miocarditis, lo que permite una aproximación sobre la frecuencia de miocarditis de 1,6 % durante el primer mes de tratamiento. Se trató de un sujeto masculino con esquizofrenia que desarrolló síntomas durante el día 6 después de haber iniciado el tratamiento con CLZ a la dosis de 200 mg por día sin titulación. No se detectaron sujetos sospechosos de miocarditis durante el tratamiento prolongado con CLZ u otro AP. Estos resultados sustentan la recomendación de comenzar el tratamiento con clozapina a dosis bajas, y la factibilidad de utilizar un protocolo sencillo para detectar miocarditis en la atención psiquiátrica primaria.

Miocarditis inducida por clozapina durante la evaluación observacional, transversal y ongitudinal: comparación con otros antipsicóticos en ambientes naturalísticos.

Myocarditis occurs more frequently during clozapine (CLZ) administration than during treatment with other antipsychotic drugs (APs). In this observational study, we transversally screened outpatients for myocarditis by comparing a CLZ group of 132 subjects, with a non-CLZ group taking other APs (n = 371) only, and in 21 CLZ-treated patients and 18 subjects treated with other APs who had been followed for more than one year. The protocol included a) assessment of symptoms such as dyspnea, tachycardia, chest discomfort, fever, cough, and edema, b) blood pressure and heart auscultation; c) a standard electrocardiogram after a 5-minute rest, d) white cell count, and qualitative determination of troponin I, creatine-kinase-MB and myoglobin, and e) a cardiologist evaluation of subjects with suspected myocarditis. Only one case of myocarditis was detected, providing an approximation of the frequency of myocarditis of 1.6% in the first month of treatment. This was a 30-year-old man with schizophrenia who developed symptoms at day 6 after starting a treatment with 200 mg of CLZ a day without titration. Myocarditis was not observed during prolonged CLZ or other AP administration. These results support the proposal of starting CLZ treatment with a low dose and the feasibility of a simple protocol for myocarditis detection in psychiatry primary care.

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.

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.

Effectiveness of melatonin in tardive dyskinesia.

Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20 mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.

Effectiveness of melatonin in tardive dyskinesia / Efectividad de la melatonina en la discinesia tardía

Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.

La Discinesia Tardía (DT) es un trastorno de los movimientos asociado al uso crónico de antipsicóticos que parece producirse, entre otros factores, por un incremento en los procesos oxidativos. La vitamina E se ha utilizado en su tratamiento, pero no hay evidencia de su efectividad. Como la melatonina (MEL) es 6 a 10 veces más efectiva como antioxidante que la vitamina E, se ha utilizado con una aparente mayor efectividad, aunque los resultados no han sido concluyentes. Se realizó un estudio doble ciego, al azar y controlado con placebo, para determinar la efectividad de la administración de la MEL durante 12 semanas en 7 pacientes con DT. Seis pacientes con DT fueron tratados con placebo. La Escala de Movimientos Involuntarios Anormales (AIMS) se usó para evaluar la evolución de los movimientos al inicio y a las 4, 8 y 12 semanas de tratamiento. La evaluación clínica psiquiátrica se hizo con la Escala Breve de Evaluación Psiquiátrica. En dos pacientes tratados con MEL se observó una mejoría clínica superior al 60% pero en los restantes, así como en los tratados con placebo los valores de la AIMS no variaron significativamente en el transcurso de las 12 semanas. Cuando se compararon los valores de la AIMS de la totalidad de los pacientes tratados con MEL, con los del grupo placebo, no se detectó ninguna diferencia significativa. Sin embargo, la mejoría clínica significativa de dos de los pacientes estudiados debe considerarse para llegar a una conclusión sobre la utilidad de la MEL en la DT.

Experimental depression induces renal oxidative stress in rats.

Depression has been associated to inflammatory and oxidative events. Previous report has shown renal oxidative stress in patients with depression. In order to analyze if depressive status is related to renal oxidative and inflammatory events, Sprague Dawley rats were submitted to forced swimming test (FST) and the renal oxidative metabolism, monocyte-macrophage infiltration and Angiotensin II (Ang II) expression were determined. Rats were submitted to FST daily (30 min) for 15 days. Motor activity was analyzed before FST. Kidney sections were homogenized to measure nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity by enzymatic and biochemical methods. Renal frozen sections were studied for superoxide anion (O2-), monocyte/macrophage infiltration and Ang II expression by histochemical and immunofluorescence methods. In addition, three groups of FST rats were treated with losartan, sertraline or water for 18 days with further renal O2-analysis. In the FST group, struggle time, motor activity, food intake and body weight gain were found decreased. Increased number of glomerular, interstitial and tubular O2-positive cells was observed in FST rats. High renal content of nitrite/nitrate (NO), MDA and decreased amount of GSH were found in FST rats. Values of renal ED-1 or Ang II positive cells in FST rats remained similar to controls; however, AT1 receptor blocking (losartan) and sertraline reduced both depressive-like behavior and renal O2-expression. These data suggests that depression-like behavior in rats is involved in kidney oxidative stress probably mediated by AT1 receptors.

The metabolic syndrome and its constituting variables in atypical antipsychotic-treated subjects: comparison with other drug treatments, drug-free psychiatric patients, first-degree relatives and the general population in Venezuela.

BACKGROUND: Few studies on the association between atypical antipsychotic drug (AAP) administration and metabolic dysfunction have concurrently evaluated the general population (GP), other psychotropic drug treatments and drug-free psychiatric patients. METHODS: We assessed the frequency of the metabolic syndrome (MS) according to the National Cholesterol Education Program criteria (NCEP) and its constituting variables in a GP sample (n=271) and in patients receiving, for at least three consecutive months, antiepileptic drugs (n=93), olanzapine (n=162), clozapine (n=105), typical antipsychotics (n=117), other AAP (n=58), other psychotropic drugs (n=185), and drug-free individuals (n=636). Subjects were clinically classified as schizophrenia, bipolar or other axis I disorders (DSM-IV-RT), and as first-degree relatives of each diagnostic group. RESULTS: The MS was detected in 26.6% of the GP (95% confidence interval: 21.5-31.8). No diagnostic or treatment group had a significantly higher age-adjusted frequency than the GP (p>0.05). Treatment duration did not significantly affect the results. However, significant differences were observed in the frequency of abnormal MS constituting variables in comparison to the GP. For example, schizophrenia patients and their relatives, bipolar subjects and olanzapine- and clozapine-treated patients had higher abnormal waist circumference values. In addition, bipolar patients and their relatives and subjects treated with olanzapine and other AAPs had higher frequencies of abnormal glucose levels. Neither schizophrenia nor bipolar patients in the diagnostic categories nor the olanzapine or the clozapine groups displayed higher proportions of abnormal triglycerides, high density cholesterol or blood pressure levels than the GP. CONCLUSIONS: While we did not demonstrate an increased frequency of the MS in AAP-treated subjects, our results confirm that specific metabolic variables must be monitored in psychiatric patients. Besides they stress the importance, in epidemiological studies, of concurrently comparing the figures recorded in AAP-treated patients with those obtained in the local GP, other drug treatment groups and drug-free subjects when referring to the magnitude of the metabolic effects of specific antipsychotic agents.

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.

Forced swimming test decreases chemotactic responsiveness and expression of CD11a in rat monocytes.

OBJECTIVES: Previous reports have shown that the depressive status in humans and experimental animals is associated with decreased immune response. Since monocyte chemotaxis and expression of CD11a are pivotal mechanisms in immune response, impairment of these events could explain the diminished immune response in depression. METHODS: To test this, rats were submitted to the forced swimming test (FST) for 3 and 15 days. Animals were sacrificed at days 4 (3 days' FST), 16 (15 days' FST) and 30 (15 days' FST and 15 days of recovery time). At these times, a blood sample was obtained for serum and leukocyte isolation. Mononuclear leukocytes were obtained by Histopaque gradient. Chemotaxis responsiveness was determined in Boyden chambers using zymosan-activated rat serum. Cellular CD11a expression and serum CD11a were determined by immunofluorescence and ELISA, respectively. RESULTS: Decreased chemotaxis was observed in FST animals at days 4 and 16 with total recovery at day 30. Diminished expression of cellular CD11a was observed at day 16 and remained decreased at day 30. There were no significant differences in serum CD11a content. CONCLUSION: Decreased chemotactic response and expression of CD11a found in this experimental model of depression could be important mechanisms to induce impairment immune response in experimental and clinical depression.

Structural and ultrastructural analysis of cerebral cortex, cerebellum, and hypothalamus from diabetic rats.

Autonomic and peripheral neuropathies are well-described complications in diabetes. Diabetes mellitus is also associated to central nervous system damage. This little-known complication is characterized by impairment of brain functions and electrophysiological changes associated with neurochemical and structural abnormalities. The purpose of this study was to investigate brain structural and ultrastructural changes in rats with streptozotocin-induced diabetes. Cerebral cortex, hypothalamus, and cerebellum were obtained from controls and 8 weeks diabetic rats. Light and electron microscope studies showed degenerative changes of neurons and glia, perivascular and mitochondrial swelling, disarrangement of myelin sheath, increased area of myelinated axons, presynaptic vesicle dispersion in swollen axonal boutoms, fragmentation of neurofilaments, and oligodendrocyte abnormalities. In addition, depressive mood was observed in diabetic animals. The brain morphological alterations observed in diabetic animals could be related to brain pathologic process leading to abnormal function, cellular death, and depressive behavioral.

Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study.

BACKGROUND: Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration. METHODS: In a double-blind, parallel group protocol, 61 patients (94.4% with schizophrenia) receiving clozapine (196.8+/-132 mg daily, range: 25-500) for more than 3 consecutive months (86.5+/-40.6 months, range: 4-168) were randomly allocated to extended release MET (n=31; 500 to 1000 mg daily) or placebo (n=30) group for 14 weeks. The BW, the body mass index, waist circumference, serum glucose, insulin, lipids, glycated hemoglobin (HBA1c), leptin and cortisol, and the HOMA-IR index were assessed at baseline, and weeks 7 and 14. RESULTS: MET was well tolerated and the mental state was not impaired during the study. The protocol was completed by all the placebo subjects and by 24 MET-treated patients. In a complete analysis at week 14, without including data of the 7 dropouts, the MET group lost -1.87+/-2.9 kg, whereas the placebo group had a stable BW: 0.16+/-2.9 kg, p=0.01 for the between group comparisons (effect size: 0.70). Leptin levels also tended to decrease after MET (p=0.08). Insulin and the triglyceride-HDL-C ratio significantly decreased (p<0.05, effect size 0.59 and 1.99 respectively) and the HDL-C significantly increased (p=0.001, effect size 0.95) after MET. CONCLUSIONS: MET improves metabolic control during prolonged clozapine administration.

Depressive status does not alter renal oxidative and immunological parameters during early diabetic nephropathy in rats.

Depression is frequently observed among patients with diabetes and depressive status has been associated to activation of inflammatory processes, suggesting a role of depression in the inflammatory events observed in diabetes. To test that proposal, it was studied the effect of depression induced by forced swimming test (FST) on the evolution of early diabetic nephropathy. Diabetes was induced by streptozotocin injection. Rats were submitted to FST for 15 days. Struggle time was determined during FST and motor activity previously to FST. Nitric oxide, malondialdehyde, reduced glutathione and catalase activity were measured in kidney homogenates by enzymatic and biochemical methods. Superoxide anion, monocyte/macrophage (ED-1 positive cells) and RAGE were determined by histochemical and immunohistochemical methods. Diabetic rats had decreased struggle time and locomotor activity at day 1 of FST. Both control and diabetic rats had those parameters decreased at day 15. Renal oxidative stress, RAGE expression and ED-1 cells were observed increased in diabetic animals. Those parameters were not significantly altered by FST. The depressive status does not alter oxidative and immune parameters during the early renal changes of diabetic nephropathy.

Frequency of abnormal correlation between leptin and the body mass index during first and second generation antipsychotic drug treatment.

BACKGROUND: Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine. METHODS: This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229). RESULTS: None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration. CONCLUSIONS: Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives.

BACKGROUND: Clinical studies suggest that the second generation antipsychotics (APs) clozapine and olanzapine and to a lesser extent the typical antipsychotics may be associated with a procoagulant and proinflammatory state that promotes venous thromboembolism. We evaluated here several blood factors associated with coagulation and inflammation in AP-treated schizophrenia patients and their first-degree relatives. METHODS: Procoagulant factors (fibrinogen and plasminogen activator inhibitor [PAI-1]), the anticoagulant factor antithrombin III [AT-III], and inflammation-related factors (C-reactive protein [CRP] and leptin) were assessed in patients chronically treated with clozapine (n=29), olanzapine (n=29), typical APs (n=30) and first degree relatives of clozapine (n=23) and olanzapine subjects (n=11). RESULTS: The typical AP group had the highest CRP level (p=0.013) in spite of having the lowest body mass index (BMI). Patients as a single group had higher CRP levels than relatives (p=0.003). The typical AP group also had the highest AT-III levels (p=0.021). Fibrinogen levels did not differ between the groups (p=0.13). Olanzapine patients displayed the highest PAI-1 and leptin levels among the drug-treated subjects, but values were similar to those observed in their relatives, and were significantly correlated with the BMI. CONCLUSIONS: A homogeneous negative profile of high inflammation and procoagulant factors along with low levels of anticoagulants was not detected in any group. While preliminary, our results suggest that the observed abnormalities were not related to a direct drug effect, but to elevated BMI (high PAI-1 and leptin in olanzapine-treated patients). We speculate that the high CRP in the typical AP group might be related to poor lifestyle habits, but this must we confirmed in future studies.

Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.

BACKGROUND: Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables. METHODS: Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment. RESULTS: The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels. CONCLUSIONS: Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.

Forced swimming test increases superoxide anion positive cells and angiotensin II positive cells in the cerebrum and cerebellum of the rat.

Situations of stress are capable of inducing depression and oxidative stress in the brain. Previous reports have shown that angiotensin II (Ang II) induces the production of superoxide anion (O(2)(-)), and impairment of endothelial function in cerebral microvessels in vivo. Substances that reduce angiotensin functions may be important in the treatment of depression. These data suggest a role for both Ang II and O(2)(-) in depression; thus, the aim of this study was to determine the effect of forced swimming test (FST), a model of stress/depression, on the cellular expression of Ang II and O(2)(-) in the central nervous system. To induce stress/depression, rats were subjected to FST daily (30 min) for 15 days. Unstressed animals were used as controls. Motor activity was automatically analyzed daily before swimming. Cerebrum and cerebellum frozen sections were studied for O(2)(-) by a histochemical method and for Ang II producing cells by a polyclonal antibody. In the FST group, struggle time, total horizontal activity, ambulatory movements, and vertical movements, were significantly decreased when the data from the 1st and 15th day were compared. Food intake and body weight gain also decreased when unstressed and FST rats were compared at the 15th day. Increased number of cerebrum and cerebellum O(2)(-), and Ang II positive cells, were observed in FST rats. Significant correlation was found between O(2)(-) positive cells and Ang II positive cell in the cerebrum. These results suggest that stress/depression situations could be involved in the increase of Ang II and oxidative stress in the central nervous system, with possible implications in the depressive condition.

[Social functioning and psychopathologic risk factors in hemophilic children]. / Funcionamiento social en niños hemofílicos. Análisis de encuesta para determinar factores psicopatológicos de riesgo.

BACKGROUND: Children with hemophilia can experience problems with their mental health status and social functioning. AIM: To assess the mental health status of hemophilic children. MATERIAL AND METHODS: Thirty four hemophilic children aged 5 to 13 years were studied. A translation of the special survey to assess mental health in children, denominated "Domingo" Mental Health Survey was applied. It consisted in animated cartoon questions related to the family, social and school life. According to the score obtained, children were classified as normal, doubtful or pathologic. The social functioning areas studied were family, school, relationship and emotional. Aggressiveness, depression/anxiety and rejection were the psychopathologic factors analyzed. RESULTS: Forty four percent of hemophilic children were considered normal, 20% doubtful and 35% pathologic. According to the severity of the disease, 67% of children with severe, 57% with moderate and 45% with mild hemophilia, were considered abnormal. Aggressiveness was the main risk factor in the emotional and family area, depression/anxiety in the family and emotional area and rejection in the family area. Fifty six percent of children had abnormalities in their social functioning and the severity of the disease was a predisposing factor. CONCLUSIONS: Psychopathologic factors in children with hemophilia appear mainly in the family environment.

Funcionamiento social en niños hemofílicos: Análisis de encuesta para determinar factores psicopatológicos de riesgo / Social functioning and psychopathologic risk factors in hemophilic children

Background: Children with hemophilia can experience problems with their mental health status and social functioning. Aim: To assess the mental health status of hemophilic children. Material and methods: Thirty four hemophilic children aged 5 to 13 years were studied. A translation of the special survey to assess mental health in children, denominated "Domingo" Mental Health Survey was applied. It consisted in animated cartoon questions related to the family, social and school life. According to the score obtained, children were classified as normal, doubtful or pathologic. The social functioning areas studied were family, school, relationship and emotional. Aggressiveness, depression/anxiety and rejection were the psychopathologic factors analyzed. Results: Forty four percent of hemophilic children were considered normal, 20% doubtful and 35% pathologic. According to the severity of the disease, 67% of children with severe, 57% with moderate and 45% with mild hemophilia, were considered abnormal. Aggressiveness was the main risk factor in the emotional and family area, depression/anxiety in the family and emotional area and rejection in the family area. Fifty six percent of children had abnormalities in their social functioning and the severity of the disease was a predisposing factor. Conclusions: Psychopathologic factors in children with hemophilia appear mainly in the family environment.