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.

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.

Prevalencia de trastornos psicóticos en comparación con trastornos no psicóticos en una población de pacientes de Venezuela sometida a estrés / Prevalence of Psychotic Disorders Compared to Non-psychotic Disorders in a Venezuelan Community Subjected to Stress

Objetivo: Describir la prevalencia de trastornos psicóticos en comparación con trastornos no psicóticos según procedencia y sexo en pacientes que acuden a la consulta de psiquiatría en una población venezolana sometida a estrés de secuestros, sicarios y altos índices de criminalidad. Método: Estudio retrospectivo, descriptivo, de morbilidad entre julio y diciembre de 2008 de la consulta de psiquiatría de un hospital general de Venezuela. Resultados: En la consulta se atendieron 1.801 pacientes, de los cuales 56,7% fueron mujeres. El 58% los pacientes provenía de San Cristóbal; 40,4% de otra ciudad del estado del Táchira, y 1,6% de otro estado. El diagnóstico que predominó entre todos los pacientes fue trastorno de ansiedad (19,7%). Los trastornos psicóticos (esquizofrenia, trastorno afectivo bipolar y trastorno mental orgánico) fueron diagnosticados en un 34,6%. Los trastornos no psicóticos (ansiedad, depresión y trastorno obsesivo-convulsivo) fueron diagnosticados en un 30,2%. El diagnóstico de psicosis predominó en los pacientes procedentes de San Cristóbal, en comparación con los que procedían de otra región (p<0,0001). En el sexo femenino predominaron los diagnósticos de ansiedad y depresión y en el masculino el diagnóstico de psicosis (p<0,0001). Conclusión: Los trastornos psicóticos se diagnosticaron con mayor frecuencia en los pacientes que viven en San Cristóbal, lo que sugiere que la tensión emocional que reina en la ciudad puede ser un factor de riesgo desencadenante de las crisis psicóticas de los pacientes.

Objective: To describe the prevalence of psychotic disorders compared with non-psychotic disorders sorted by residence and sex in patients attending psychiatric consultation in a Venezuelan community under stress due to kidnappings, murder and high crime rates. Method: Retrospective and descriptive study of morbidity of psychiatric disorders between July and December 2008 in the psychiatric services at a general hospital in Venezuela. Results: 1.801 patients were seen at the psychiatric services, 56.7% were women. 58% came from San Cristobal, 40.4% from other cities and 1.6% from the state of Tachira. The diagnosis that prevailed among all patients was anxiety disorder (19.7%). Psychotic disorders (schizophrenia, bipolar disorder and organic mental disorder) were diagnosed in 34.6%. Non-psychotic disorders (anxiety, depression and obsessive compulsive disorder) were diagnosed in 30.2%. The diagnosis of psychosis predominated in patients from San Cristobal in comparison with those from other areas (p<0.0001). Anxiety and depression predominated in females and the diagnosis of psychosis in male patients (p<0.0001). Conclusion: Psychotic disorders were more frequently diagnosed in patients living in San Cristobal, which might suggest that emotional tension present and experienced in urban areas could be a risk factor triggering crisis in psychotic patients.

Metformin plus sibutramine for olanzapine-associated weight gain and metabolic dysfunction in schizophrenia: a 12-week double-blind, placebo-controlled pilot study.

Metformin (850-1700 mg) plus sibutramine (10-20 mg, n=13) or placebo (n=15) was administered for 12 weeks in olanzapine-treated chronic schizophrenia patients. Weight loss was similar in both groups: -2.8+/-3.2 kg vs. -1.4+/-2.6 kg. Except for preventing a triglyceride increase, the drug combination lacked efficacy for metabolic control in this clinical population.

Similar frequency of abnormal correlation between serum leptin levels and BMI before and after olanzapine treatment in schizophrenia.

Melkersson proposed leptin dysregulation as a factor in the olanzapine-induced metabolic dysfunction. Their suggestion was based on the absence of the expected positive correlation between serum leptin levels and the BMI, and the loss of the sex-dependent difference in leptin levels, which are higher in women. Although subsequent studies did not confirm that proposal, few of them assessed basal leptin levels and corrected for body fat percentage. Along with these variables, we added a precise definition of participants out of the expected positive correlation in a large sample of schizophrenia patients. Sixty patients (26 women and 34 men) with severe schizophrenia undergoing chronic hospitalization and conventional antipsychotic treatment were switched to olanzapine (10-20 mg/day). We assessed at baseline, and at weeks 8 and 16 of treatment, the percentage of participants with abnormal correlation (out of the 95% confidence interval in the regression line) between leptin levels and the BMI, and the correlation between leptin and insulin, glucose, the insulin resistance index, c-reactive protein (CRP) and treatment response. Leptin levels were higher in women than in men (P<0.01). The positive correlation between leptin levels, BMI and percentage of fat were preserved. After olanzapine, 3.8% of women and 2.9-5.8% of men were out the 95% confidence interval, and the proportion was similar at baseline. Glucose, insulin, the insulin resistance index and the CRP levels significantly increased after olanzapine. The impact of olanzapine on leptin regulation appears discrete and limited to a small number of participants. Additional studies must clarify the features that render them to metabolic dysregulation.

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.

Insulin counter-regulatory factors, fibrinogen and C-reactive protein during olanzapine administration: effects of the antidiabetic metformin.

In this study, the Authors assessed some insulin counter-regulatory factors, fibrinogen and C-reactive protein after olanzapine administration, and the effect of metformin on these variables, 37 patients with chronic schizophrenia were given olanzapine (10 mg/day for 14 weeks). Nineteen patients received metformin (850-2550 mg/day) and 18 received placebo in a randomized, double-blind protocol. The following variables were quantified before and after olanzapine: cortisol, leptin, tumor necrosis factor-alpha, glucagon, growth hormone, fibrinogen and C-reactive protein. Results were correlated with the changes in body weight and the insulin resistance index. We have reported elsewhere that metformin did not prevent olanzapine-induced weight gain, and the insulin resistance index significantly decreased after metformin and placebo; Baptista T, et al. Can J Psychiatry 2006; 51: 192-196. Cortisol, tumor necrosis factor-alpha and fibrinogen levels significantly decreased in both groups. Glucagon significantly increased after metformin (P=0.03). Leptin tended to increase after placebo (P=0.1) and displayed a small nonsignificant reduction after metformin. The C-reactive protein did not change significantly in any group. Contrarily to most published studies, olanzapine was associated with decreased insulin resistance. Decrements in cortisol, fibrinogen and tumor necrosis factor-alpha levels point to an improvement in the metabolic profile. The trend for leptin to increase after placebo, but not after metformin in spite of similar weight gain suggests a beneficial effect of this antidiabetic agent.

Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial.

OBJECTIVE: To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine. METHOD: Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment. RESULTS: At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly. CONCLUSIONS: Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.