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.

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.