Buletin de Psihiatrie Integrative Clozapine treatment and risk of miocarditis in patients with refractory schizophrenia.
Schizophrenia is a psychotic disorder of unknown ethiology, characterised by positive symptoms (delirium, hallucinations, disorganized behavior) and negative symptoms (affective flattening, alogia, avolition, anhedonia). It is a chronic disease with an evolution that includes 3 phases: prodromal phase, an active phase and a residual one (1). Approved in 1989 for the treatment of resistent schizophrenia (2), clozapine is an antagonist of 5-HT2A, D1, D3 and a receptors and presents a relatively decrease potence as an antagonist of D2 receptors (3). It is an atipical antypsichotic that is used for the treatment of resistant mania, schizophrenia with addictive comorbidities, schizophrenic patients with suicidal risk, aggresive and hostile patients, with severe depression that is treatment resistant, borderline personality disorder with severe automutilation and high autolytic risk as well as other treatment resistent disorders like obsessive compulsive disorder and autism (4). It is rapidly absorbed into the gastrointestinal tract, and the peak plasma levels are reached after 1-4 hours. The half-life is between 10 and 16 hours and is generally reached after 3-4 days if the treatment is administered twice a day (3). A study conducted in 2017 shows that administration of clozapine causes a reduction in the effort capacity, evidenced by the drug's antagonistic action on alpha adrenergic receptors. Thus, the results of the study advocate for physical activity in clozapinetreated patients in the prevention of cardiovascular disease and decreases the mortality in this category of patients (5). Another study published in 2018 shows that clozapine treatment increases the risk of both cardiovascular and metabolic disease in patients with schizophrenia (6). Moreover, the data reveals that myocarditis is the main adverse reaction to clozapine treatment and that cardiac death occurred in 24% of cases (7). Compared to dopamine receptor antagonists, clozapine produces fewer extrapyramidal side effects, such as dystonia, parkinsonism and akinezia (3, 8). However, it is not indicated as a first-line treatment because of its hematotoxicity and multiple cardiovascular side effects (3, 9). Myocarditis occurs in approximately 3% of patients treated with clozapine, but monitoring the patient reduces the risk of more serious complications (10).
RAPID TITRATION OF CLOZAPINE AND THE RISK OF MYOCARDITIS
Clinical studies suggest a gradual titration of clozapine doses every two weeks to reduce the risk of adverse effects such as seizures, hypotension, agranulocytosis and myocarditis (8). Unfortunately, this slow titration is delaying the time for the therapeutic response (11). Standard titration starts with 25 mg clozapine/day, administered in 2 divided doses, then increases by 25-50 mg/day, every day, to the desired efficacy. The maintenance dose is 300-450 mg/day (12). According to articles published in 2014 that included two studies comparing the safety and efficacy of clozapine with different titration rates in patients with refractory schizophrenia, it was demonstrated that in the first cohort study where the starting dose of clozapine was 25-50 mg, followed by 50-100 mg every 6 hours on day 1, then 50-100 mg/day, there was a decrease in the number of days of hospitalization and a faster remission of symptomatology, but with a higher rate in the development of myocarditis compared to the second study, where standard clozapine titration was used (13, 14).
DIAGNOSIS AND MANAGEMENT OF MYOCARDITIS
Studies show that myocarditis occurs within the first 2-8 weeks of clozapine treatment, patients developing dyspnea, fever, tachypnea, palpitations and fatigue without an apparent cause (4, 15). It is very important to exclude other etiologies of myocarditis with testing for viral infections, autoimmune diseases and giant cell myocarditis. Myocardial lesion serum markers, electrocardiogram and chest x-ray imaging are standard measurements for diagnosing myocarditis. Recent studies suggest that elevated levels of Troponin I are more common than CK-MB in acute myocarditis. On the electrocardiogram, changes in the ST segment, sinus tachycardia and flattening of the T wave can be observed. Ecocardiography is usefull for the evaluation of the ventricular function and for the confirmation of the ventricular insufficiency (15). Blood samples reveal the presence of an inflammatory syndrome (high values of C reactive protein and erythrocyte sedimentation rate) (7).
The management of myocarditis is supportive and empirical (2). After the diagnosis of myocarditis induced by clozapine, the medication is immediately discontinued. The administration of diuretics, beta-blockers and angiotensin converting enzyme inhibitors have been shown to support myocardial function. According to studies, the mortality rate is 12,5-24% (16) .
The pathogenesis of myocarditis induced by clozapine treatment has not been well established. Studies suggest possible links with the geographical area, genetic predisposition, and IgE-mediated hypersensitivity. Most cases of clozapine-induced myocarditis have been reported in New Zealand and Australia, possibly due to M2 receptor blockage and cholinergic receptor dysfunction in these areas that have a higher ozone concentrations. In an study conducted on 47 patients with myocarditis, 66% had eosinophilia, suggesting an IgE-mediated hypersensitivity reaction. The genetic predisposition is considered to be mediated by mutations in the CYP450 and CY450-1A3 pharmacokinetic enzymes (2, 16).
Clozapine is very effective in treating psychotic symptoms in patients with refractory schizophrenia but its use is limited due to potential life-threatening side effects. Rapid titration of clozapine increases the risk of inducing myocarditis. The rapid cessation of clozapine treatment and supportive and empirical management in establishing myocarditis diagnosis are essential for the recovery of cardiac function. The mechanism of clozapine-induced myocarditis is not yet well known. Myocarditis is a rare cardiovascular complication but with a fatal potential.
ACKNOWLEDGEMENTS AND DISCLOSURES
The authors state that they are no declared conflicts of interest regarding this paper.
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Florin Mitu, Andreea Bucan, Alexandra Mastaleru, Ovidiu Mitu, Maria-Magdalena Leon-Constantin
Maria-Magdalena LEON-CONSTANTIN -"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Department of Medical Specialties (I), address: University street nr 16, Iasi, Romania; Clinical Rehabilitation Hospital--Cardiovascular Rehabilitation Clinic, address: Pantelimon Halipa street nr 14, Iasi, Romania
Ovidiu MITU -"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Department of Medical Specialties (II), address: University street nr 16, Iasi, Romania; Sf. Spiridon Hospital--Cardiology Clinic, address: Piata Universitatii street nr 1, Iasi, Romania--e-mail: email@example.com
Stefan PAVILIU--"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Department of Medical Specialties (I), address: University street nr 16, Iasi, Romania; Clinical Rehabilitation Hospital --Cardiovascular Rehabilitation Clinic, address: Pantelimon Halipa street nr 14, Iasi, Romania
Cristina FURNICA--"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Departament of Morphofunctional Sciences I, adress: University street nr 16, Iasi, Romania; Forensic Medicine Institute, adress: Buna Vestire street nr 2, Iasi, e-mail firstname.lastname@example.org
Alexandra MASTALERU -"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Department of Medical Specialties (I), address: University street nr 16, Iasi, Romania; Clinical Rehabilitation Hospital --Cardiovascular Rehabilitation Clinic, address: Pantelimon Halipa street nr 14, Iasi, Romania Correspondent author: Alexandra Mastaleru--email: email@example.com
Florin MITU--"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Romania, Faculty of Medicine, Department of Medical Specialties (I), address: University street nr 16, Iasi, Romania; Clinical Rehabilitation Hospital--Chief of Cardiovascular Rehabilitation Clinic, address: Pantelimon Halipa street nr 14, Iasi, Romania e-mail: firstname.lastname@example.org
"Grigore T Popa" University of Medicine and Pharmacy--Iasi, Faculty of Medicine Departament of Medical Specialties (I), Discipline of Medical Semiology, Department of Medical Specialties (II), Discipline of Cardiology 3--Departament of Morphofunctional Sciences I, Discipline of Anatomy, E-mail: email@example.com
Submission: 19 mar 2018
Acceptance: 09 may 2018
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|Author:||Mitu, Florin; Bucan, Andreea; Mastaleru, Alexandra; Mitu, Ovidiu; Leon-Constantin, Maria-Magdalena|
|Publication:||Bulletin of Integrative Psychiatry|
|Date:||Jun 1, 2018|
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