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The effects of antipsychotics, antidepressants and mood stabilizer medication over the cardiovascular disease in patients with schizophrenia, depression and mood disorders.

INTRODUCTION

Patients with severe psychiatric disorders, especially schizophrenia, bipolar disorder and recurrent major depression have a 2-3 times higher mortality rate compared to general population, corresponding to a cut life expectancy by 10-25 years (1, 2). The most common cause of death at these patients is somatic disorders.

Factors related to the psychiatric pathology, unhealthy life style, discrepancies in the provision of the medical assistance and addressability to the physician lead to a reserved prognostic in psychiatric patients. Using psychotropic medication can increase the risk of somatic complications (3). Therefore, it is necessary a thorough knowledge of the side effects of the psychotropic medication that is frequently used in the somatic state in patients with severe psychiatric disorders (4).

HIGH BLOOD PRESSURE

Even if antipsychotics have as a side effect gaining weight and are associated with obesity, the effect over the blood pressure is less pronounced, most probably due to the action of blocking the alpha-1 receptor, which can decrease the blood pressure. In the same time, the criteria for metabolic syndrome are met more often in patients with schizophrenia than in the general population (OR = 1.36, 95% CI: 1.21-1.53) and in chronic patients with schizophrenia under antipsychotic treatment (39,7%) compared to the patients with a first psychotic episode (30,4%) or without medication (24,3%) (2). There has been observed a high risk of developing pathologies like high blood pressure and metabolic syndrome in patients with depression and bipolar disorder, pronounced in the ones treated with antipsychotics (5). From the antidepressant medication, venlafaxine is most frequently associated with high blood pressure, while mirtazapine is less associated with it compared to tricyclic antidepressants (6). Mood stabilizers have no effect over the blood pressure, with the exception of chronic renal insufficiency induced by lithium.

CORONARY HEART DISEASE AND STROKE

Actual data suggest that patients with schizophrenia, bipolar disease and recurrent major depression have a significant higher risk of cardiovascular morbidity and mortality compared to general population. The risk is approximately 1,5-3 times higher in patients with schizophrenia and bipolar disorder and only 1,5 times higher in recurrent major depression. Moreover, cardiovascular disease is the most frequently cause of death in patients with severe psychiatric disease, with a 10 times higher risk compared to suicide (7, 8). The literature that talks about the cardiovascular prognostic regarding the antipsychotics is insufficient and the data are contradictory.

Even if some studies reported a high risk of cerebrovascular disease in patients that received antipsychotic treatment, others had inconclusive results. In case-control studies on old patients, the probability of stroke on the ones that received antipsychotic treatment compared to the ones without medication was approximately 1,3-2 times higher.

The risk of cerebral infarction is increased in the first weeks of treatment. A meta-analysis of 20 cohort studies has concluded that old people (>65 years) that are treated with first generation antipsychotic medication have no statistical significant increased risk (RR= 1.4; 95% CI: 0.81-1.91) of myocardial infarction compared to the ones treated with second generation antipsychotics (9).

Few studies have analyzed the association between antipsychotics and myocardial infarction, being a controversial topic because of the clinical and methodological different approaches. Some studies have reported a higher risk of myocardial infarction in old people ([greater than or equal to] 66 years) with or without dementia or in patients with severe psychiatric disease treated with antipsychotics compared to control subjects (RR= 1.15-6.2) (10). In a study conducted by Lin et al. on a significant number of patients with schizophrenia, affective disorders or dementia, AOR for the risk of acute myocardial infarction was 2,52 (95% CI: 2.37-2.68) for antipsychotics in general, 2,32 (95% CI: 2.17-2.47) for the first generation ones and 2,74 (95% CI: 2.49-3.02) for the second generation ones (11). A meta-analysis reported an increased risk of myocardial infarction in old people ([greater than or equal to] 65 years) treated with first generation antipsychotics (RR= 1.2; 95% CI: 1.16-1.23), compared to the ones treated with second generation. Instead, some studies haven't found an association between the exposure to antipsychotic medication and the risk of myocardial infarction (12).

The risk of cardiovascular events varies with each of the second generation antipsychotics, being reduced for aripiprazole and ziprasidone. For the first generation antipsychotics, a 5 year follow-up study on patients at the debut of schizophrenia detected a high cardiovascular mortality risk in patients treated with levomepromazine (OR = 2.68; 95% CI:1.37-5.25, p = 0.004) (13).

Literature data regarding cardiovascular safety of the second generation antipsychotics in young people are limited. In a cohort study (N = 48.625), the risk of major cardiovascular events (cardiovascular mortality, acute coronary syndrome or ischemic stroke) in adult psychiatric patients (18-64 years) that are ambulatory monitored was similar for risperidone, olanzapine and quetiapine in the first year of treatment. In another cohort study were enrolled 284.234 patients with ages between 18 and 65 years old; the ones with second generation antipsychotic treatment that was started less than one year had an higher risk of developing high blood pressure (adjusted HR, AHR = 1.16, 95% CI: 1.12-1.21), diabetes mellitus (AHR= 1.43, CI: 1.33-1.53), hypertensive cardiomyopathy (AHR=1.34, CI: 1.10-1.63), strokes (AHR=1.46, CI: 1.22-1.75), coronary heart disease (AHR = 1.17, CI: 1.05-1.30) and hyperlipidemia (AHR = 1.12, CI: 1.07-1.17) compared to the ones exposed to antidepressant medication (14).

In obese patients, the ones with psychiatric pathology have a significant higher cardiovascular risk. It is possible that, additional to the weight gain and the mechanisms correlated with obesity, to be a direct effect of the antipsychotics over the cardiovascular risk. For example, an autonomic nervous system dysfunction triggered by schizophrenia could be exacerbated by the antipsychotic treatment by blocking the peripheral dopamine receptors, increasing the sympathetic activity. A direct effect of antipsychotic treatment over the insulin resistance that induces impaired glucose tolerance can be another mechanism that leads to the increase of the appearance of cardiovascular disease (15).

Potential cardiovascular side effects of the tricyclic antidepressants are well known. They can cause orthostatic hypotension, lower cardiac conduction, increase heart rate, meaning that they should be avoided as much as possible in patients with preexistent cardiovascular disease. SSRIs (e.g. citaloprame) seems like having a superior cardiovascular safety, still in patients with high risk it can be associated a slight QTc interval prolongation. Serotonin-norepinephrine reuptake inhibitors are associated with a slightly increased incidence of the cardiovascular side effects (hypertension, tachycardia and orthostatic hypotension), but they do not prolong QTc interval at therapeutic doses. Even if lithium can have side effects over cardiac conduction, it can generally be used in patients with cardiovascular disease (16).

MYOCARDITIS

Myocarditis can appear after the treatment with clozapine, being diagnosed mostly at the beginning of the treatment and in young patients. Therefore, routine electrocardiographic monitoring in the first 4 weeks of treatment and interrupting clozapine if the myocarditis appears can prevent death. However, case reports suggest that gradually resuming clozapine may have success in most of the cases (15).

CARDIAC ARREST

Patients with schizophrenia have 2-4 times higher risk of cardiac arrest compared to general population. Even if the causes of this high risk remain unclear, the individual susceptibility (e.g. coronary heart disease) and an increase prevalence of Brugada electrocardiographic anomalies seem relevant. Important additional risk factors include unhealthy life style and psychotropic medication.

The association between cardiac arrest and specific psychotropic medication has been explained by the prolonging of the ventricular depolarization (prolonged QTc), that predisposes to life-threatening ventricular tachyarrhythmia (e.g. torsades de pointes). There is a consensus that the values of QTc>500 ms or an absolutely increase with [greater than or equal to] 60 ms compared to the basal values without medication includes the patient at a significant risk of torsades de pointes and cardiac arrest. However, even if there is a bond between QTc and torsades de pointes, this is not direct. Torsades de pointes can appear at therapeutic doses with antipsychotics or antidepressants with a QTc interval <500 ms (17, 18).

Patients under treatment with first or second generation antipsychotics have an increased risk of cardiac arrest compared to the ones without treatment, with or without psychiatric disease, from 1,5 to 5,8 times higher according to the type on antipsychotic and the defining criteria of the cardiac arrest that we take into consideration. The largest study until now (459.614 patients treated with antipsychotics) has reported an incidence of cardiac arrest of 3,4 at 1000 persons/year (19). First generation antipsychotics with an increased risk of QTc prolonging include tioridazina (the highest risk), pimozide, droperidole, mesoridazine and haloperidole with intravenous administration (total cumulative dose > 2 mg) and from the second generation sertindole, amisulpride and ziprasidone. QTc prolonging for lurasidone and aripiprazole is not clinically significant and the one associated with asenapine and iloperidone is comparable with risperidone, olanzapine and quetiapine (20).

A meta-analysis reported the fact that SSRIs have a statistical significance association (but insignificant clinically) and dose dependent with the increasing QTc interval (+6.10 milliseconds; 95% CI: 3.47-8.73, p<0.001) compared to placebo. The most potent effect seems to be with citaloprame. Tricyclic antidepressants prolong the QTc with a factor > 2 compared to SSRIs. Studies that correlate antipsychotic and antidepressant medication with an increased risk of cardiac arrest suggest a dose dependent relationship (18).

Cases of torsades de pointes have been reported for antipsychotics, tricyclic antidepressants and SSRIs. The ARITMO project (Arrhythmogenic Potential of Drugs) classified beside ziprasidone five other second generation antipsychotics (amisulpride, clozapine, olanzapine, quetiapine and risperidone) as having a high risk of developing torsades de pointes. However, these antipsychotics (with the exception of amisulpride and possibly quetiapine) have generally been associated with a relatively low potential of prolonging QTc interval. SSRIs determine very rarely torsades de pointes, with a small number of reported cases. The association between SSRIs and second generation antipsychotics determine exceptional torsades de pointes. There haven't been reported cases of torsades de pointes induced by lithium (21). We don't have to forget that coronary heart disease are underlying to most of the cardiac arrests. The actual recommendations don't suggest routinely electrocardiographic monitoring for the initiation of the antipsychotic treatment in the absence of the cardiovascular risk factors, but only if the prescribed antipsychotic has a high risk of torsades de pointes or cardiac arrest (20).

CONCLUSIONS

Patients with severe psychiatric disorders have a high risk of cardiovascular disease and in consequence an increased mortality rate. Additional to the factors regarding the psychiatric disorder, like the discrepancies in the access and in the use of healthcare and the unhealthy life style, the psychotropic medication can contribute to the development or aggravation of the cardiovascular disease. We summarized the existing evidence over the antipsychotic, antidepressants and mood stabilizers medication side effects in the somatic state of the patients with schizophrenia, recurrent major depression and bipolar disorder. Generally, the side effects regarding the health are pronounced for antipsychotics, followed by mood stabilizers, tricyclic antidepressants and new generation antidepressants. Increased doses, polymedication and the treatment of the vulnerable persons (young or old) seem to be associated with a more pronounced effect over most of the cardiovascular disease. Even if the antipsychotic medication has a high potential to affect the physical condition of the patients, it is important to retain that a number of large studies that obtained data that could be generalized suggest that mortality has higher rates in schizophrenic patients without antipsychotic medication (2, 22). Moreover, clozapine, antidepressants, lithium and antiepileptic medication have a low mortality rate through suicide. Thus, the potential risk of antipsychotic, antidepressants and mood stabilizer medication should be compared to the risk of the psychiatric diseases for which they are used and to the long term potential benefit induced by the medication.

In the same time, there should be paid more attention to the possible impact of the psychotropic medication and its side effects over the cardiovascular system in patients with severe psychiatric diseases. This could help the medical staff in selecting the optimal treatment for each and every one of the patients. Moreover, information regarding the side effects for some of the medication might be useful in implementing an adequate monitoring and strategies in order to improve prognosis both somatically and psychiatrically.

ACKNOWLEDGEMENTS AND DISCLOSURES

The authors state that they are no declared conflicts of interest regarding this paper.

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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 e-mail: leon_mariamagdalena@yahoo.com

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: mituovidiu@yahoo.co.uk

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 cristinafurnica@yahoo.com

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: alexandra.mastaleru@gmail.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: mitu.florin@yahoo.com

Correspondence:

Alexandra Mastaleru,

"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: alexandra.mastaleru@gmail.com

Submission: 18sep 2017

Acceptance: 21 dec 2017
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Author:Leon-Constantin, Maria-Magdalena; Mitu, Ovidiu; Furnica, Cristina; Mastaleru, Alexandra; Paviliu, St
Publication:Bulletin of Integrative Psychiatry
Article Type:Report
Date:Mar 1, 2018
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