Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function

Nikolić‐Kokić, Aleksandra; Tatalović, Nikola; Nestorov, Jelena; Mijović, Milica; Mijušković, Ana; Miler, Marko; Oreščanin-Dušić, Zorana; Nikolić, Milan; Milošević, Verica; Blagojević, Duško; Spasić, Mihajlo; Miljević, Čedo

doi:10.1080/15287394.2018.1495587

Cited by 21 publications

(12 citation statements)

References 39 publications

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“…not certified by peer review) (which was The copyright holder for this preprint this version posted October 11, 2019. . https://doi.org/10.1101/19008649 doi: medRxiv preprint of inflammatory lesions and lymphocytic infiltrates within the myocardium (42). Therefore, antipsychotic treatment could account for some of the cardiac changes we demonstrate.…”

Section: Implications Of Our Findingsmentioning

confidence: 80%

“…With regards to antipsychotic treatment, there is direct animal evidence that dopamine receptor occupancy contributes to regulating cardiac function, and that antipsychotics impair this by blocking D2/3 receptors(40), thus potentially contributing to cardiac fibrosis(41). Antipsychotics are also associated with the development of inflammatory lesions and lymphocytic infiltrates within the myocardium(42). Therefore, antipsychotic treatment could account for some of the cardiac changes we demonstrate.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac structure and function in schizophrenia: a cardiac MR imaging study

Osimo

Brugger

Marvao

et al. 2019

Preprint

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Background: Heart disease is the leading cause of death in schizophrenia. Aims: We investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. Methods: 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area. Results: Patients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume, end-systolic volume, stroke volume, right ventricular (RV) end-diastolic volume, end-systolic volume, and stroke volume but unaltered ejection fractions relative to controls. LV concentricity and septal thickness were significantly larger in schizophrenia. The findings were largely unchanged after adjusting for smoking or exercise levels and were independent of medication dose and duration. Conclusions: Patients with schizophrenia show evidence of prognostically-adverse cardiac remodelling compared to matched controls, independent of conventional risk factors.

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Section: Implications Of Our Findingsmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Cardiac structure and function in schizophrenia: a cardiac MR imaging study

Osimo

Brugger

Marvao

et al. 2019

Preprint

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“…In rats, antipsychotics are also associated with the development of inflammatory lesions and lymphocytic infiltrates within the myocardium. 38 In humans, it remains to be determined whether antipsychotics directly act on cardiomyocytes. Aside from this, some, but not all, antipsychotics have been associated with higher rates of metabolic syndrome, 36 which might mediate cardiovascular changes.…”

Section: Discussionmentioning

confidence: 99%

Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study

et al. 2020

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Background Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia. Aims To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. Method In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia (‘patients’) and controls were matched for age, gender, ethnicity and body surface area. Results Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = −0.82, P = 0.001), LV end-systolic volume (d = −0.58, P = 0.02), LV stroke volume (d = −0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = −0.79, P = 0.002), RV end-systolic volume (d = −0.58, P = 0.02), and RV stroke volume (d = −0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. Conclusions Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.

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“…Specifically, antipsychotics have been found to reduce cardiac myocyte viability 7 , increase myocyte apoptosis 6 and induce autophagy of cardiac myocytes 8 , potentially leading to cardiac fibrosis 9 . Antipsychotics are also associated with development of inflammatory lesions and lymphocytic infiltrates within the myocardium 10,11 . D3 knock-out mice show increased interstitial fibrosis in cardiac myocyte samples 12 , and antipsychotics have also been found to induce interstitial and endocardial fibrosis, as well as myolysis and other changes seen in dilated cardiomyopathy 7,9 .…”

Section: Introductionmentioning

confidence: 99%

Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study

et al. 2019

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Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86–1.08; all p -values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups ( p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

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Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function

Cited by 21 publications

References 39 publications

Cardiac structure and function in schizophrenia: a cardiac MR imaging study

Cardiac structure and function in schizophrenia: a cardiac MR imaging study

Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study

Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study

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