406
Views
36
CrossRef citations to date
0
Altmetric
Review

Etiology of cardiovascular disease in patients with schizophrenia: current perspectives

&
Pages 2493-2503 | Published online: 01 Oct 2015

Abstract

Cardiovascular morbidity and mortality are important problems among patients with schizophrenia. A wide spectrum of reasons, ranging from genes to the environment, are held responsible for causing the cardiovascular risk factors that may lead to shortening the life expectancy of patients with schizophrenia. Here, we have summarized the etiologic issues related with the cardiovascular risk factors in schizophrenia. First, we focused on heritable factors associated with cardiovascular disease and schizophrenia by mentioning studies about genetics–epigenetics, in the first-episode or drug-naïve patients. In this context, the association and candidate gene studies about metabolic disturbances in schizophrenia are reviewed, and the lack of the effects of epigenetic/posttranscriptional factors such as microRNAs is mentioned. Increased rates of type 2 diabetes mellitus and disrupted metabolic parameters in schizophrenia are forcing clinicians to struggle with metabolic syndrome parameters and related issues, which are also the underlying causes for the risk of having cardiometabolic and cardiovascular etiology. Second, we summarized the findings of metabolic syndrome-related entities and discussed the influence of the illness itself, antipsychotic drug treatment, and the possible disadvantageous lifestyle on the occurrence of metabolic syndrome (MetS) or diabetes mellitus. Third, we emphasized on the risk factors of sudden cardiac death in patients with schizophrenia. We reviewed the findings on the arrhythmias such as QT prolongation, which is a risk factor for Torsade de Pointes and sudden cardiac death or P-wave prolongation that is a risk factor for atrial fibrillation. For example, the use of antipsychotics is an important reason for the prolongation of QT and some other cardiac autonomic dysfunctions. Additionally, we discussed relatively rare issues such as myocarditis and cardiomyopathy, which are important for prognosis in schizophrenia that may have originated from the use of antipsychotic medication. In conclusion, we considered that the studies and awareness about physical needs of patients with schizophrenia are increasing. It seems logical to increase cooperation and shared care between the different health care professionals to screen and treat cardiovascular disease (CVD)-risk factors, MetS, and diabetes in patients with psychiatric disorders, because some risk factors of MetS or CVD are avoidable or at least modifiable to decrease high mortality in schizophrenia. We suggested that future research should focus on conducting an integrated system of studies based on a holistic biopsychosocial evaluation.

Introduction

Cardiovascular death is a major contributor to the increased mortality rate (two- to threefold) and to the decreased life expectancy of 20% in schizophrenia victims according to normal population.Citation1Citation3 The causes for increasing the mortality rate in schizophrenia victims are mostly similar to those in the general population with metabolic syndrome and diabetes mellitus. In addition, some disease-specific risk factors may also contribute to the increasing mortality rate such as follows: being genetically liable or having overlapping genes between cardiovascular disease, sudden cardiac death and schizophrenia. Requiring antipsychotic drugs and outcomes of such drugs, lifestyle due to negative symptoms, smoking, and alcohol abuse, and inability to obtain good medical care or inability to reach qualitative medical opportunities might also add some risks. In this review, we conducted a retrospective database study to assess the primary potential risk factors of cardiac mortality in first-episode and chronic patients with schizophrenia in light of recent findings in the literature.

Methods

We conducted a systematic search for potentially relevant articles published between the year 1995 and 2015. Our search strategy was to assess the studies in earlier stages of schizophrenia including first-episode psychosis/schizophrenia, first-degree relatives, schizophrenia and cardiac mortality (single nucleotide polymporhisms or microRNA (miRNA) or modifiable risk factors or sudden death or QTc, or P-wave, Torsade de Pointes [TdP]), and glucose or insulin or cholesterol or triglycerides, or blood pressure or weight using health-related databases such as MEDLINE (via PubMed), Embase, and PsycINFO. We have focused on risk factors for mortality and we included systematic reviews, meta-analyses, and studies. We did not attempt to identify unpublished work or search in non-English- written journals.

Findings about genetic and epigenetic mechanisms

The increase in cardiovascular risk factors has also been revealed in antipsychotic naïve first-episode patients,Citation4 before antipsychotic drug invention in the 1920sCitation5 and even in their healthy relatives.Citation6 Thus, one may consider whether some common candidate genes are present or not between schizophrenia and cardiovascular risk-prone victims ().

Table 1 Genetics in cardiometabolic risk factors in schizophrenia

Atypical antipsychotic-related weight gain was revealed to be associated with INSIG2,Citation7 or the interaction of INSIG2 with INSIG1.Citation8 The same investigators detected a significant association between rs498177 single nucleotide polymorphism (SNP) in the serotonin 5-HT2C receptor gene and metabolic syndrome only in female patients with schizophrenia.Citation9 An association was shown between the endothelial nitric oxide synthetase (eNOS) T-786C genetic variant and endothelial functioning, which was no longer detectable if patients met the criteria of metabolic syndrome.Citation10

Besides possible cardiovascular outcomes, in a genome-wide association study (GWAS), common SNPs in the cardiomyopathy-associated gene (CMYA5) were also accused for schizophrenia.Citation11 Some authors have revealed an association between rs10503929 within the NRG1 gene and sudden unexpected deaths due to ventricular fibrillation in schizophrenia victims.Citation12Citation14 In a five-drug-specific GWAS, genome-wide significance was detected with SNP rs4959235 at SLC22A23 which mediated the effects of quetiapine on QTc prolongation in patients from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study ().Citation15

Table 2 Genetics in cardioautonomic risk factors

miRNAs are small noncoding RNAs that bind to the 30-UTR (untranslated region) of usually many messenger RNAs. Through multiple mechanisms affecting transcription and translation, miRNAs are among the key regulators of posttranscriptional gene expression.Citation16 In a systematic review, different alterations among miRNA were reported in the postmortem brains of schizophrenia patients.Citation17 Perkins et al have investigated alterations of miRNAs in 179 rats treated with haloperidol and detected increments of miR-199a, miR-128a, and miR-128b.Citation18 On the contrary, the downregulation of miR-31 and miR-342-5p was shown in peripheral blood mononuclear cells in vivo in schizophrenia patients.Citation19 In a recent study, for the first time, the alteration of miRNAs after olanzapine has been found to be associated with metabolic pathway via pathway analysis in mice.Citation20

Findings on cardiometabolic risk factors

Data from the general population estimated five metabolic risk factors for predisposition to cardiovascular disease (CVD) approximately twofold increaseCitation21 and to diabetes approximately three- to fourfold increaseCitation8,Citation22 and widely shaped as: abdominal obesity, elevated triglycerides, reduced high density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose levels.

In a systematic review of 25 studies in which the average follow-up duration was 31.7 weeks (from January 1990 to June 15, 2010), no difference in metabolic syndrome (MetS) was detected in drug-naïve patients than healthy controls.Citation1 On the contrary, some authors had found a higher waist/hip ratioCitation23,Citation24 and more visceral fatCitation25 in first-episode patients with schizophrenia than controls although inadequate control matching was an important limitation of these studies. The European First Episode Schizophrenia Trial (EUFEST) was a 1-year open label study in which first-episode (<2 years) or partially antipsychotic naïve patients were recruited. Partially antipsychotic naïve was defined as the use of any antipsychotic drug <2 weeks in the previous year or <6 week antipsychotic treatment at any time including haloperidol, amisulpride, ziprasidone, quetiapine and olanzapine. In that study, the baseline rate of MetS was similar in the drug-naïve and brief antipsychotic use groups and in the general population in Europe (). Interestingly, 58.5% of the patients have shown individual risk factors for one or more elevated metabolic risks at the baseline as following: 28.5% suboptimal HDL, 24.2% hypertension, 17.7% hyper-triglyceridemia, 8.2% abdominal obesity, and 7.3% hyperglycemia.Citation28 A meta-analysis was performed with 126 valid analyses from 77 published studies (n=25,692) and data from 14 of these 77 studies (n=800) were included for analysis which had examined first-episode psychosis and/or drug-naïve patients. Although no comparison with general population was detected within all these 14 studies, the MetS rate was established to be 11.3% (95% CI =7.3%–16.1%)Citation27 that was surprisingly lower, while the estimated prevalence of the MetS rate in Europe was 18%–20%Citation28 and 25% in the general population in the USA.Citation29

Table 3 Cardiometabolic risk factors in first-episode psychosis

It is commonly accepted that the prevalence of MetS in patients with chronic schizophrenia is higher than that in the normal population. In the CATIE study, the rate of MetS in schizophrenia was found to be 40.9% vs 23.7% in controls (for males 36.0% vs 19.7%; for females 51.6% vs 25.1%).Citation30 In the aforementioned meta-analysis (126 analyses from 77 published studies, n=25,692), the overall rate of MetS was 32.5% (34.8% in males and 34.8% in females). Additionally, MetS was present in 39.2% of older patients with a mean age of 50 years or aboveCitation27 which shows that the MetS rate is rising with aging in patients with schizophrenia ().

Table 4 Cardiometabolic risk factors in patients with chronic schizophrenia

The overall findings according to this meta-analysis were as follows: the rate of being overweight was 49.4% (N=53) and 44.4% (N=8) according to two different criteria of waist circumference measurement. Hyperglycemia was detected in 19.5% of patients (N=147, n=13,784), while increased triglyceride was 39.3% (N=77, n=19,831), decreased HDL was 42.6% (N=76, n=19,280), high blood pressure was 38.7% (N=72, n=18,657), and presence of diabetes was 10.9% (N=14, n=2,186).Citation27 In addition, the rate of diabetes was reported as being 16% in females and 11% in males with schizophrenia, and only 3% in controls,Citation31 or reported to be 2.5–3-fold higher in the 1990s even before the extensive presence of atypical antipsychotics on the counter.Citation32

In the EUFEST study, the patients had a significantly greater weight gain and increased waist circumference in amisulpride and haloperidol groups than the ziprasidone group at weeks 26, 39, and 52, while no significant change was detected with respect to weight gain between groups at the first visit. Besides, weight gain and waist circumference were significantly higher at each time-point in the olanzapine and quetiapine groups than in the ziprasidone group.Citation26 In this study, no significant changes were seen between antipsychotic trial groups with respect to the blood levels of glucose, total cholesterol, triglyceride, and HDL. However, in a systematic review of FEP trials, the influences of antipsychotic drugs were tested in 25 studies in which the average follow-up time across was 31.7 weeks (ranged from 4 weeks to 2.5 years). Significant changes were common at the sixth month with regard to the total body weight, HDL, low density lipoprotein (LDL), triglycerides, fasting glucose and insulin levels.Citation1 In this review, the weight gain in olanzapine (5–6 kg) was significantly higher than risperidone (4 kg), and haloperidol (3 kg) at weeks 6–8, while the difference between olanzapine and risperidone was waned at weeks 12–16 (7–9 kg vs 6 kg, respectively).Citation1 The weight gain did not differ for 1 year across olanzapine, risperidone, clozapine, amisulpride, quetiapine fumarate, and haloperi-dol.Citation1 Interestingly, a question was raised as to whether orally disintegrating tablets may have lesser effects on weight gain or not than standard tablets ().Citation35 Although the number of hyperglycemia cases had increased after 52 weeks in the first episode of the psychosis Comparison of Atypicals in First Episode of Psychosis (CAFÉ) studyCitation36 and small amounts of increases in the blood glucose level was noted in the EUFESTCitation28 study groups, no difference was informed between various first- and second-generation antipsychotics. Risperidone was related to the smallest elevations of the triglyceride level in fasting and the smallest reduction in the HDL level than the other comparators such as olanzapine and quetiapine in the CAFÉ study.Citation36

The pathophysiology of the underlying MetS is not clear due to antipsychotic use, and an increased risk of CVD cannot be exactly attributed to antipsychotics or socio-demographical aspects of patients with schizophrenia.Citation34 In a Sweden study, the MetS rate was higher in chronic patients treated with clozapine.Citation39 In CATIE study (n=689), at the time of assessment, the groups were as follows: 24.8% were drug free/-naïve, 58.4% were taking an atypical antipsychotic, 11.9% were under conventional antipsychotic treatment, and 5.0% were taking a combination of antipsychotics. It was found that diabetes mellitus and hypertension and a significantly lower HDL level was significantly more frequent in patients with schizophrenia than that in controls.Citation33 In the seminal meta-analysis of Mitchell et al (N=112 studies and n=24,892 patients), 35.3% frequency of MetS in all schizophrenia patients and a 39.2% frequency of MetS in older patients (N=14, n=6,396) have been reported.Citation27 According to this meta-analysis, using Adult Treatment Panel III criteria, only three drug monotherapy comparisons were possible: the MetS rate was 51.9% (N=13, n=673) for clozapine; 28.2% (N=12, n=1,056) for olanzapine; and 27.9% (N=9, n=659) for risperidone. However, the finding of clozapine in this meta-analysis might have confounders as old age and a longer duration of illness.Citation27

Findings on cardiomyopathic risk factors and sudden cardiac death

In 1899, Emil Kraepelin mentioned extensive autonomic alterations in patients with schizophrenia, such as increased heart rates, altered pupillary function, increased sweating and salivation, and body temperature changes; these described signs suggest increased sympathetic output, decreased parasympathetic modulation, or both.Citation38

In the last 2 decades, the compromised autonomic system in schizophrenia patientsCitation38Citation40 and in first-degree relatives of patients with schizophreniaCitation43 has been accused for a number of cardiac abnormalities (). Autonomic dysfunction is most likely the consequence of long-lasting stressful experiences associated with the psychotic state, in addition to a genetic underlying predisposition to autonomic dysfunction as observed in the relatives of patients.Citation38 For example, decreased RR interval variability (RRV), which is a marker for cardiac parasympathetic activity, has been reported to predict potential fatal ventricular tachycardia.Citation42 Depression with psychotic features in a Finnish studyCitation43 has also been suggested as a risk factor for sudden death and other arrhythmic events.Citation44 Jindal et al concluded that drug-naïve patients with first-episode psychosis may have an impaired cardiac autonomic function.Citation42

Table 5 Cardiomyopathic risk factors in first-episode schizophrenia or at risk populations

In a meta-analysis study, antipsychotics were reported to increase risk by two- to sixfold for ventricular arrhythmias, sudden cardiac death, and lengthening of heart rate-corrected QT interval (QTc), and it has been widely accepted as a marker of predicting drug-associated cardiac eventsCitation45 although no clear evidence for the QT interval prolongation (>500 ms) is related with increased risk for TdP – an increased risk of ventricular tachyarrhythmia – or sudden cardiac death.Citation44,Citation46 Some questions rise whether there is any difference between atypical and typical antipsychotic drugs in the literature.Citation47 In a recently published study, no meaningful changes after ziprasidone use was detected in 27 first-episode psychosis (illness duration of <3 years, previous antipsychotic exposure lasting for <2 consecutive weeks).Citation48

Indeed, the prolonged QT interval was detected in 8%–23% of patients under antipsychotics treatment and in 2% of healthy controls, while a dose-dependent correlation between the risk of QT lengthening effects and antipsychotic use has also been emphasized.Citation49,Citation50

In a meta-analysis study of seven atypicals (aripiprazole, amisulpride, sertindole, risperidone, quetiapine, olanzapine, and ziprasidone), the authors have collected data of 16 randomized controlled trials (RCTs) from 42 RCTs.Citation45 They have found that aripiprazole was the only atypical drug that shows both significantly smaller mean change in QTc (P=0.03) and significantly lower risk to cause QTc prolongation (P=0.04), while sertindole was informed with a significant QTc prolongation (P<0.0001).Citation45 In another study, the QTc interval prolongation effects were ranked as: thioridazine > ziprasidone > quetiapine > risperidone > olanzapine > haloperidol.Citation52 One of the main questions was sex differences, because it is well-known that females are more prone to QT prolongation as found in a study that the mean QTc interval was shorter in males (391±31 ms vs 400±37 ms, P<0.001).Citation52 In a recent study according to the mean QTc interval, the results were as follows: quetiapine = olanzapine but quetiapine > risperidone and aripiprazole, and olanzapine > risperidone (). However, in this study, the mean chlorpromazine equivalent doses of olanzapine and quetiapine were significantly higher than risperidone and aripiprazole groups. In this study, the average QTc in females was significantly longer only in the olanzapine group.Citation53 However, in a few studies, no sex difference in QTc was demonstrated in various antipsychotic use such as depot, atypical, or typicals.Citation49,Citation54,Citation55

Table 6 Cardiomyopathic risk factors in chronic schizophrenia and use of antipsychotic drugs

Although there are extensive studies on QTc, very few studies have emphasized on the PR interval in the literature.Citation39,Citation57 In fact, prolongation of the PR interval might lead to atrial fibrillation, pacemaker indication, and mortality.Citation58 Emul et al have not found a difference on PR after intramuscular ziprasidone administrationCitation39 while a significantly increased PR interval after the third electroconvulsive therapy (ECT) session was reported in patients with schizophrenia who were under antipsychotic polypharmacy treatmentCitation61 or olanzapine is accounted for PR prolongation in a recent study.Citation57

Findings about sudden death due to cardiomyopathy related with antipsychotic drug use in schizophrenia

In the literature, a widely accepted etiologic factor for cardiomyopathy is the use of clozapine. In a 11-year follow-up study, clozapine was found to be related with the lowest mortality rate and the fewest number of deaths due to ischemic cardiac disease than the most frequently used typical and atypical antipsychotic drugs.Citation60 Previously, the rate of clozapine-related cardiomyopathy had been considered to be similar to that within the normal population (8.9/100,000) in the USA.Citation61 Now, the rate of clozapine-induced cardiomyopa-thy is demonstrated to be five times more frequent than that in the normal population.Citation62 In a study after 10 years from the first described clozapine-induced cardiomyopathy, Reinders et al estimated the prevalence to be 9.6%. This relatively high rate may be the real rate of clozapine-related cardiomyopathy because of the increase in the awareness of the clinicians.Citation63 In case reports, usually myocarditis initiates within the first month of clozapine administration, independent from dosing with tachycardia, shortness of breath, cough, and fatigue symptoms in which 12.5%–24% may have mortal outcomes.Citation63,Citation64 In the literature, there are few individual case reports on cardiomyopathy due to antipsychotic use such as amisulpride,Citation65 after quetiapine (n=3),Citation66Citation68 haloperidol, Citation69 and risperidone.Citation70

Discussion

Similar to schizophrenia, metabolic syndrome and cardiovascular symptoms in schizophrenia are also multifactorial and associated with the influences of multiple genes in combination with environmental factors. NRG1 is a signaling protein that mediates cell–cell interactions, which is a shared development process in schizophrenia and cardiac function. Interestingly, the minor allele of the non-synonymous SNP rs10503929 within the NRG1 gene was associated with sudden cardiac deaths. Functional polymorphisms in cytochrome P450, which play important roles in the metabolism of antipsychotic drugs, might be associated with prolongation of QTc.Citation71 The SLC22A23 gene expression is in the development of heartCitation72 and SNPs in that the gene might be related with QT prolongation in some antipsychotics. However, there are some debates in genetic studies which were searching for the association of SNPs with schizophrenia: an association of polymorphism with schizophrenia might be a chance of observation, replication of the SNP findings are almost infrequent, the detected SNPs that are not specific to schizophrenia may also be involved in bipolar disorder, etc, in a relatively small sample size under psychiatric conditions (few hundreds to few thousands in GWAS vs >50,000 diabetes/cardiac studies). Thus, to boost the power of the associated SNPs in GWASs, some innovative statistical approaches are considered in recent studies aiming to neglect the need of larger and larger samples for detecting cardiovascular risk factors in schizophrenia,Citation73,Citation74 although the richest findings from GWAS may still have very limited power to predict the genetic variation in schizophrenia.

In the last decade, a new window is opened after the discovery of the role of miRNAs to molecular pathology of schizophrenia with related implication for metabolic syndrome, being the target of antipsychotic drugs and interaction of neurotransmitters including serotonin–dopamine–glutamate. Changes in miRNA expression levels may reflect schizophrenia-related issues, conditions of high-risk individuals/first-episode psychotic, and/or intermediate targets of antipsychotic drug action that may lead to MetS, diabetes, and/or sudden cardiac death that are lacking in the literature. In addition, there are still no clinical and very few preclinical studies in association with miRNAs and after antipsychotic drug use. Thus, clarifying the potential role of miRNA in the pathophysiology of cardiovascular risks in schizophrenia might lead to the discovery of new therapeutic agents such as agonist miRNA (agomiR) or antagonist miRNA (antagomiR).

To clarify the related risk factors for increased MetS in patients with schizophrenia, drug-naïve patients or those who are at the very beginning stage of the illness and treatment seems crucial. In the literature, the findings seem far away from a consistent conclusion about glucose tolerance or insulin resistance in first-episode and/or drug-naïve patients. In addition, there is no consensus about the inclusion criteria of the first-episode psychosis/schizophrenia. Usually, the first-episode studies do not prolong >1 year and high dropout rates in longer trials are major concerns. Meanwhile, inconclusive findings as impaired/non-impaired glucose tolerance or insulin resistance/no effect can be seen in the literature about first-episode and/or drug-naïve patients. However, a question rises about the slightly higher waist/hip ratio at the initial phase just prior to antipsychotic drugs that justify to be investigated.Citation1 Thus, we considered that the prevalence of MetS rate is not increased at the very beginning of the illness as prior to antipsychotic use that may give opportunity to clinicians for earlier interventions regarding prevention of cardiometabolic events. In addition to waist size, the duration of illness was found to be an important predictor for MetS in schizophrenia in a large-scale meta-analysis study in 2013.Citation27 Naturally, patients with first-episode psychosis are more frequently males than females, and females might be more liable to the metabolic side-effects of antipsychotic drugs and to the increment of waist circumference. Questionably, the antipsychotic drug use is increasing and reached top-selling drugs, surpassing lipid regulators or pump inhibitors in the USA in 2008.Citation33 Although, the pathophysiology underlying MetS due to antipsychotic use is not clear,Citation34 there are reasons to assume that treatment effects are related to the risk factors for cardiovascular problems. Interestingly, the studies about the influences of antipsychotics on cardiovascular problems do not exceed 1 year and patients who are compliant beyond 1 year might be underestimated. It is important to consider that individuals with schizophrenia may have a disadvantageous lifestyle that may lead to additional reasons for the development of MetS such as substance abuse, stress, inadequate self-care and unavailability of health care, financial problems, smoking, poor diet, low mobility, and lack of exercise, which are beyond this review.

According to the literature, to rank each antipsychotic for QTc prolongation risk seems difficult. Furthermore, the clinical significance for QT prolongation is unclear while QTc >450 ms or >30 ms prolongation of QTc versus baseline is widely accepted as important. Nevertheless, there are few studies investigating cardiac autonomic dysfunction prior to antipsychotic use or after introducing antipsychotic drugs in patients with first-episode psychosis in the literature. There is no reported case of TdP in therapeutic doses of antipsychotics except overdose conditions in the literature. Furthermore, the relation between atypical or typical antipsychotics and sudden cardiac death was questioned after Ray et al’s published registry-based study that had reported similar rates of sudden deaths between atypical and typical drugs.Citation75 However, this study is considerably criticized because of the definition of sudden death and inattentiveness for deaths due to secondary coronarymetabolic side effects. In general, atypical antipsychotics were thought to be safer than typical ones among the QTc interval or sudden deaths.Citation47 Although the possible mechanism in the sex difference in the QTc interval among various antipsychotics remains unclear, the serum testosterone level is accused for QTc interval differences.Citation76 However, in a few studies, no sex difference in QTc was demonstrated in various antipsychotic use such as depot, atypical, or typical;Citation49,Citation54,Citation55 thus there might be some other determinants of QTc changes such as age (particularly, >60 years), drug interactions, and serum electrolytes (ie, hypokalemia or hypomagnesemia).Citation56 Therefore, some new assessments might be conducted to determine the influences of antipsychotic drugs such as fragmented QRS or the T-wave peak to T-wave end (TpTe) interval and TpTe/QT, which have been accepted as predictors of ventricular arrhythmia more than QTc.Citation77 In addition, the influence of antipsychotics on atrial conduction is very limited that may be observed on the PR interval or P-wave dispersion.

In the literature, a widely accepted etiologic factor for cardiomyopathy is the use of clozapine. The clozapineinduced immunoglobin E (IgE)-mediated hypersensitivity reaction, hypereosinophilic syndrome with direct cardiotoxic effects of eosinophils through the blockade of the cholinergic M2 receptor, and importantly, increase in noradrenalin after clozapine use than other antipsychotics were accounted for the clozapine-induced cardiomyopathy.Citation64 In the literature, there are few individual case reports on cardiomyopathy due to other antipsychotics.

Conclusion

The studies and awareness about the physical needs of patients with schizophrenia are increasing, which had been neglected for a long time. The health care authorities or organizations are inviting physicians for increased cooperation and shared care between the different health care professionals to screen and treat CVD-risk factors, MetS, and diabetes in patients with psychiatric disorders because some risk factors of MetS or CVD are avoidable or at least modifiable to decrease high mortality in schizophrenia. These outcomes are reinforcing the importance of assessing all patients for cardiometabolic risk prior to and throughout treatment, choosing best fitting antipsychotics, and monitoring cardiometabolic adverse effects. Thus, aiming to realize this serious challenge, further understanding of the underlying mechanisms and improved CVD prevention and treatment are needed. Finally, these future research groups should focus on conducting an integrated system of studies based on a holistic biopsychosocial evaluation.

Disclosure

The authors report no conflicts of interest in this work.

References

  • FoleyDLMorleyKISystematic review of early cardiometabolic outcomes of the first treated episode of psychosisArch Gen Psychiatry201168660961621300937
  • CorrellCURobinsonDGSchoolerNRCardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP studyJAMA Psychiatry201471121350136325321337
  • RingenPAEnghJABirkenaesABDiesetIAndreassenOAIncreased mortality in schizophrenia due to cardiovascular disease – a non-systematic review of epidemiology, possible causes, and interventionsFront Psychiatry2014513725309466
  • RyanMCCollinsPThakoreJHImpaired fasting glucose tolerance in first-episode, drug-naïve patients with schizophreniaAm J Psychiatry2003160228428912562574
  • RaphaelTPParsonsJPBlood sugar studies in dementia praecox and manic-depressive insanityArch Neurol Psychiatry19215687709
  • HansenTIngasonADjurovicSAt-risk variant in TCF7L2 for type II diabetes increases risk of schizophreniaBiol Psychiatry2011701596321414605
  • Le HellardSTheisenFMHaberhausenMAssociation between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?Mol Psychiatry200914330831718195716
  • LiouYJBaiYMLinEGene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychoticsPharmacogenomics J2012121546120877301
  • BaiYMChenTTLiouYJHongCJTsaiSJAssociation between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychoticsSchizophr Res20111252–317918621185157
  • BurghardtKGroveTEllingrodVEndothelial nitric oxide synthetase genetic variants, metabolic syndrome and endothelial function in schizophreniaJ Psychopharmacol201428434935624346810
  • ChenXLeeGMaherBSGROUP Investigators; International Schizophrenia ConsortiumGWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophreniaMol Psychiatry201116111117112920838396
  • NicodemusKKLawAJRadulescuEBiological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controlsArch Gen Psychiatry20106710991100120921115
  • MeyerDBirchmeimerCMultiple essential functions of neuregulin in developmentNature199537865583863907477375
  • Huertas-VazquezATeodorescuCReinierKA common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac deathHeart Rhythm201310799499823524320
  • AbergKAdkinsDELiuYGenome-wide association study of antipsychotic-induced QTc interval prolongationPharmacogenomics J201212216517220921969
  • SevenMKaratasOFDuzMBOzenMThe role of miRNAs in cancer: from pathogenesis to therapeutic implicationsFuture Oncol20141061027104824941988
  • de BartolomeisAIasevoliFTomasettiCBuonaguroEFMicroRNAs in schizophrenia: implications for synaptic plasticity and dopamine-glutamate interaction at the postsynaptic density. New avenues for antipsychotic treatment under a theranostic perspectiveMol Neurobiol Epub20141114
  • PerkinsDOJeffriesCDJarskogLFmicroRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorderGenome Biol200782R2717326821
  • GardinerEBeveridgeNJWuJQImprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cellsMol Psychiatry201217882784021727898
  • SantarelliDMLiuBDuncanCEGene-microRNA interactions associated with antipsychotic mechanisms and the metabolic side effects of olanzapinePsychopharmacology (Berl)20132271677823318695
  • GamiASWittBJHowardDEMetabolic syndrome and risk of incidence cardiovascular events and death: a systematic review and meta-analysis of longitudinal studiesJ Am Coll Cardiol200749440341417258085
  • HanleyAJKarterAJWilliamsKPrediction of type 2 diabetes mellitus with alternative definitions of the metabolic syndrome: the insulin resistance atherosclerosis studyCirculation2005112243713372116344402
  • SaddichhaSManjunathaNAmeenSAkhtarSEffect of olanzapine, risperidone, and haloperidol treatment on weight and body mass index in first-episode schizophrenia patients in India: a randomized, double-blind, controlled, prospective studyJ Clin Psychiatry200768111793179818052574
  • ZhangZJYaoZJLiuWFangQReynoldsGPEffects of antipsychotics on fat deposition and changes in leptin and insulin levels: magnetic resonance imaging study of previously untreated people with schizophreniaBr J Psychiatry2004184586214702228
  • RyanMCFlanaganSKinsellaUKeelingFThakoreJHThe effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naïve patients with schizophreniaLife Sci200474161999200814967195
  • FleischhackerWWSiuCOBodénREUFEST Study GroupMetabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia TrialInt J Neuropsychopharmacol201316598799523253821
  • MitchellAJVancampfortDSweersKvan WinkelRYuWDe HertMPrevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders – a systematic review and meta-analysisSchizophr Bull201339230631822207632
  • Van GaalLFLong-term health considerations in schizophrenia: metabolic effects and the role of abdominal adiposityEur Neuropsychopharmacol200616suppl 3S142S14816863690
  • FordESGilesWHDietzWHPrevalence of the metabolic syndrome among US adults: findings from the third national health and nutrition examination surveyJAMA2002287335635911790215
  • McEvoyJPMeyerJMGoffDCPrevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the clinical antipsychotic trials of intervention effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES IIISchizophr Res2005801193216137860
  • GoffDCSullivanLMMcEvoyJPA comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controlsSchizophr Res2005801455316198088
  • DixonLWeidenPDelahantyJPrevalence and correlates of diabetes in national schizophrenia samplesSchizophr Bull200026490391211087022
  • KuehnBMQuestionable antipsychotic prescribing remains common, despite serious risksJAMA2010303161582158420424239
  • RaedlerTJCardiovascular aspects of antipsychoticsCurr Opin Psychiatry201023657458120838345
  • ArranzBSanLDueñasRMLower weight gain with the orally disintegrating olanzapine than with standard tablets in first-episode never treated psychotic patientsHum Psychopharmacol2007221111517191265
  • McEvoyJPLiebermanJAPerkinsDOEfficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparisonAm J Psychiatry200716471050106017606657
  • HäggSLindblomYMjörndalTAdolfssonRHigh prevalence of the metabolic syndrome among a Swedish cohort of patients with schizophreniaInt Clin Psychopharmacol2006212939816421460
  • BärKJCardiac autonomic dysfunction in patients with schizophrenia and their healthy relatives – a small reviewFront Neurol2015613926157417
  • EmulMDalkiranMCoskunOP wave and QT changes among inpatients with schizophrenia after parenteral ziprasidone administrationPharmacol Res200960536937219647079
  • ToichiMKubotaYMuraiTThe influence of psychotic states on the autonomic nervous system in schizophreniaInt J Psychophysiol19993121471549987060
  • BärKJBergerSMetznerMAutonomic dysfunction in unaffected first-degree relatives of patients suffering from schizophreniaSchizophr Bull20103651050105819366982
  • JindalRDKeshavanMSEklundKStevensAMontroseDMYeraganiVKBeat-to-beat heart rate and QT interval variability in first episode neuroleptic-naïve psychosisSchizophr Res20091132–317618019570654
  • Valkonen-KorhonenMTarvainenMPRanta-AhoPHeart rate variability in acute psychosisPsychophysiology200340571672614696725
  • VrtovecBStarcVStarcRBeat-to-beat QT interval variability in coronary patientsJ Electrocardiol200033211912510819405
  • ChungAKChuaSEEffects on prolongation of Bazett’s corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysisJ Psychopharmacol201125564666620826552
  • WitchelHJHancoxJCNuttDJPsychotropic drugs, cardiac arrhythmia and sudden deathJ Clin Psychopharmacol2003231587712544377
  • ZemrakWRKennaGAAssociation of antipsychotic and antidepressant drugs with Q-T interval prolongationAm J Health Syst Pharm200865111029103818499875
  • ZhaoTParkTWYangJCEfficacy and safety of ziprasidone in the treatment of first-episode psychosis: an 8-week, open-label, multicenter trialInt Clin Psychopharmacol201227418419022426471
  • ReillyJGAyisSAFerrierINJonesSJThomasSHQTc-interval abnormalities and psychotropic drug therapy in psychiatric patientsLancet200035592091048105210744090
  • WarnerJPBarnesTRHenryJAElectrocardiographic changes in patients receiving neuroleptic medicationActa Psychiatr Scand19969343113138712033
  • HarriganEPMiceliJJAnzianoRA randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibitionJ Clin Psychopharmacol2004241626914709949
  • YangFDWangXQLiuXPSex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychoticsPsychopharmacology (Berl)2011216191621301815
  • SuzukiYSugaiTFukuiNSex differences in the effect of four second-generation antipsychotics on QTc interval in patients with schizophreniaHum Psychopharmacol201328321521923553637
  • OzekiYFujiiKKurimotoNQTc prolongation and antipsychotic medications in a sample of 1,017 patients with schizophreniaProg Neuropsychopharmacol Biol Psychiatry201034240140520079791
  • Ramos-RíosRArrojo-RomeroMPaz-SilvaEQTc interval in a sample of long-term schizophrenia inpatientsSchizophr Res20101161354319892525
  • HasnainMViewegWVQTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive reviewCNS Drugs2014281088792025168784
  • SuzukiYOnoSTsuneyamaNEffects of olanzapine on the PR and QT intervals in patients with schizophreniaSchizophr Res2014152131331424275577
  • ChengSKeyesMJLarsonMGLong-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular blockJAMA2009301242571257719549974
  • BayarREmülMTuranSElectrocardiographical P wave changes after electroconvulsive therapy in patients with schizophrenia: a preliminary studyJ ECT2009251263018665103
  • TiihonenJLönnqvistJWahlbeckK11-Year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)Lancet2009374969062062719595447
  • La GrenadeLGrahamDTrontellAMyocarditis and cardiomyopathy associated with clozapine use in the United StatesN Engl J Med2001345322422511463031
  • AlawamiMWasywichCCicovicAKenediCA systematic review of clozapine induced cardiomyopathyInt J Cardiol2014176231532025131906
  • ReindersJParsonageWLangeDPotterJMPleverSClozapine related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric serviceAust N Z J Psychiatry20043811–1291592215555025
  • De BerardisDSerroniNCampanellaDUpdate on the adverse effects of clozapine: focus on myocarditisCurr Drug Saf201271556222663959
  • BrakouliasVBannanECohenPGearyGAmisulpride and cardiomyopathyAust N Z J Psychiatry200539873816050932
  • BushABurgessCFatal cardiomyopathy due to quetiapineN Z Med J20081211268U290918256721
  • Roesch-ElyDVan EinsiedelRKathöferSSchwaningerMWeisbrodMMyocarditis with quetiapineAm J Psychiatry200215991607160812202290
  • CoffeySWilliamsMQuetiapine-associated cardiomyopathyN Z Med J2011124133710510721946883
  • BhatiaMSGuptaRDhawanJMyocarditis after overdose of conventional antipsychoticsWorld J Biol Psychiatry2009104 pt 260660817965989
  • MartiVSudden cardiac death due to risperidone therapy in a patient with possible hypertrophic cardiomyopathyAnn Pharmacother200539597315827070
  • TayJKTanCHChongSATanECFunctional polymorphisms of the cytochrome P450 1A2 (CYP1A2) gene and prolonged QTc interval in schizophreniaProg Neuropsychopharmacol Biol Psychiatry20073161297130217611010
  • ChristoforouNMillerRAHillCMJieCCMcCallionASGearhartJDMouse ES cell-derived cardiac precursor cells are multipotent and facilitate identification of novel cardiac genesJ Clin Invest2008118389490318246200
  • AndreassenOAThompsonWKDaleAMBoosting the power of schizophrenia genetics by leveraging new statistical toolsSchizophr Bull2014401131724319118
  • AndreassenOADjurovicSThompsonWKInternational Consortium for Blood Pressure GWAS, Diabetes Genetics Replication and Meta-analysis Consortium, Psychiatric Genomics Consortium Schizophrenia Working GroupImproved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factorsAm J Hum Genet201392219720923375658
  • RayWAChungCPMurrayKTHallKSteinCMAtypical antipsychotic drugs and the risk of sudden cardiac deathN Engl J Med2009360322523519144938
  • van NoordCDörrMSturkenboomMCThe association of serum testosterone levels and ventricular repolarizationEur J Epidemiol2010251212819957021
  • GuptaPPatelCPatelHT (p-e)/QT ratio as an index of arrhythmogenesisJ Electrocardiol20084156757418790499