Etiology of cardiovascular disease in patients with schizophrenia: current perspectives

Figures & data

Table 1 Genetics in cardiometabolic risk factors in schizophrenia

Authors	Participants	Design	Results
Hansen et al^Citation6	420 Danish patients with schizophrenia, two healthy controls for each patient	Type 2 diabetes mellitus-risk-related single nucleotide polymorphism	At-risk allele in TCF7L2 (rs79031146) was associated with schizophrenia
Le Hellard et al^Citation7	160 first-time users of clozapine with a mean dose was 285±121 mg/day in schizophrenia patients	All were monitored for the changes in body mass index during clozapine treatment	Strong association between weight gain and rs17587100, rs10490624, and rs17047764, localized in/near INSIG2 gene
Liou et al^Citation8	456 schizophrenia patients with an average treatment of 45.5±27.6 months; with clozapine (n=171), olanzapine (n=91), risperidone (n=194)	The association of SNPs in INSIG1 and INSIG2 in MetS or without MetS. The gene–gene interaction model of INSIG1 and INSIG2	The INSIG2 rs11123469-C homozygous genotype was more frequent in patients with MetS. Interactions between INSIG1 and INSIG2 were significant
Bai et al^Citation9	456 schizophrenia inpatients; clozapine (n=171), olanzapine (n=91, risperidone (n=194)	6 tag SNPs, capturing all common genetic variations in the HTR2C gene	The rs498177 SNP showed a significant association with MetS in female patients
Burghardt et al^Citation10	203 patients under-treatment with schizophrenia or schizoaffective disorder	eNOS genetic variants and endothelial function (artery tonometry) were assessed	Association between eNOS T-786C and worse endothelial functioning only in patients without MetS

Note: Data are presented as mean ± standard deviation.

Abbreviations: SNP, single nucleotide polymorphism; eNOS, endothelial nitric oxide synthetase; MetS, metabolic syndrome.

Table 2 Genetics in cardioautonomic risk factors

Authors	Participants	Design	Results
Chen et al^Citation11	25 samples with a total of 33,834 subjects, including 912 families with 4,160 subjects, 13,038 cases and 16,636 controls	GWA analyses study in the CMYA5 gene	rs10043986 and rs4704591 were significantly associated with schizophrenia
Nicodemus et al^Citation12	296 schizophrenia, 365 healthy controls and a separate sample of controls for neuroimaging (n=172)	Association between SNPs and the relationship between SNPs and BOLD during the working memory by fMRI	Interaction between NRG1 5′ and rs4560751–rs3802160 and schizophrenia, validated using fMRI of working memory
Huertas-Vazquez et al^Citation14	Oregon study, 340 SCD cases presenting with ventricular fibrillation and 342 controls	17 SNPs mapped to 14 loci related with schizophrenia and epilepsy was tested	SNP rs10503929 within the NRG1 gene was associated with SCD
Aberg et al^Citation15	492,000 SNP genotypes from 738 schizophrenia patients from the CATIE study	Antipsychotic-induced QTc prolongation; a GWA study	Association of rs4959235 and quetiapine/QTc within gene SLC22A23
Santarelli et al^Citation20	miRNA profile in mice treated with haloperidol (n=11), olanzapine (n=11) or clozapine (n=12) for 7 days and saline group (n=11)	45 total mouse whole brain RNA samples were used for microarray profiling	Down regulation of miR-193, miR-223, miR-544 in DLPC by olanzapine; upregulation of miRNA-339 in BA22 in haloperidol

Abbreviations: GWA, genome-wide association; SNP, single nucleotide polymorphism; RNA, ribonucleic acid; miRNA, microRNA; QTc, heart rate-corrected QT interval; CATIE, Clinical Antipsychotic Trial of Intervention Effectiveness; fMRI, functional magnetic resonance imaging; SCD, sudden cardiac death; DLPFC, dorsolateral prefrontal cortex; BOLD, blood oxygen level-dependent.

Table 3 Cardiometabolic risk factors in first-episode psychosis

Authors	Participants	Design	Results
Foley et al^Citation1	Drug naïve or with a short-time drug treatment, sample size varied (n=9–555)	Review of 25 longitudinal studies and of which 8 have controls	No difference in cardiometabolic indices; risk increases after first exposure to any antipsychotics
Correll et al^Citation2	Patients in FES programs, had less than 6 months of antipsychotic treatment	Baseline findings in the RAISE study	13.2% of FES patients met the criteria of MetS
Saddichha et al^Citation23	66 FEP patients initiating to olanzapine, haloperidol, or risperidone	Randomized, case-control and a prospective study (for a period of 6 weeks)	Baseline obesity prevalence was 30 times higher in patients; olanzapine, 5.1 kg > risperidone, 4.1 kg > haloperidol, 2.8 kg
Ryan et al^Citation25	19 drug naïve, FEP patients, and 19 matched controls, started to receive olanzapine or risperidone	Fatness and fat distribution parameters were measured	Baseline intra-abdominal fat was significantly higher in patients; no significant increase in intra-abdominal fat distribution after atypicals
Fleischhacker et al^Citation26	498 patients with FEP, EUFEST study; visits at the 13th, 26th, 39th and 52nd weeks	1-year open label study including baseline MetS indices	Baseline MetS prevalence was 5.7% in drug-naïve and 6.1% in briefly antipsychotics exposed patients

Abbreviations: FES, first-episode schizophrenia; FEP, first-episode psychosis; EUFEST, European First Episode Schizophrenia Trial; MetS, metabolic syndrome; RAISE, Recovery After an Initial Schizophrenia Episode.

Table 4 Cardiometabolic risk factors in patients with chronic schizophrenia

Authors	Participants	Design	Results
McEvoy et al^Citation30	n=689 chronic patients with schizophrenia	CATIE, a national, multisite, prospective trial of anti-psychotic effectiveness	Baseline MetS was 40.9%–42.7% in patients, 23.7% in normal subjects
Goff et al^Citation31	n=689 chronic patients with schizophrenia	CATIE	The presence of diabetes was 13% and 3% in normal subjects
Dixon et al^Citation32	Large population under treatment for schizophrenia (n=20,248)	The schizophrenia Patient Outcomes Research Team study	The rate of diabetes was found to be 2.5–3-fold higher than general population
Arranz et al^Citation35	Patients with schizophrenia; standard olanzapine tablets (n=19), and disintegrating olanzapine (n=19)	Prospective study (6 weeks)	Significant increase in weight 6.3±1.9 kg vs 3.3±3.2 kg and in BMI 2.1 kg/m^2 vs 1.1 kg/m^2 in standard than disintegrating olanzapine
Hägg et al^Citation37	269 under-treatment patients with schizophrenia	A cross-sectional Northern Sweden study	MetS was 34.6% and the highest in clozapine-treated patients, ie, 48%

Note: Data are presented as mean ± standard deviation.

Abbreviations: CATIE, clinical antipsychotic trial of intervention effectiveness; MetS, metabolic syndrome; BMI, body mass index.

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

Authors	Participants	Design	Results
Emul et al^Citation39	Schizophrenia inpatients (n=11), drug free (<4 weeks), 11 controls	ECG reports prior to ziprasidone and 1.5–2 h after an IM injection	Baseline P-wave dispersion was significantly longer in patients; no changes after ziprasidone IM have detected among ECG variables
Toichi et al^Citation40	53 chronic patients (n=22 acute psychotic attack, n=31, stable), 53 healthy controls	In ECG, cardiac autonomic functions were based on heartbeat intervals	In psychotic attack, parasympathetic index was significantly decreased without significant changes in the sympathetic index
Bär et al^Citation41	Paranoid schizophrenia (n=36), 36 first-degree relatives, controls (n=36)	Cross-sectional, case-control study	Evidence for reduced HRV as well as augmented QT variability in first-degree relatives
Jindal et al^Citation42	24 neuroleptic-naïve FEP patients, 26 controls	ECG data were collected between 8 and 10 am	Significantly increased QTV and decreased RRV. No correlation between psychotic symptom severity and HRV abnormalities
Zhao et al^Citation48	27 FEP, the initiation of oral ziprasidone (up to 120–160 mg/day)	Prospective, 8 weeks; 16 dropped out; data of 11 patients were analyzed	The mean QT prolongation was 20 ms, no QTc prolongation >500 ms

Abbreviations: ECG, electrocardiogram; RRV, RR interval variability; QTc, heart beat-corrected QT interval; FEP, first-episode psychosis; h, hour; IM, intramuscular; HRV, heart rate variability; QTV, QT interval variability; QT, QT interval.

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

Authors	Participants	Design	Results
Harrigan et al^Citation51	Haloperidol (n=27) 15 mg/day; thioridazine (n=30) 300 mg/day; ziprasidone (n=31) 160 mg/day; quetiapine (n=27) 750 mg/day; olanzapine (n=24) 20 mg/day, or risperidone 6–8 mg/day increased to 16 mg/day (n=25/20)	Psychotic patients, open-label, randomized, parallel-group, the influences of 6 antipsychotics on QTc	None of drugs >500 ms on QTc; the mean QTc increments: in thioridazine (30.1 ms), in olanzapine (1.7 ms), in ziprasidone (15.9 ms), in haloperidol (7.1 ms), in quetiapine it was (5.7 ms) and in risperidone groups (3.9 ms and 3.6 ms)
Yang et al^Citation52	Under-treatment inpatients schizophrenia (n=1,006) (male, 689 and female, 317) and age- and sex-matched controls (n=456)	Naturalistic	Prolonged QTc was 4.5%; (3.2% in males and 7.3% in females); QTc in clozapine was significantly longer than risperidone and typicals; QTc in risperidone = typical
Suzuki et al^Citation53	Schizophrenia (n=222) with OLZ (n=69), RIS (n=60), ARP (n=62), or QTP (n=31)	QTc interval in chronic schizophrenic patients	QTP > RIS (P=0.002) QTP > ARP (P=0.029) OLZ > RIS (P=0.006)
Hasnain et al^Citation56	Amisulpride (n=83); clozapine (n=73); quetiapine mono/combined (n=286); risperidone (n=45), ziprasidone (n=56)	Overdoses of different antipsychotics on QTc and TdP	Amisulpride, 7%, TdP; clozapine, 8.2% QTc prolongation; quetiapine, 8.4% borderline QTc; risperidone, 58% tachycardia ziprasidone, 2% TdP and 12.5% borderline QTc prolongation
Suzuki et al^Citation57	25 schizophrenia outpatients	Follow-up study after olanzapine use	Significant increase in PR interval, not more than 200 ms; no significance in the QT interval
Bayar et al^Citation59	15 schizophrenia receiving antipsychotics, 15 controls	ECG records at baseline and after the 3rd ECT	Baseline P minimum duration was shorter in patients; significant increase in P maximum duration after the 3rd ECT; no changes after the 3rd ECT in P-wave dispersion, QTc, and QT dispersion

Abbreviations: OLZ, olanzapine; RIS, risperidone; QTP, quetiapine QT interval; ECG, electrocardiogram; QTc, heart beat-corrected QT interval; TdP, Torsade de Pointes; ECT, electroconvulsive therapy; ms, milliseconds; ARP, aripiprazole; QT, QT interval.

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