Risk of Ischemic Stroke Associated with the Use of Antipsychotic Drugs in Elderly Patients: A Retrospective Cohort Study in Korea

<div><p>Objective</p><p>Strong concerns have been raised about whether the risk of ischemic stroke differs between conventional antipsychotics (CAPs) and atypical antipsychotics (AAPs). This study compared the risk of ischemic stroke in elderly patients taking CAPs and AAPs.</p><p>Method</p><p>We conducted a retrospective cohort study of 71,584 elderly patients who were newly prescribed the CAPs (haloperidol or chlorpromazine) and those prescribed the AAPs (risperidone, quetiapine, or olanzapine). We used the National Claims Database from the Health Insurance Review and Assessment Service (HIRA) from January 1, 2006 to December 31, 2009. Incident cases for ischemic stroke (ICD-10, I63) were identified. The hazard ratios (HR) for AAPs, CAPs, and for each antipsychotic were calculated using multivariable Cox regression models, with risperidone as a reference.</p><p>Results</p><p>Among a total of 71,584 patients, 24,668 patients were on risperidone, 15,860 patients on quetiapine, 3,888 patients on olanzapine, 19,564 patients on haloperidol, and 7,604 patients on chlorpromazine. A substantially higher risk was observed with chlorpromazine (HR = 3.47, 95% CI, 1.97–5.38), which was followed by haloperidol (HR = 2.43, 95% CI, 1.18–3.14), quetiapine (HR = 1.23, 95% CI, 0.78–2.12), and olanzapine (HR = 1.12, 95% CI, 0.59–2.75). Patients who were prescribed chlorpromazine for longer than 150 days showed a higher risk (HR = 3.60, 95% CI, 1.83–6.02) than those who took it for a shorter period of time.</p><p>Conclusions</p><p>A much greater risk of ischemic stroke was observed in patients who used chlorpromazine and haloperidol compared to risperidone. The evidence suggested that there is a strong need to exercise caution while prescribing these agents to the elderly in light of severe adverse events with atypical antipsychotics.</p></div

Sub-group analysis of the risk of ischemic stroke with quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone according to the age group, gender, the presence and type of dementia, and comorbidity.

<p>Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>The estimated HRs were finally accepted as the SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score is > 99.99 in quetiapine, < 0.05 in olanzapine, > 0.90 in haloperidol, and < 0.05 in chlorpromazine</p><p>* Could not be estimated.</p><p>† P for trend was calculated using likelihood ratio test.</p><p>Sub-group analysis of the risk of ischemic stroke with quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone according to the age group, gender, the presence and type of dementia, and comorbidity.</p

Cumulative hazard rate for ischemic stroke after the initiation of risperidone, quetiapine, olanzapine, haloperidol, and chlorpromazine.

<p>Cumulative hazard rate for ischemic stroke after the initiation of risperidone, quetiapine, olanzapine, haloperidol, and chlorpromazine.</p

General characteristics of new users of conventional and atypical antipsychotic medications.

<p>* The P value was calculated by using the Mantel-Haenszel chi-squared test.</p><p>† The P value was calculated by using an ANOVA test with the Bonferroni correction.</p><p>General characteristics of new users of conventional and atypical antipsychotic medications.</p

Incidence rates and hazard ratios of ischemic stroke after the initiation of conventional and atypical antipsychotic medications.

<p>(SMR, standardized morbidity ratio)</p><p>* (No. of events/total No. of days per 365 days)× 1,000.</p><p>† Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score was > 99.99 in quetiapine, < 0.05 in olanzapine, > 0.90 in haloperidol, and < 0.05 in chlorpromazine.</p><p>Incidence rates and hazard ratios of ischemic stroke after the initiation of conventional and atypical antipsychotic medications.</p

Dose-response relationship and time-varying risks of ischemic stroke of quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone.

<p>(Mean PDD, mean Prescribed Daily Dose)</p><p>*Adjusted for age, gender, presence or absence of dementia (F00-F03, G30, G31.8), depression (F32–33, F34.1, F41.2), dyslipidemia (E78.0), coronary heart disease (I21-I25), COPD (J40-J44, J47), and the use of antidepressants, benzodiazepine, anticoagulants, or antithrombotic agents during the follow-up period.</p><p>The estimated HRs were finally accepted as the SMR weighted and multivariable adjusted HR after exclusion of the patients whose propensity score is > 99.99 in quetiapine, < 0.05 in olanzapine, >0.90 in haloperidol, and < 0.05 in chlorpromazine</p><p>†Could not be estimated.</p><p>‡P for trend was calculated using the likelihood ratio test.</p><p>§Short- and long-term periods were distinguished by the cross-point using a log-log survival curve.</p><p>Dose-response relationship and time-varying risks of ischemic stroke of quetiapine, olanzapine, haloperidol, and chlorpromazine compared with risperidone.</p

<i>In vitro</i> and <i>In vivo</i> effect of PL-PP on implantation in the presence of a progesterone antagonist.

(A) Ishikawa cells in the absence or presence of RU486 (10 μM) were treated with or without PL-PP (50 μg/mL) in serum free medium for 48 h. Twenty JAr spheroids were added onto the Ishikawa cell monolayer. The number of adherent JAr spheroids to Ishikawa cells was counted in representative pictures and calculated as the mean ± SD of three independent experiments (* P P (B) Female mice were treated with or without RU486 and PL-PP. After 7 days, all mice were euthanized and both uterine horns were excised to determine the number of implantation sites. Pictures of implanted embryos are shown. Arrows indicate implanted embryos. The number of implantation sites was counted and calculated as the mean ± SD of three independent experiments (** P P (C) The uterin tissue sections were analyzed histologically after H&E staining. Embryo implantation sites are indicated by arrows.</p

<i>Paeonia lactiflora</i> Enhances the Adhesion of Trophoblast to the Endometrium via Induction of Leukemia Inhibitory Factor Expression

<div><p>In the present study, we investigated the role of <i>Paeonia lactiflora Pall</i>. extract on embryo implantation <i>in vitro</i> and <i>in vivo</i>. A polysaccharides depleted-water extract of <i>P</i>. <i>lactiflora</i> (PL-PP) increased LIF expression in human endometrial Ishikawa cells at non-cytotoxic doses. PL-PP significantly increased the adhesion of the human trophectoderm-derived JAr spheroids to endometrial Ishikawa cells. PL-PP-induced LIF expression was decreased in the presence of a p38 kinase inhibitor SB203580 and an MEK/ERK inhibitor U0126. Furthermore, endometrial LIF knockdown by shRNA reduced the expression of integrins β3 and β5 and adhesion of JAr spheroids to Ishikawa cells. <i>In vivo</i> administration of PL-PP restored the implantation of mouse blastocysts in a mifepristone-induced implantation failure mice model. Our results demonstrate that PL-PP increases LIF expression via the p38 and MEK/ERK pathways and favors trophoblast adhesion to endometrial cells.</p></div

PCR conditions and amplified size for each target gene, and the primers used in this study.

PCR conditions and amplified size for each target gene, and the primers used in this study.</p

PL-PP HPL chromatogram.

HPLC was performed as described in the Materials and Methods. Retention times of the standard compounds were 4.8, 10.5, 11.5, 17.5, and 28 min for gallic acid, catechin, methyl gallate, paeoniflorin, and benzoic acid, respectively.</p