Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review

Luijendijk, Hendrika J.; Bruin, N. C. De; Hulshof, Tessa A.; Koolman, Xander

doi:10.1002/pds.3912

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…Similarly, it is possible that haloperidol is more often used in terminally ill patients as a comfort medication. 33 But the trend of care characteristic of terminal illness before antipsychotic initiation such as opioid use or discontinuation of chronic disease care was similar between the two groups. Lastly, the mechanism of the increased risk of death is unknown since we did not have information on cause of death.…”

Section: Discussionmentioning

confidence: 91%

“…Terminal illness in haloperidol users has been suggested as a source of potential residual confounding in outpatient studies. 33 We therefore examined the patterns of use of medications frequently used in patients who are approaching the end-of-life stage (short acting and long acting opioids, benzodiazepines), 34 and discontinuation of chronic disease treatments (statins, β blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers) before the index date. 35 …”

Section: Methodsmentioning

confidence: 99%

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Use of haloperidol versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial infarction: cohort study

Park

Bateman

Kim

et al. 2018

BMJ

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ObjectiveTo compare the risk of in-hospital mortality associated with haloperidol compared with atypical antipsychotics in patients admitted to hospital with acute myocardial infarction.DesignCohort study using a healthcare database.SettingNationwide sample of patient data from more than 700 hospitals across the United States.Participants6578 medical patients aged more than 18 years who initiated oral haloperidol or oral atypical antipsychotics (olanzapine, quetiapine, risperidone) during a hospital admission with a primary diagnosis of acute myocardial infarction between 2003 and 2014.Main outcome measureIn-hospital mortality during seven days of follow-up from treatment initiation.ResultsAmong 6578 patients (mean age 75.2 years) treated with an oral antipsychotic drug, 1668 (25.4%) initiated haloperidol and 4910 (74.6%) initiated atypical antipsychotics. The mean time from admission to start of treatment (5.3 v 5.6 days) and length of stay (12.5 v 13.6 days) were similar, but the mean treatment duration was shorter in patients using haloperidol compared with those using atypical antipsychotics (2.4 v 3.9 days). 1:1 propensity score matching was used to adjust for confounding. In intention to treat analyses with the matched cohort, the absolute rate of death per 100 person days was 1.7 for haloperidol (129 deaths) and 1.1 for atypical antipsychotics (92 deaths) during seven days of follow-up from treatment initiation. The survival probability was 0.93 in patients using haloperidol and 0.94 in those using atypical antipsychotics at day 7, accounting for the loss of follow-up due to hospital discharge. The unadjusted and adjusted hazard ratios of death were 1.51 (95% confidence interval 1.22 to 1.85) and 1.50 (1.14 to 1.96), respectively. The association was strongest during the first four days of follow-up and decreased over time. By day 5, the increased risk was no longer evident (1.12, 0.79 to 1.59). In the as-treated analyses, the unadjusted and adjusted hazard ratios were 1.90 (1.43 to 2.53) and 1.93 (1.34 to 2.76), respectively.ConclusionThe results suggest a small increased risk of death within seven days of initiating haloperidol compared with initiating an atypical antipsychotic in patients with acute myocardial infarction. Although residual confounding cannot be excluded, this finding deserves consideration when haloperidol is used for patients admitted to hospital with cardiac morbidity.

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Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Use of haloperidol versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial infarction: cohort study

Park

Bateman

Kim

et al. 2018

BMJ

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“…In this regard, it should be noted that several reports have claimed minimal effects of antipsychotic drugs on risk of mortality with dementia patients [ 41, 57, 60–67 ]. However, the latter studies have been based on older literature or culminated from extracting heavily selected and refined data, adjusted by many exclusions made for clinical factors deemed as confounders such as mortality risks and co-morbidities relating to terminal illness [ 65 ]. Amongst the more stringent criteria applied for exclusion have been factors such as the severity of dementia, gender, advanced age or co-morbidities including cardiovascular, diabetes, cancer, respiratory or other somatic disease burdens or neuropsychiatric behavioral problems with some of the studies involving nearly 40 exclusion criteria in their adjustments [ 41, 57, 60–66 ].…”

Section: Discussionmentioning

confidence: 99%

Increased All-Cause Mortality by Antipsychotic Drugs: Updated Review and Meta-Analysis in Dementia and General Mental Health Care

Ralph

Espinet

2018

Journal of Alzheimer's Disease Reports

123

114

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It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta-analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients.

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“…Atypical antipsychotics (AAPs) are considered to possess superior efficacy for treating both the positive and negative symptoms of schizophrenia compared to typical antipsychotics 1 , 2 . However, a high prevalence of metabolic syndrome 3 – 6 and increased mortality rate 7 , 8 were observed in schizophrenic patients, and were considered to be adverse effects of AAPs. AAP-induced metabolic syndrome consists of excessive weight gain, type II diabetes mellitus, hyperglycemia, dyslipidemia, insulin resistance and cardiovascular disease 3 – 7 , 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Insig-2 inhibits atypical antipsychotic-induced adipogenic differentiation and lipid biosynthesis in adipose-derived stem cells

Chen

Hsu

Huang

et al. 2017

Sci Rep

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Atypical antipsychotics (AAPs) are considered to possess superior efficacy for treating both the positive and negative symptoms of schizophrenia; however, AAP use often causes excessive weight gain and metabolic abnormalities. Recently, several reports have demonstrated that AAPs activate sterol regulatory element-binding protein (SREBP). SREBP, SREBP cleavage-activating protein (SCAP) and insulin-induced gene (Insig) regulate downstream cholesterol and fatty acid biosynthesis. In this study, we explored the effects of clozapine, olanzapine and risperidone on SREBP signaling and downstream lipid biosynthesis genes in the early events of adipogenic differentiation in adipose-derived stem cells (ASCs). After the induction of adipogenic differentiation for 2 days, all AAPs, notably clozapine treatment for 3 and 7 days, enhanced the expression of SREBP-1 and its downstream lipid biosynthesis genes without dexamethasone and insulin supplementation. Simultaneously, protein level of SREBP-1 was significantly enhanced via inhibition of Insig-2 expression. By contrast, SREBP-1 activation was suppressed when Insig-2 expression was upregulated by transfection with Insig-2 plasmid DNA. In summary, our results indicate that AAP treatment, notably clozapine treatment, induces early-stage lipid biosynthesis in ASCs. Such abnormal lipogenesis can be reversed when Insig-2 expression was increased, suggesting that Insig/SCAP/SREBP signaling may be a therapeutic target for AAP-induced weight gain and metabolic abnormalities.

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Terminal illness and the increased mortality risk of conventional antipsychotics in observational studies: a systematic review

Abstract: We conclude that terminal illness has not been adjusted for in observational studies that reported an increased risk of mortality risk in elderly users of conventional antipsychotics. As the validity of the evidence is questionable, so is the warning based on it.

Cited by 10 publications

References 53 publications

Use of haloperidol versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial infarction: cohort study

Use of haloperidol versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial infarction: cohort study

Increased All-Cause Mortality by Antipsychotic Drugs: Updated Review and Meta-Analysis in Dementia and General Mental Health Care

Overexpression of Insig-2 inhibits atypical antipsychotic-induced adipogenic differentiation and lipid biosynthesis in adipose-derived stem cells

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