We know that for people with schizophrenia, life expectancy could be reduced by 15-20 years due to various factors, such as increased risk of cancers, respiratory diseases, and cardiovascular disease (Reilly et al., 2015; Osborn et al., 2007). We’ve seen early mortality decrease over recent years for the general population, but this hasn’t been the case for people with schizophrenia.
We have begun to understand the wider causes for this inequality and the important role of factors such as lifestyle, stigma, unemployment and poverty. Research to untangle this web of inequality is growing, but there is little evidence on how the medications used to treat schizophrenia can affect people’s long-term physical health.
Antipsychotics are effective for preventing schizophrenia relapse and this has been demonstrated in randomised controlled trials (RCTs) (Leucht et al., 2012) and in the real world (Taipale et al., 2017). Despite this, antipsychotics are associated with increased risk of adverse physical health effects (Correll et al., 2015) and linked with weight gain, metabolic problems and negative cardiac effects in the short-term. It may seem logical that these increased short-term risks would lead to greater long-term health risks. However, we know very little about the association between long-term antipsychotic use and their effects on the cardiometabolic system, physical morbidity, and mortality. We should ask and address an important question – do antipsychotics help people to live longer?
Recent evidence from placebo-controlled RCTs, systematic reviews and meta-analyses exploring the short-term effects of antipsychotics indicate that taking antipsychotics reduces the risk of early mortality compared to non-use (Schneider-Thoma et al., 2018; Khan et al., 2013). Large-scale observational studies also suggest that all-cause mortality is reduced when taking antipsychotics and this is attributed to healthier lifestyles, less psychosis-related cortisol increase, and increased engagement with health services (Tiihonen et al., 2009; Taipale et al., 2018; Crump et al., 2013).
Taipale and colleagues (2020) aimed to explore the risk of hospitalisation due to physical health problems and risk of all-cause mortality associated with antipsychotics to treat schizophrenia over the course of 20 years. Let’s take a look.
The study involved all people treated for schizophrenia under inpatient hospital care in Finland between 1974 and 2014. Participants were followed up from 1996 to 2015. Two cohorts were utilised:
- a prevalent cohort of 62,250 people with schizophrenia
- an incident cohort of 8,719 people who were experiencing a psychotic episode, stayed in hospital due to schizophrenia between 1996 and 2014, and had not used antipsychotics in the year before hospitalisation.
Prescription register data was used to record antipsychotic medication start and end date, amount prescribed, and personal medication use patterns. Utilising hospital registry data is a useful way to reduce sampling bias by capturing a large portion of a population.
Outcomes and analyses
All somatic and cardiovascular hospitalisations were measured during the 20 year follow-up period. These were analysed using within-individual design which is appropriate for recurrent events. All-cause mortality, cardiovascular mortality, and deaths by suicide were recorded and analysed with multivariate-adjusted Cox regression models. The models were adjusted for gender, age, time since diagnosis, previous exposure to antipsychotics, other medication use, non-adherence, previous suicidal behaviour and physical comorbidities, and other factors. Sensitivity analyses were also conducted to ensure the statistical power of the findings.
Overall, the study reported the following results:
- Antipsychotic use was not associated with an increased risk of hospitalisation for somatic or cardiovascular reasons in people with schizophrenia
- Antipsychotic use was associated with decreased risk of all-cause mortality and deaths by suicide.
In short, this study found that people with schizophrenia were likely to be overall better off for taking antipsychotics as prescribed by their clinician and that taking the medication provided a longer, healthier life.
Antipsychotics appear to be good when used effectively and are properly managed. Side-effects can be a cost for better mental health and these results on reduced mortality show that this should not be understated.
Strengths and limitations
The results may be surprising to many as the short-term effects of weight gain, impaired glucose tolerance, and cardiovascular problems are risk factors for morbidity and mortality, but the results are consistent with previous research (Crump et al., 2016; Taipale et al., 2018; Tiihonen et al., 2009; Tiimohen et al., 2016; Tiimohen et al., 2018; Vermeulen et al., 2017).
The findings support results from a previous Swedish study, but one interesting difference arose (Taipale et al., 2018). They indicated that antipsychotic injections were associated with 33% reduction in all-cause mortality compared to oral antipsychotics, whereas this study found no differences between administration methods. The authors note that this could be explained by differential approaches between countries; injection administration is much more common in Sweden (accounting for 29% of all antipsychotic use) compared to Finland (8.5%) (Taipale, H. et al, 2018).
The study allowed adverse events due to long-term cumulative exposure to be understood. The within-individuals design allowed researchers to control for individual characteristics including diet, exercise, genetic factors and severity of schizophrenia. However, it would have been useful to collect data on key lifestyle factors, such as smoking, which can interact with antipsychotics. Somatic comorbidities were only based on hospital diagnoses so were likely under-reported in this study and not accounted for in the analysis. This could introduce bias, particularly if one group was more likely to experience comorbidities that did not require hospital admission.
Survivorship bias likely affected the comparisons between first line antipsychotics and clozapine, which is typically prescribed later in the illness course, but the depth of analyses allowed for this and similar factors to be accounted for in the stats. The PRE2DUP method used to collect prescription data is not without inaccuracies, but it has a 70-94% evaluated correctness and is currently deemed the most reliable method by many (Tankskannen, A. et al, 2017).
This is the largest cohort of its kind. Participants were identified using a Hospital Discharge register which captures a large portion of a population. The study sample of over sixty thousand people in Finland is therefore likely to be a good representation of the target population, although it may not be directly relevant to other countries and settings. Previous studies followed people up between 5 and 11 year periods whereas this study collected data over 20 years, developing a large cohort with a truly a long-term follow-up. Thus, the study design adds a great deal of weight to the findings.
The analysis does not address why antipsychotic use was associated with increased life expectancy. The authors theorise that the increased control of psychiatric symptoms linked with antipsychotic use could in-turn lead to improved healthy lifestyle behaviours and use of healthcare services for physical morbidities. Antipsychotics’ reduction of positive schizophrenia symptoms could be a big factor in the reduction of suicide deaths. However, this is likely to be a complex relationship and it remains to be explored further. Research in this area is much needed and the study makes a large step towards filling this gap with a robust analysis.
Implications for practice
I’m not qualified to discuss the implications of this study on practice for prescribers, but I am familiar with the health and lifestyle factors of people with schizophrenia. Supporting people with schizophrenia to enjoy physical activity, healthy diets and smoke-free lives is very important for managing antipsychotic side effects.
We have a duty to ensure that all people have the ability to lead full lives regardless of the health problems they experience. How can we do this? Research is needed to beat this health inequality, and it’s happening right now. Closing the Gap Network uses scientific rigour to address physical health inequalities for people with severe mental illness and close this gap in mortality.
Statement of interests
Paul Heron works for the Closing the Gap Mental Health Research Network in York: a network to understand why people with severe mental illness have some of the worst physical health issues of any section of the population.
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