30th July 2009
An observational study in Finland confirms the large gap in life expectancy between people with schizophrenia and the general population. However, it also suggests that long-term antipsychotic use in people with schizophrenia is associated with lower all-cause mortality compared with no antipsychotic use. Individual antipsychotics do not appear equal in this respect. Clozapine appears to be associated with a lower risk of all-cause mortality compared with all other antipsychotics.
Level of evidence:
Level 2 (limited-quality patient-oriented evidence) according to the SORT criteria
People with schizophrenia are at increased risk of suicide as well as death from a wide range of physical health problems compared with the general population. They should be managed according to the NICE clinical guideline for schizophrenia issued in March 2009 (CG82), paying particular attention to their physical health and following the appropriate NICE guidance for prevention and treatment of these conditions (i.e. lipid modification CG67, type 1 diabetes CG15, type 2 diabetes CG87).. Although this study suggests that clozapine may be associated with a lower risk of mortality than other antipsychotics, it is only licensed for use where there has been an inadequate response to two different antipsychotics.
What is the background to this?
As pointed out in the NICE full clinical guideline for schizophrenia, mortality associated with schizophrenia is reported to be about 50% above that of the general population, partly as a result of an increased risk of suicide (about 10% die from suicide) and violent death, and partly as a result of an increased risk of a range of physical health problems. Lifestyle factors (e.g. smoking, unhealthy diet) make an important contribution to increased cardiovascular risk. Antipsychotics may induce endocrine abnormalities, neurological disorders, metabolic disorders, and cardiovascular side effects, although the contribution they make to reduced life expectancy is unclear.
Previously, Saha and colleagues conducted a systematic review of 37 population-based studies from around the world reporting primary data on deaths in people with schizophrenia. They identified that people with schizophrenia have, on average, a 2.5 times greater risk of dying compared with the general population and that the differential mortality gap had worsened in recent decades. Although the authors of this review recognised that antipsychotic use had been associated with increases in cardiovascular and all-cause mortality, they were unable to explore the contribution this use made in their analysis.
The authors of the present study, using national registry data in Finland, evaluated the association between mortality and individual antipsychotic use in schizophrenia between 1996 and 2006, a period when second generation antipsychotics were increasingly used.
What does this study claim?
From 1996 to 2006 the proportional use of second generation antipsychotics in Finland rose from 13% to 64%, but the gap in life expectancy did not widen, indeed it reduced slightly from 25 years to 22.5 years. In people with schizophrenia, long-term cumulative exposure (7 to 11 years) to antipsychotics was associated with lower mortality than was no drug use (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.77 to 0.84).
The risks associated with individual antipsychotics varied. Clozapine was the only antipsychotic that was associated with a significantly lower risk of both all-cause mortality (HR 0.74, 95% CI 0.60 to 0.91; P<0.0045) and suicide (HR 0.34, 95% CI 0.20 to 0.57) than the reference drug, perphenazine. Clozapine was associated with a highly significant lower risk of all-cause mortality compared with all other antipsychotics (P<0.0001). There were indications that risperidone▼, haloperidol and quetiapine were associated with higher risks of all-cause mortality compared with perphenazine (HRs from 1.34 to 1.41)
Interpretation of the study results is limited by the observational nature of the study. Not all potentially confounding factors were taken into account in the analysis, and as it was conducted solely in Finland, the results can only be generalised to those countries with similar healthcare systems and sociodemographic features. Nevertheless, this article confirms the considerably reduced life expectancy that is associated with a diagnosis of schizophrenia. Healthcare professionals in primary care have an important role in monitoring both the mental and physical health of people with schizophrenia, and providing necessary re-referrals to secondary care or providing treatments for comorbid conditions, as outlined in NICE guidance.
The study suggests that the increased use of second generation antipsychotics, with the possible exception of risperidone▼ and quetiapine, has not had a harmful effect on the life expectancy of patients with schizophrenia. The study found that clozapine, use of which is normally restricted to those patients resistant to two or more other antipsychotics and requires regular blood monitoring, is associated with reduced mortality compared with other antipsychotics. The authors of the study raise the issue of whether clozapine should be reconsidered as first-line therapy — clozapine has the most robust evidence for efficacy in studies of patients with treatment resistant schizophrenia, and it would appear from this study to be the safest antipsychotic. However, first-line use use would require a change in the licensed indications for clozapine, and first-line use is not recommended by NICE currently.
People with schizophrenia are at increased risk of suicide as well as death from a wide range of physical health problems compared with the general population. They should be managed according to the NICE clinical guideline for schizophrenia issued in March 2009 (CG82). GPs should urgently refer all people presenting with psychotic symptoms for the first time to a local community-based secondary mental health service. People diagnosed with schizophrenia will normally be offered antipsychotic treatment. Choice of agent should be made in partnership with the patient, and carer if appropriate, after due consideration of their side-effect profiles. Although this study suggests that clozapine may be associated with a lower risk of mortality than other antipsychotics, it is only licensed for use where there has been an inadequate response to two different antipsychotics. Regardless of the antipsychotic prescribed, it is important that the physical health of people with schizophrenia is monitored on a regular basis in primary care (at least once a year). Those who have, or who are at increased risk of cardiovascular disease and/or diabetes, should be identified at the earliest opportunity and managed using the appropriate NICE guidance for prevention and treatment of these conditions (i.e. lipid modification CG67, type 1 diabetes CG15, type 2 diabetes CG87).
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Tiihonen J, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study), Lancet (2009) 10.1016/S0140-6736(09)60742-X published online July 13, 2009
Patients: All patients (30,803 men, 36,078 women) admitted to hospital in Finland with a diagnosis of schizophrenia made between January 1973 and December 2004 inclusive.
Methods: Antipsychotic medication history was obtained from dispensing records, and mortality and cause of death from Finish nationwide registers. Cause specific mortality was compared between the study population and the total population (5.2 million) between 1996 and 2006. From these data, all-cause mortality of patients with schizophrenia in outpatient care was calculated during current and cumulative exposure to any antipsychotic drug versus no use of these drugs. These outcomes associated with use of the six most frequently used antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine, thioridazine, haloperidol) was compared with perphenazine use.
Results: From 1996 to 2006 the proportional use of second generation antipsychotics rose from 13% to 64%. At the age of 20 years, patients with schizophrenia had a life expectancy of 32.5 years in 1996 compared with 57.5 years in the general population (difference 25 years). In 2006 the difference was 22.5 years (37.4 years vs. 59.9 years). Long-term cumulative exposure (7 to 11 years) to antipsychotics was associated with lower mortality than was no drug use (HR 0.81; 95% CI 0.77 to 0.84).
Overall risk of death was lower (HR 0.68, 95%CI 0.65 to 0.71, P<0.0001) during current use of any antipsychotic compared with no antipsychotic. The risks associated with current use of individual antipsychotics varied. Clozapine was the only antipsychotic that was associated with a significantly lower risk of both all-cause mortality (HR 0.74, 95% CI 0.60 to 0.91) and suicide (HR 0.34, 95% CI 0.20 to 0.57) than perphenazine. Clozapine was associated with a statistically significant lower risk of all-cause mortality (P<0.0001) compared with all other antipsychotics. Whereas, risperidone, haloperidol and quetiapine were all associated with significantly higher risks of all cause mortality compared with perphenazine (HRs were: 1.34, 95%CI 1.12 to 1.62; 1.37, 95%CI 1.10 to 1.72; 1.41, 95%CI 1.09 to 1.82, respectively). There were no pronounced differences between any of the antipsychotics with regard to mortality from ischaemic heart disease or, with the exception of clozapine, suicide.