Journal of Psychopharmacology
Mortality in Schizophrenia - Emerging trends and mechanisms
Supplement editor: Professor TG Dinan
Volume 24 Number 9 Supplement September 2010
In Memory of Dora Kohen
Schizophrenia: a multisystem disease?
AJ Mitchell and TG Dinan5
The paradox of premature mortality in schizophrenia:
new research questions
HJ Wildgust, R Hodgson and M Beary9
Mortality in schizophrenia: a measurable clinical
CJ Bushe, M Taylor and J Haukka17
Mortality trends in the general population: the
importance of cardiorespiratory fitness
D-c Lee, EG Artero, X Sui and SN Blair27
Are there modifiable risk factors which will reduce
the excess mortality in schizophrenia?
HJ Wildgust and M Beary 37
Cancer and schizophrenia: is there a paradox?
R Hodgson, HJ Wildgust and CJ Bushe51
Inequalities in healthcare provision for people
with severe mental illness
D Lawrence and S Kisely61
Do deficits in cardiac care influence high mortality
rates in schizophrenia? A systematic review and
AJ Mitchell and O Lord69
Suicide and schizophrenia: a systematic review
of rates and risk factors
K Hor and M Taylor81
A systematic review of hypothalamic–pituitary–adrenal
axis function in schizophrenia: implications for mortality
AJ Bradley and TG Dinan91
Sponsorship details: This supplement was produced with the funding of Eli Lilly and company. A publication fee was paid to the publisher. No
financial honoraria payments were made to any of the contributing authors. Eli Lilly funded a one-day authors’ meeting near Coventry, United
Kingdom (travel and overnight accommodation costs only, and a computer link up with Australia) where the supplement editor facilitated a forum
with authors to discuss in detail the content and key themes running through the supplement. All the papers have been written by the named
authors without editorial assistance. All the papers have been peer reviewed through the normal journal peer review process.
In Memory of Dora Kohen
Dora Kohen trained both in neurology and psychiatry. She
contributed enormously to British medicine. Sadly she died
prematurely. In so many ways Dora was a breath of fresh air,
in both clinical and academic circles. She frequently chal-
lenged orthodox accepted viewpoints but did so in a
manner that was always friendly and never condescending.
She had a capacity to view the obvious from a not so obvious
perspective. When she put forward a view she made others sit
up and take note. She ascribed to the philosophy that nothing
should be accepted, simply because it always had been. If
something could be done in a more effective, but less tradi-
tional manner, then so be it.
She had a resourceful, robust personality and always stood
up for what she believed. In a conservative profession, as is
medicine, that is not always an easy path, but Dora never
took the path of least resistance. She always took the road
she considered was right. There were occasions when divert-
ing and turning a blind eye would have avoided personal
stress, but selling-out was not part of her agenda.
As a clinician with a background in both neurology and
psychiatry she was superb. Patients loved her and she was
always prepared to go the extra mile on their behalf. She
had clinical skill few could match.
If one was to attribute a single characteristic to Dora it
would be optimism. Whatever difficulties she faced, right to
the end, she took an optimistic viewpoint. She always believed
that things would work out for the best.
To her husband Karabey and her beloved daughter Cemile
her loss is inestimable. Those of us who knew her well have
lost a very dear friend.
Journal of Psychopharmacology
24(9) Supplement 4. 3
! The Author(s) 2010
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Schizophrenia: a multisystem disease?
Alex J Mitchell1and Timothy G Dinan2
A multisystem disease is one that usually affects a number of
organs and tissues during the course of the illness (Dorland,
2008). It has long been observed that some individuals with
schizophrenia have levels of general physical illnesses in
excess of that seen in the general population, but recent stud-
ies suggest that most people with schizophrenia have co-
morbid physical disease and multiple related risk factors.
Jones et al. (2004) reported that 74% of patients with schizo-
phrenia had at least one chronic co-morbid medical condi-
tion. Bell et al. (2009) found that 90% of Medicaid recipients
with schizophrenia had at least one major metabolic risk
factor. Using a higher standard of at least three major risk
factors (NCEP-ATP-III guidelines: abdominal obesity, hyper-
triglyceridemia, dyslipidemia, hypertension and hyperglyce-
mia) approximately 40% of European patients and up to
51.6% patients with schizophrenia in the United States satisfy
criteria for the metabolic syndrome (De Hert et al., 2009;
Meyer et al., 2005). In the METEOR study, the largest anal-
ysis of risk factors in schizophrenia and related disorders
reported that 69.9% had lipid disorders and 43.4% had
hypertension (De Hert et al., 2008). Together this evidence
suggests that most people with schizophrenia have a signifi-
cant co-morbid physical illness and further the great majority
have metabolic risk factors (Mitchell and Malone, 2006).
Rates of co-morbidity appear to be influenced by the
severity of psychiatric symptoms, the setting of study and
nature of prescribed medication. Physical co-morbidity in
turn has an impact upon quality of life, suicide attempts
and mortality, even when suicide is eliminated (Heila et al.,
2005; Hennekens et al., 2005; Joukamaa et al., 2006; Kolotkin
et al., 2008). While core symptoms of schizophrenia usually
first emerge in the late teens and early twenties, peripheral
physical disease gradually increases with age (Bresee et al.,
2010). Similarly metabolic risk factors are usually elevated
at first episode but accumulate with time (Saddichha et al.,
2008). Lifestyle and cardiovascular risk factors play an
important role in the physical complications but they do
not appear to account for the entire variance (Connolly and
Kelly, 2005). Antipsychotic drugs certainly contribute to
physical co-morbidity (Oriot et al., 2008), but this effect is
risk factors are important but we should give special attention
to those that are potentially reversible. Recent research has
highlighted some valuable insights in the following areas.
Body weight and lipids
Body weight, and in particular abdominal obesity, is a major
concern in schizophrenia and one that directly influences
quality of life (Kolotkin et al., 2008). A recent meta-analysis
suggested a typical weight gain of 3.8 kg in drug-naı¨ve
patients upon starting antipsychotic treatment (Tarricone
et al., 2010). Approximately 50% of those with schizophrenia
are overweight judging by waist circumference (De Hert et al.,
2009) and this figure may be around 20% in first episode
patients (De Hert et al., 2006). The cardiovascular risk attrib-
utable to obesity and elevated levels of cholesterol, triglycer-
ides or low levels of high-density lipoproteins (HDLs) is well
recognized. Saari et al. (2005) examined serum lipids in
schizophrenia and related psychoses. Mean fasting total cho-
lesterol in patients with schizophrenia was 20 mg/dl higher
than in the healthy comparison group. In a controlled study
of drug-naı¨ve Chinese patients that used magnetic resonance
imaging, Zhang et al. (2004) found slight elevations in fat
indicators at baseline, but significantly increased subcutane-
ous and intra-abdominal fat, following 10-week administra-
tion of chlorpromazine and risperidone. This is important
because visceral (intra-abdominal) adiposity is closely associ-
ated with hyperinsulinaemia, dyslipidaemia and impaired glu-
Glucose and insulin resistance
The link between schizophrenia and diabetes mellitus was
reported before the advent of antipsychotics (Braceland
et al., 1945; Kasanin, 1926; Lorenz, 1922). In approximately
half of the cases, hyperglycaemia resolves when the antipsy-
chotic drug is withdrawn and recurs if it is reintroduced
(Ananth et al., 2002). This would suggest that a large percent-
age of cases are drug-induced but many cases are not
1Department of Liaison Psychiatry, Leicestershire Partnership Trust,
Leicester General Hospital, Leicester, UK and University of Leicester, UK.
2Department of Psychiatry, University College Cork, Ireland.
Professor Ted Dinan, Department of Psychiatry, Cork University Hospital,
Wilton, Cork, Ireland
Journal of Psychopharmacology
24(9) Supplement 4. 5–7
! The Author(s) 2010
Reprints and permissions:
iatrogenic. Diabetes can be seen in first episode patients and
impaired glucose tolerance or insulin resistance is manifest in
first episode drug-naı¨ve patients with schizophrenia (Ryan
et al., 2003; Cohn et al., 2006; Spelman et al., 2007;
Fernandez-Egea et al., 2009; Verma et al., 2009). However,
these problems accumulate especially in those taking atypical
antipsychotics (Gianfrancesco et al., 2006; Smith et al., 2008)
although this effect is debated (Holt and Peveler, 2006).
Walsh et al. (2002) found that drug-naı¨ve, first-episode
schizophrenic patients had altered platelet function as evi-
denced by a significantly increased number of integrin
aIIbbIIIa receptors/platelet. Such an increase might be
expected to indicate early platelet activation and to cause
increased platelet aggregation, thereby potentially contribut-
ing to the observed increased risk of development of cardio-
vascular disease in schizophrenic patients compared with the
Schizophrenia and inflammation
There is an evolving body of literature to support the view
that schizophrenia is a disorder with a pro-inflammatory phe-
notype, not just centrally but in the periphery also. Such a
view is consistent with the hypothesis that schizophrenia is a
multisystem disease and may help explain the high level of
physical co-morbidity. Postmortem brain studies have shown
activated microglial cells in at least a subset of patients with
schizophrenia (Radewiscz et al., 2000). There are also reports
of an increased frequency of activated lymphocytes in the
cerebrospinal fluid (CSF) of patients with acute schizophrenia
(Nikkila ¨ et al., 1999).
Cytokines are key inflammatory messengers which may be
divided into a number of functional categories including
T-helper type 1 (Th1) and T-helper type 2 (Th2) groups. In
brief, Th1 cytokines are concerned with cell-mediated immu-
nity and Th2 cytokines with humoral immunity. Higher white
cell counts provide a crude inflammatory marker, an indirect
index of cytokine activity and are associated with an
increased risk for metabolic syndrome and more severe psy-
chopathology in non-diabetic patients with schizophrenia
(Fan et al., 2010). Several investigators have demonstrated
elevated interleukin (IL)-6 levels, a cytokine secreted by the
innate immune system and the Th2 arm of the adaptive
response, in the plasma of patients with schizophrenia.
Further evidence in support of Th2 arm activation derives
from studies reporting increased levels of IL-10 and IL-8 in
patients with schizophrenia. Overall, the data suggest a Th1/
Th2 imbalance. For a review see Stober et al. (2009) and
Potvin et al. (2008).
Schizophrenia is a disorder characterized by high rates of
physical co-morbidity and very high rates of metabolic risk
factors, many of which remain undiagnosed and untreated.
Physical co-morbidity often impacts upon quality of life and
ultimately mortality. We propose there is sufficient evidence
to consider schizophrenia a multisystem disease. We suggest
that reframing schizophrenia as a multisystem disease will
help focus the attention of mental health specialists and
non-mental health specialists on the physical needs of such
patients. Further work should attempt to clarify whether the
pro-inflammatory phenotype observed in schizophrenia is in
essence the basis of a multisystem disorder.
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chotic drug use diabetes. Psychother Psychosom 71: 244–254.
Bell RC, Farmer S, Ries R, et al. (2009) Metabolic risk factors among
Medicaid outpatients with schizophrenia receiving second-genera-
tion antipsychotics. Psychiatr Serv 60: 1686–1689.
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insulin in schizophrenia. Am J Psychiatry 102: 108–110.
Bresee LC, Majumdar SR, Patten SB, et al. (2010) Prevalence of
cardiovascular risk factors and disease in people with schizophre-
nia: a population-based study. Schizophr Res 117: 75–82.
Cohn TA, Remington G, Zipursky RB, et al. (2006) Insulin resistance
and adiponectin levels in drug-free patients with schizophrenia:
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Fan X, Liu EY, Freudenreich O, et al. (2010) Higher white cell counts
are associated with an increased risk for metabolic syndrome and
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schizophrenia. Schizophr Res, in press.
Fernandez-Egea E, Bernardo M, Donner T, et al. (2009) Metabolic
profile of antipsychotic-naive individuals with non-affective psy-
chosis. Br J Psychiatry 194: 434–438.
Gianfrancesco F, Pesa J, Wang RH, et al. (2006) Assessment of anti
psychotic-related risk of diabetes mellitus in a Medicaid psychosis
population: sensitivity to study design. Am J Health-System
Pharm 63: 431–441.
Heila H, Haukka J, Suvisaari J and Lonnqvist J (2005) Mortality
among patients with schizophrenia and reduced psychiatric hos-
pital care. Psychol Med 35: 725–732.
Hennekens CH, Hennekens AR, Hollar D and Casey DE (2005)
Schizophrenia and increased risks of cardiovascular disease. Am
Heart J 150: 1115–1121.
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tes—an application of the Austin Bradford Hill criteria.
Diabetologia 49: 1467–1476.
Jones DR, Macias C, Barreira PJ, et al. (2004) Prevalence, severity,
and co-occurrence of chronic physical health problems of persons
with serious mental illness. Psychiatr Serv 55: 1250–1257.
Joukamaa M, Heliovaara M, Knekt P, et al. (2006) Schizophrenia,
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Andersson LC (1999) Accumulation of macrophages in the CSF
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Increase in HLA-DR immunoreactive microglia in frontal and
temporal cortex of chronic schizophrenics. J Neuropathol Exp
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tolerance in first-episode, drug-naı¨ve patients with schizophrenia.
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Mitchell and Dinan7
The paradox of premature mortality
in schizophrenia: new research
Hiram Joseph Wildgust1, Richard Hodgson2and Mike Beary3
The life expectancy of patients with schizophrenia is reduced by between 15 and 25 years. Those patients dying of natural causes die of the same
diseases as in the general population. In 2009 the World Health Organization (WHO) identified underlying global risk factors for mortality in the general
population. However, there is little evidence in the literature assessing their validity in those with schizophrenia. The WHO report on global health risks
(2009) identifies hypertension, smoking, raised glucose, physical inactivity, overweight and obesity, and high cholesterol as the six leading global
mortality risk factors. Currently, there are minimal data on the contribution to mortality that these risk factors make in schizophrenia, and their
optimum management. Both short and long-term studies are needed to address these gaps. New research has raised important questions about risk
balance with regards to ideal body mass, with some studies showing that being overweight is associated with lower all-cause mortality and lower suicide
rates. Cardiorespiratory fitness is being recognized as a more powerful predictor of mortality than smoking, hypertension or diabetes in men. However,
there are virtually no published data on assessment of fitness levels in schizophrenia. New studies have raised concerns about the quality of physical
care for patients with schizophrenia, which is another important avenue of future research. A greater biological understanding of the relationship
between these disorders and schizophrenia would inform clinical practice. Low birth weight has been associated with increased risk for schizophrenia,
and it will be important to explore this risk factor for both physical and mental health outcomes.
Cardiorespiratory fitness, diabetes, hypertension, lipids, mortality, obesity, schizophrenia, smoking
The World Health Organization (WHO) report on global
health risks identified 24 mortality risk factors (WHO,
2009). The six leading risks were, in order of priority, high
blood pressure, tobacco use, high blood glucose, physical
inactivity, overweight and obese, and high cholesterol.
Together, these six risk factors are responsible for raising
the risk of chronic disease and account for 42.1% of
global mortality. The relative importance of these risk fac-
tors variesacross countries
Understanding the role of these risk factors is pivotal to
developing a clear and effective strategy for improving
In economically developed countries, people with schizo-
phrenia die 20–25 years prematurely (Kilbourne et al., 2009).
Much of this loss of life span is due to the same natural causes
(cancer, respiratory disease, heart disease, digestive disease,
etc.) as seen in the general population (Brown et al., 2000).
Although in the general population the relative contribution
of these risk factors to all-cause mortality and disease-specific
mortality is now well described (WHO, 2009), the relative
importance of these risk factors in schizophrenia is much
less well understood. There is some evidence to support the
view that schizophrenia may be a disease mimicking
andby income group.
accelerated ageing (Fernandez-Egea et al., 2009; Kirkpatrick
et al., 2008), which would suggest a need for reappraisal of
guidelines both for risk assessment and for optimum medica-
tion doses. A systematic review and two recent studies in
schizophrenia (Table 1) show the standardized mortality
ratios (SMRs) are raised for all-cause mortality and also
across disease categories of cancer, circulatory disease, respi-
ratory disease and digestive diseases. These findings support
the view that the relative contribution of risk factors to all-
cause mortality and by disease in schizophrenia is likely to be
different to that in the general population. Guidelines for
physical health in schizophrenia are based on extrapolations
from the general population; however, the attributable risks
in schizophrenia for all-cause mortality and disease-specific
mortality have been minimally evaluated.
1Hiram Consulting Ltd, Ackworth, UK.
2Lyme Brook Centre, Stoke on Trent, UK.
3Priory Hospital North London, London, UK.
Dr Hiram Wildgust, Hiram Consulting Ltd, 11 Cricketers Close, Ackworth,
Pontefract, West Yorkshire WF7 7PW, UK
Journal of Psychopharmacology
24(9) Supplement 4. 9–15
! The Author(s) 2010
Reprints and permissions:
Mortality trends in schizophrenia show a pattern of high
rate of suicide in patients aged less than 40 years
(SMR¼8.38), followed by increased rates of cardiovascular
(SMR¼2.80), digestive disease (SMR¼1.85) and genito-
urinary diseases (SMR¼1.61) in older patients (Brown,
1997). To understand the mortality pattern in schizophrenia,
it will be important to examine the mortality risk of patients
by age group. For example, in the general population leukae-
mia is the most common cancer in people aged less than 40
years, whereas lung and breast cancer become the leading
killers in older patients (Jemal et al., 2008).
Our understanding of the genetics of schizophrenia is
incomplete, and more research is required to understand
metabolism of drugs and toxic chemicals such as carcinogens
in tobacco smoke in this patient population. There are likely
to be differences between the sexes and between ethnic
Recent studies in the general population suggest a re-va-
luation of accepted beliefs. Intentional weight loss seems to be
associated with increased mortality (Sørensen et al., 2005).
Low lipids are associated with frailty and increased mortality
(Okamura et al., 2008). Overweight has been shown to be
associated with the lowest risk of all-cause mortality (Flegal
et al., 2007; Tunstall-Pedoe et al., 1997) as well as lower sui-
cide rates (Gravseth et al., 2010; Magnusson et al., 2006). This
paper will explore some of these paradoxes and propose new
targets for future research.
The theme of this paper will be to explore whether the risk
factors for premature mortality in the general population are
directly relevant to people with schizophrenia. This will lead
to the identification of new research targets in schizophrenia
which may help address the paradox of excess premature
A search was carried out in Medline, Embase and PsycINFO
using the following terms: schizophrenia and mortality and
modifiable (OR reduction OR intervention). The search was
conducted for the time period 1987 to January 2010. Papers
were included which examined the link between schizophrenia
and mortality, with reference to smoking, hypertension, dia-
betes, physical inactivity, overweight/obesity and lipids.
Papers which failed to separate out patients with schizophre-
nia from other mental disorders were excluded. Papers
included in this review were limited to systematic reviews
and meta-analyses when available; otherwise high-quality
studies were reported. In addition, the literature was non-
systematically reviewed to identify the leading mortality risk
factors in the general population and whether these risk fac-
tors can be reduced in patients with schizophrenia.
The systematic literature search identified 974 papers.
Together with hand searches, 60 papers have been included
in this paper and the results are presented under the headings
mortality risk factors and antipsychotic medication.
Mortality risk factors
Hypertension. The WHO report on global health risks
highlights hypertension as the leading global risk factor for
mortality, accounting for 12.8% of deaths (WHO, 2009). A
US study, in just over 22,000 patients with schizophrenia,
showed that hypertension was an important risk factor for
cardiac mortality (Kilbourne et al., 2009). There are excellent
studies in the general population showing the benefits and the
effectiveness of treatments to lower blood pressure. There is
little in the literature examining the efficacy of antihyperten-
sives in patients being treated with antipsychotics, some of
which target similar receptors. However, Piette et al. report
a study in 1686 veterans with schizophrenia and comorbid
diabetes and hypertension which examined the issue of med-
ication compliance (Piette et al., 2007). This study showed
that the adjusted odds of poor adherence were significantly
higher for hypoglycaemic and antihypertensive medications
than for antipsychotic medication (both adjusted odds
ratios were 1.5, p<0.001). Antihypertensive therapy may be
associated with sexual dysfunction (Ferrario and Levy, 2002),
which is also a common adverse event associated with anti-
psychotics medications. The schizophrenia literature shows
that many patients have untreated hypertension. Therefore
it will be important to design studies in schizophrenia to accu-
rately assess incidence, issues of management of hypertension
and effectiveness of treatments and, in the long term, the
Table 1. Standardized mortality ratios (SMRs) by disease category in schizophrenia
Causes of death
by disease category
(Saha et al., 2007)
SMR (% deaths)
(Tran et al., 2009)
(Prospective cohort study)
n¼3470, 11 years
3.6 male/4.3 females (13.9%)
SMR not reported (2.0%)
SMR (% deaths)
(Brown et al., 2010)
(Prospective linkage study)
n¼370, 25 years
10Journal of Psychopharmacology 24(9)
impact on morbidity and mortality. In theory this would be
a simple project; however, in practice it would be a large
Smoking. Tobacco is the second most important global
mortality risk factor and accounts for 8.7% deaths globally
(WHO, 2009). Patients with schizophrenia have higher rates
of smoking than the general population (Catts et al., 2008;
Tran et al., 2009). Recent studies in schizophrenia have shown
that cardiac-related deaths are 12-fold higher in young smo-
kers relative to non-smokers: hazard ratio (HR)¼12.4,
p¼0.0005 (Kelly et al., 2009). Smoking approximately dou-
bles the rate of cancer deaths (Tran et al., 2009). In the gen-
eral population, smoking cessation has been associated with
significant reduction in CVD risk and cancer deaths.
However, the results of smoking cessation programmes to
date in schizophrenia are poor (Campion et al., 2008).
There is evidence demonstrating that excess cancer and car-
diac mortality in schizophrenia is in part related to poor qual-
ity of physical treatments and late diagnosis (Kisely et al.,
2007, 2008; Laursen et al., 2009; Mitchell et al., 2009).
Smoking has also been linked with increased risk of suicide
(Malone et al., 2003). Prospective studies are needed to unra-
vel this complex area. Another issue which needs to be con-
sidered is the impact of smoking on heart rate variability,
which has already been shown to be abnormal in schizophre-
nia (Jindal et al., 2009). It will also be important to establish
whether two main carcinogenic components in cigarette
smoke, polycyclic aromatic hydrocarbons and the tobacco-
derived nitrosamines, have normal metabolism, as in the gen-
eral population, or whether this is impaired in patients with
schizophrenia, which will provide valuable insight into the
risk of lung cancer. The histology of lung cancer in the gen-
eral population has changed over the last 40 years from being
predominantly squamous cell carcinoma to adenocarcinoma,
but to date there is little information in the schizophrenia
literature on the histology of lung cancer. Mortality rates
for lung cancer are raised in schizophrenia (SMR¼2.65)
(Brown et al., 2010). However, a meta-analysis suggested
that the standardized incidence rates are lower in schizophre-
nia than in the general population, after controlling for smok-
ing (Catts et al., 2008).
Blood glucose. High blood glucose is the third most impor-
tant global risk factor for mortality and explains 5.8% of
global deaths (WHO, 2009). It is well established that patients
with schizophrenia and their families are at increased risk of
diabetes mellitus. A US study showed that diabetes is an
important risk factor for cardiac-related death in schizophre-
nia (Kilbourne et al., 2009). In the general population it has
been shown that low birth weight is a risk factor for diabetes
(Phillips et al., 1994). This study needs to be repeated in
schizophrenia, as this may prove a useful risk signal. The
management of diabetes in schizophrenia is less well estab-
lished than in the general population. However, one study has
reported that the management of diabetes in schizophrenia
does not alter the course of the illness at 3 years (Ascher-
Svanum et al., 2007). A community study showed better
control of diabetes in patients with schizophrenia than con-
trols (Dixon et al., 2004). However, some antipsychotic drugs
have been shown to reduce the effectiveness of hypoglycaemic
medication in older patients (Pham and Dickman, 2007).
Kahn et al. found that first-episode patients with schizophre-
nia present with high levels of abnormal glucose (Kahn et al.,
2008). Further, this study reported that antipsychotics were
associated with significant worsening of glucose levels at 12
months. Piette et al. reported that 46% of patients with
schizophrenia and comorbid diabetes were taking at least
two or more medications to manage their diabetes (Piette
et al., 2007). These findings support the view that it would
be valuable to follow up patients with schizophrenia and
monitor the relationship between their mental illness, their
diabetes and treatment in relation to morbidity and mortality.
accounts for 5.5% of global deaths (WHO, 2009). There are
now several studies in the general population which show that
low physical fitness, defined in terms of cardiorespiratory fit-
ness (CRF), better predicts CVD mortality than traditional
risk factors such as smoking, hypertension or diabetes in men
(Kodama et al., 2009; Myers et al., 2002). Furthermore, a
recent study of 22,817 patients with schizophrenia also
found that low physical activity had a higher HR than smok-
ing for heart disease mortality (HR¼1.66; 95% CI 1.59–1.74
versus HR¼1.32; 95% CI 1.26–1.39) (Kilbourne et al., 2009).
High CRF and muscle strength are not only associated with a
reduction in CVD mortality but also with all-cause mortality
(Lee et al., 1999; Ruiz et al., 2008). A study in young adoles-
cents with schizophrenia showed lower physical activity levels
and CRF than their peers (Koivukangas et al., 2010), which
supports the view that schizophrenia itself is linked to
increased mortality vulnerability. Low CRF is associated
with insulin resistance and other risk factors for CVD mor-
tality (Leite et al., 2009).
These findings raise several important research questions
in schizophrenia. For example, what is the best measure of
fitness in patients with schizophrenia (resting heart rate,
treadmill test or questionnaire?). As there are virtually no
findings in schizophrenia, it will be important to mirror
some of the studies already performed in the general popula-
tion. These have examined long-term mortality and its asso-
ciation with fitness, pre and post training. This approach is
important, as training people can improve their physical fit-
ness and reduce their risk of CVD and all-cause mortality
(Blair et al., 1995). The association between CRF and insulin
resistance should also be explored in schizophrenia. The
WHO report also highlights fitness as being highly protective
against breast and colon cancer in the general population
(WHO, 2009), so these cancers should be studied first.
fitnessand inactivity. Physical inactivity
Overweight and obesity. An increased body mass index
(BMI) is the fifth most important global risk factor for mor-
tality and accounts for 4.8% of global deaths (WHO, 2009).
However, the Monica study (Tunstall-Pedoe et al., 1997) and
an American study (Flegal et al., 2007) based on data analysis
from 2.3 million deaths show that overweight patients have
Wildgust et al. 11
significantly decreased all-cause mortality compared with
those with ideal weight and the obese. Overweight and obesity
are major issues for patients with schizophrenia, and it is
important to establish how this impacts on all-cause and
CVD mortality in schizophrenia. A study from Sweden
found that, in the general population of 1.3 million army
recruits followed up to 31 years, compared with those with
a normal BMI, those who were overweight on recruitment
had a 15% lower suicide rate and the obese had a 30% reduc-
tion subsequently (Magnusson et al., 2006). A population-
based cohort study of 610,359 Norwegians, 1967–1976,
found that low body weight was a significant risk factor
for suicide (Gravseth et al., 2010). A prospective study,
1986–2002, of 46,755 men showed that a higher BMI was
related to a reduced suicide mortality rate, from 52 per
100,000 person-years with a BMI of less than 21 to 13 per
100,000 person-years with a BMI of 30 or higher (Mukamal
et al., 2007). The literature is speculative regarding the possi-
ble mechanisms associated with this lowered suicide risk. It
may simply be correlational, with no causal link. However, as
suicide and accidental death are associated with 40% of the
deaths in schizophrenia, it is an important question to address
regarding the risk balance of overweight and obese categories
in schizophrenia. Moreover, suicides tend to occur in young
patients, so this has potentially more impact on their family
than later mortality. Two systematic reviews in schizophrenia
show that modest intentional weight loss can be achieved in
the short term, in both overweight and obese patients (Bushe
et al., 2009; Faulkner et al., 2007). However, there are studies
in older patients in the general population raising some con-
cerns about intentional weight loss (Adams, 2009). One well-
designed 18-year follow-up study shows a very significant
increase in mortality (Sørensen et al., 2005). The relevance
of this in schizophrenia should be evaluated as soon as pos-
sible, as most patients will be overweight secondary to anti-
psychotic medication use. We were unable to find studies in
schizophrenia which examined the relationship between BMI
Lipids. High cholesterol accounts for 4.5% of global deaths
(WHO, 2009). In the general population, familial hypercho-
lesterolaemia is a well-established risk factor for premature
mortality. The role of statins in the management of diabetes
and CVD are also well established in the general population.
However, there are emerging data that in older patients low
cholesterol may be associated with increased frailty and mor-
tality (Okamura et al., 2008; Ra ¨ iha ¨ et al., 1997). Recent
research has linked the use of statins with increased risk of
diabetes in the general population (Sattar et al., 2010), but to
date there are few data in the schizophrenia literature. As
patients with schizophrenia are at an elevated risk of devel-
oping diabetes, this may alter the risk–benefit balance of
treatment with statins. Paradoxically, in patients who respond
to clozapine it has been reported that a reduction in the pos-
itive and negative symptom score (PANSS) correlates with
increasesin lipid levels(Huang
Kilbourne’s study in 22,817 patients with schizophrenia
(Kilbourne et al., 2009) showed that hyperlipidaemia was pro-
tective for CVD mortality (HR for mortality from heart
and Chen, 2005).
disease 0.86; 95% CI 0.82–0.89), whereas diabetes (HR¼
1.51; 95% CI 1.44–1.57) and hypertension (HR¼1.38; 95%
CI 1.32–1.46)both increased
Moreover, if schizophrenia is a disease mimicking rapid
ageing, it will be important to establish the best lipid levels
by age and their impact on mortality in this population. To
date there are only data from one study (Kilbourne et al.,
Medical care. Patients with schizophrenia are not engaged
with and tend to be treated poorly by health services
(Kreyenbuhl et al., 2009; Rethink, 2010). There is evidence
that people with schizophrenia are less likely to receive cancer
screening and secondary care interventions even if identified
with a disorder (Lawrence et al., 2000; Kisely et al., 2007,
2008). Even when a physical healthcare need is identified,
treatment is less intensive than in the general population.
Further research is needed to identify why this is so and
how it may be remedied.
The primary theme of this paper is to explore whether the
major risk factors for premature mortality in the general pop-
ulation are directly relevant and manageable in people with
schizophrenia. However, treatments for schizophrenia may
also affect physical health, which may lead to early mortality.
This topic is complex, and here we present a summary of
some the most recent findings. A systematic review examining
the differential effects on mortality of second-generation anti-
psychotics compared with first-generation antipsychotics
showed inconsistent findings (Weinmann et al., 2009).
However, Tiihonen et al. describe one of the longest and larg-
est studies, examining cause-specific mortality in 66,881
patients with schizophrenia versus the total population of
Finland (5.2 million) between 1996 and 2006 (Tiihonen
et al., 2009). Long-term treatment with antipsychotics was
associated with lower mortality compared with no antipsy-
chotics (HR¼0.81: 95% CI 0.77–0.84). Their findings also
showed that for both clozapine and olanzapine, the two anti-
psychotics associated with greatest weight gain, there were no
signs of increased risk of death from ischaemic heart disease
after 7–11 years of cumulative exposure to these agents. A
Cochrane review of olanzapine versus other atypicals in
schizophrenia found no differential risk of death, although
(Komossa et al., 2010). A study in patients with tardive dys-
kinesia found higher rates of mortality in older patients, par-
ticularly those on conventional antipsychotics (Dean and
Thuras, 2009). Mortality studies which have not separated
out the schizophrenia cohort from patients with other
severe mental illnesses have not been included in this
review, as interpretation of these findings is complex
(Osborn et al., 2007; Ray et al., 2009).
Patients with schizophrenia have an elevated incidence of the
six leading global mortality risk factors described by the
12Journal of Psychopharmacology 24(9)
WHO (WHO, 2009). If research findings from the general
population are directly applicable to schizophrenia, this
may account for the premature mortality associated with
the illness. However, there is little evidence in the literature
to support this assertion, or indeed refute it. Moreover, there
are indications that schizophrenia is a metabolic disease with
associated higher rates of diabetes, differing patterns of adi-
posity and elevated lipids. Furthermore, low birth weight,
which is more common in those with schizophrenia, diabetes
and CVD, may be an early common pathway for this excess
mortality. Comorbidity is often associated with a poorer
treatment response for a variety of factors including adher-
ence, medication interactions and complications arising from
the underlying disorders.
Currently, there is a dearth of basic data for these impor-
tant parameters in schizophrenia. While some questions will
require long-term prospective studies, others may be more
amenable to shorter and less costly investigation. It will be
important to establish appropriate measures of CRF, and
how interventions to improve CRF impact on other risk fac-
tors in the short-to-medium term, such as insulin resistance,
obesity (including disposition) and hypertension.
a retrospective view of the outcomes in treated hypertension,
are the same or differ significantly from the general population.
tion would have to be exercised in interpreting the findings.
However, such studies could inform the design and feasibility
of prospective longer-term studies of interventions aimed at
both primary and secondary prevention.
There are suggestions that from the genetic perspective,
schizophrenia may confer advantages and disadvantages in
disease risk, such as elevated CVD but lower incidence of
autoimmune disorders (Eaton et al., 2006). A greater under-
standing of the relationship between these disorders at a
molecular level would be advantageous in advancing their
treatment. Such molecular understanding would also allow
us to understand whether carcinogens in cigarette smoke act
in precisely the same way irrespective of whether the smoker
has or does not have schizophrenia. Our review suggests that
direct extrapolation of results from the general population to
schizophrenia may not always be appropriate, and that opti-
mum treatment may require a compromise between physical
and mental health outcomes.
Since the introduction of atypical antipsychotics in the
1990s, there has been a debate about whether these drugs
might be associated with increased cardiovascular mortality
compared with typical antipsychotics, because of their ten-
dency for causing greater weight gain and metabolic changes.
Whereas smoking has now been strongly linked with a high
risk of cardiovascular mortality in schizophrenia (Kelly et al.,
2009; Kilbourne et al., 2009), the much larger study of anti-
psychotics with 7–11 years follow-up failed to show an
increased all-cause mortality or increased CVD mortality
with atypical antipsychotics
(Tiihonen et al., 2009). This supports the view that if there
is differential cardiovascular mortality risk between antipsy-
chotic classes, it is likely to be small and may require even
larger and longer studies to answer this question. These
findings may be partially explained by the observation that
weight gain in middle-aged and elderly individuals has a min-
imal impact on mortality at 14 years (Myrskyla ¨ and Chang,
2009). Further, Weiler et al. report that high-quality evidence
is now available from large cohort studies confirming that
physical inactivity, rather than obesity, is the causal factor
for cardiovascular disease, coronary heart disease, type 2 dia-
betes, dyslipidaemias, hypertension, arrhythmias, increased
inflammatory markers, myocardial infarction, stroke, cancer
and ultimately death (Weiler et al., 2010). To date, there are
few research findings on the impact of antipsychotics on phys-
ical activity levels or cardiovascular fitness in schizophrenia;
these studies need to be completed urgently.
Suicide and accidental deaths account for up to 40% of all
deaths in schizophrenia (Brown, 1997; Tran et al., 2009).
However, the schizophrenia literature has largely ignored the
balance equation for antipsychotics. A large Finnish study in
first-admitted patientswith schizophrenia showed significantly
increased risk for suicide in patients not receiving antipsy-
chotics (Tiihonen et al., 2006). Paradoxically, the literature
in the general population supports the view that patients
with a high BMI are at lower risk of suicide. This finding
may partially explain lower suicide rates with clozapine
(Hennen and Baldessarini, 2005) and may be relevant to all
antipsychotics. Studies are required to examine the link
between BMI and suicide risk in schizophrenia, which may
provide understanding into the risk factors for suicide and
improve management. A relatively simple population study
may help to address this hypothesis. Patients with schizophre-
nia tend to have higher BMIs in the US as compared with
Taiwan; as antipsychotics are used widely in both populations,
by examining the rates of suicide in these countries it may be
possible to see a differential impact of BMI on suicide risk by
population. This will be an important test of hypothesis.
The authors would like to thank Jan Yonge and Eli Lilly for
their assistance with the literature search.
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
Hiram J Wildgust received lecture and consultancy fees from
Eli Lilly & Co Ltd. Mike Beary received lecture fees and
hospitality from Eli Lilly & Co Ltd. Richard Hodgson
received educational support and speaker fees from a
number of drug companies.
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