J
Original papers
Metabolic Syndrome and
Cardiovascular Disease
Leslie Citrome New York University School of Medicine, Department of Psychiatry, and the Nathan S. Kline Institute for Psychiatric Research,
Orangeburg, NY, USA.
Abstract
Metabolic syndrome is a constellation of clinical findings that identify
individuals at higher than normal risk of developing diabetes mellitus or
cardiovascular disease. There are two principal definitions, one emerging
from the American National Cholesterol Education Program Expert Panel
on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults, and the other from the World Health Organization. Both
definitions share the common elements of abdominal obesity,
hypertriglyceridaemia, low HDL-cholesterol, hypertension and abnormal
glucose regulation. The syndrome is relatively common across continents,
and also among those without marked obesity. It is even more common
among patients with major mental health disorders such as
Introduction
Metabolic syndrome has been referred to as ‘Syndrome X’ and
‘Insulin Resistance Syndrome’ and the various definitions prof-
fered for these entities have included the traditional cardiovascular
risk factors and metabolic alterations associated with excess fat
weight (Ford and Giles, 2003). The metabolic syndrome can thus
be conceptualized as a public health construct designed to identify
individuals at risk for developing diabetes mellitus and/or cardio-
vascular disease, and can be used as a starting point for clinical
interventions known to reduce that risk (Meigs, 2004).
Metabolic syndrome has been compared to cigarette smoking as
an equal partner in the development of premature coronary heart
disease (NCEP, 2001; NCEP, 2002). Metabolic syndrome may
enhance the risk for coronary heart disease at any given LDL-cho-
lesterol level. The risk of developing type 2 diabetes mellitus in the
presence of metabolic syndrome can be quantified independent of
impaired glucose tolerance or fasting insulin, as seen in the San
Antonio Heart Study, where 1734 participants completed 7–8 years
of follow-up (odds 3.30, 95% CI 2.27–4.80) (Lorenzo et al., 2003).
There has been increasing interest in the metabolic syndrome,
resulting in a new section in the influential journal, Diabetes Care,
Corresponding author: Leslie Citrome, MD, MPH, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Email: citrome@nki.rfmh.org
Psychopharm
Journal of Psychopharmacology
19(6) Supplement (2005) 84–93
© 2005 British Association
for Psychopharmacology
ISSN 0269-8811
SAGE Publications Ltd,
London, Thousand Oaks,
CA and New Delhi
10.1177/0269881105058375
schizophrenia. Metabolic syndrome can be used to assess risk for
cardiovascular disorder and death, and is an alternative to Framingham
Risk Calculations. C-reactive protein may play an additional role in risk
prediction. Ongoing monitoring for all components of the metabolic
syndrome is necessary. Individuals at high risk require multimodal
interventions, including lifestyle interventions and targeted medications
as appropriate.
Keywords
metabolic syndrome, cardiovascular disease, schizophrenia,
antipsychotics
entitled ‘Metabolic Syndrome/Insulin Resistance Syndrome/Pre-
Diabetes’ (Davidson, 2003a). In the welcoming editorial, David-
son noted that ‘there is no denying that ~50% of type 2 diabetic
patients at the time of diagnosis have cardiovascular disease, at
least another 25% will develop it, and two-thirds or more will die
from it’. In this review we will cover the definitions of the meta-
bolic syndrome, its prevalence in the general population, the
association with cardiovascular disease, the emerging role of
C-reactive protein, and the special issues surrounding metabolic
syndrome and mental health disorders, including monitoring,
treatment, and perhaps most importantly, prevention.
Competing definitions
There are two current competing definitions of metabolic syn-
drome (Table 1) (Ford and Giles, 2003; Grundy et al., 2004). One
is the Third Report of the National Cholesterol Education Program
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III), which is
commonly referred to as the ATP III criteria or the NCEP criteria.
The other operational definition comes from the World Health

Organization, and is commonly abbreviated as the WHO criteria.
Although both definitions include criteria relating to the risk
factors of abdominal obesity, hypertriglyceridaemia, low HDL-
cholesterol and hypertension, the WHO criteria mandate the pres-
ence of abnormal glucose regulation, whereas the NCEP criteria
do not. Microalbuminuria is an additional risk factor in the WHO
criteria but is absent from those of the NCEP. Microalbuminuria
may be important in the prediction of cardiovascular risk, as
demonstrated in a large family study of type 2 diabetes in Finland
and Sweden, which found that microalbuminuria conferred the
strongest risk of cardiovascular death (RR 2.80; p = 0.002) among
4483 subjects aged 35–70 years (Isomaa et al., 2001).
Other definitions of metabolic syndrome also exist, including
that from the American Association of Clinical Endocrinologists
(AACE) (Bloomgarden, 2004), and from the European Group for
the Study of Insulin Resistance (EGIR) (Bloomgarden, 2004).
Both refer to ‘Insulin Resistance Syndrome’, and include criteria
relating to abdominal obesity, hypertriglyceridaemia, low HDL-
cholesterol, abnormal fasting glucose and hypertension. The EGIR
definition mandates the presence of fasting hyperinsulinaemia; the
AACE definition includes a range of other risk factors including
family history, ethnicity and sedentary lifestyle.
These definitions may not apply in all circumstances. For
example, waist circumference for Asians is generally lower,
requiring a lower cut-off of 90 cm in men (instead of 102 cm in the
NCEP definition) or 80 cm in women (instead of 88 cm), when
assessing the prevalence of central obesity (Tan et al., 2004).
Table 1 Definitions of metabolic syndrome
Risk Factor NCEP/ATP III*
Three or more of . . .
Abdominal Waist circumference:
obesity men >102 cm (>40 in)
women >88 cm (>35 in)
Triglycerides At least 150 mg/dL
(1.695 mmol/L)
HDL-Cholesterol men <40 mg/dL
(1.036 mmol/L)
women <50 mg/dL
(1.295 mmol/L)
Blood pressure At least 130/85 mm Hg
Fasting glucose At least 100 mg/dL(5.5 mmol/L)
Microalbuminuria NA
* Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III)
** World Health Organization
Metabolic Syndrome and Cardiovascular Disease 85
Moreover, the definition of obesity in Japan is a Body Mass Index
(BMI) greater than 25 kg/m2, rather than the 30 kg/m2 used among
Caucasians (Anuurad et al., 2003).
The presence of metabolic syndrome is not the only means
available for predicting cardiovascular risk, and there is some
debate that other methods may be more sensitive or specific. A
recent report demonstrated that metabolic syndrome was inferior
to the Diabetes Predicting Model in predicting type 2 diabetes
mellitus, and inferior to the Framingham Risk Score in predicting
cardiovascular disease when, data from the San Antonio Heart
Study (n = 1709 followed for 7.5 years) and the Mexico City Dia-
betes Study (n = 2570 followed for 6.5 years) were re-examined
(Stern et al., 2004). Metabolic syndrome was no better at predict-
ing risk than the Framingham Risk Score in another recently
reported study in which 12,089 individuals were followed for 11
years (McNeill et al., 2005). NCEP criteria also appear to have
low sensitivity for identifying insulin resistance with dyslipi-
daemia in non-diabetic individuals who are at increased risk for
cardiovascular disease and diabetes, as determined in 74 non-
diabetic Caucasians undergoing hyperinsulinaemic-euglycaemic
clamp assessments of glucose disposal rate (Liao et al., 2004).
Epidemiology
The prevalence of metabolic syndrome in the USA is estimated to
be 24% (Ford et al., 2002), with that for obesity (BMI > 30 kg/m2)
WHO**
Diabetes mellitus, impaired
glucose tolerance, impaired
fasting glucose, or insulin
resistance, plus two or more of . . .
BMI >30 kg/m2 and/or
Waist-to-hip ratio:
men >0.90
women >0.85
At least 150 mg/dL
(1.695 mmol/L) and/or
men <35 mg/dL
(0.9 mmol/L)
women <39 mg/dL
(1.0 mmol/L)
At least 160/90 mm Hg
MUST HAVE (see above)
Urinary albumin excretion rate at
least 20 mcg/min or an albumin-to-
creatinine ratio at least 20 mg/g
86 Metabolic Syndrome and Cardiovascular Disease
Obesity
Type 2
Diabetes
mellitus
Metabolic
syndrome
Figure 1 The overlap of obesity, type 2 diabetes mellitus, and the
metabolic syndrome. Adapted from Citrome et al., 2005.
being 31% (Flegal et al., 2002), and for diabetes mellitus being
6% (US DHHS, 2003). Figure 1 illustrates the overlapping nature
of these three entities.
Not everyone who has the metabolic syndrome is obese, sug-
gesting that there may be people who are ‘metabolically obese’,
having as high a risk for developing diabetes or cardiovascular
disease as those who are obese. Metabolic syndrome has been
described in normal-weight Americans who participated in the
Third National Health and Nutrition Examination Survey
(n = 7602) (St-Onge et al., 2004), where metabolic syndrome was
found in approximately 18% of white males and 23% of white
females with a BMI between 25.0 and 26.9 kg/m2, and in 9% of
white males and 12% of white females with a BMI between 23.0
and 24.9 kg/m2. For both sexes, the likelihood of the metabolic
syndrome increased significantly with an increasing BMI cat-
egory, with and without a waist circumference within the meta-
bolic syndrome definition. The prevalence rate of metabolic
syndrome in Canada is approximately 25% (Anand, 2002) despite
an obesity rate of about 15%, as determined by the 1998 National
Population Health Survey (Katzmarzyk, 2002).
In Japan, prevalence rates of obesity (defined by a BMI greater
than 30 kg/m2) are low at about 2%, as measured in a cross-
sectional study in the Japanese workplace (n = 811) (Anuurad et
al., 2003). With a cut-off BMI of 25 kg/m2, the prevalence was
22% (Anuurad et al., 2003). Almost identical results were found
in another survey of 1559 healthy Japanese adults (Ota et al.,
2002). Nonetheless, rates of metabolic syndrome were 20%
among 506 Japanese individuals taking no antihypertensive med-
ication (Kanauchi et al., 2004). Thus ‘metabolic obesity’ is not
exclusively a Western phenomenon.
The prevalence of metabolic syndrome increases dramatically
as age advances (Ford et al., 2002). The National Health and
Nutrition Examination Survey III, which was conducted among
8814 US adults aged at least 20 years, demonstrated that the
prevalence of metabolic syndrome was about 7% for men and 5%
for women between the ages of 20–29 years, and 44% for both
genders aged 60–69 years. The survey noted that the most
common component of the metabolic syndrome was increased
abdominal fat for women (46%) and hypertension for men (38%),
although rates for elevated triglycerides and low HDL-cholesterol
for men were similar. Elevated fasting plasma glucose or treat-
ment for hyperglycaemia had the lowest prevalence rates of all
components of the metabolic syndrome (16% for men, 10% for
women). The percentage of individuals with at least one metabolic
abnormality was 71%, at least two was 44%, and at least three
(meeting criteria for metabolic syndrome) was 24%. Notably, 10%
of individuals had at least four metabolic abnormalities, and 3%
had all five components of the metabolic syndrome.
Predictors of incident metabolic syndrome were studied in 714
participants in the Insulin Resistance Atherosclerosis Study who
did not have metabolic syndrome or diabetes at baseline (Pala-
niappan et al., 2004). During the 5-year follow-up, 139 (19%)
developed NCEP-defined metabolic syndrome. The best predictors
of metabolic syndrome were waist circumference (odds 1.7 per 11
cm, 95% CI 1.3–2.0), HDL-cholesterol (odds 0.6 per 15 mg/dL,
95% CI 0.4–0.7) and proinsulin levels (odds 1.7 per 3.3 pmol/l,
95% CI 1.4–2.0).
Risk factors for incident metabolic syndrome were also
assessed among 4192 persons aged 18–30 years enrolled in the
Coronary Artery Risk Development in Young Adults study (Car-
nethon et al., 2004). All were free of the metabolic syndrome at
baseline and were followed-up from 1985 to 2001. The presence
of NCEP-defined metabolic syndrome was assessed 7, 10 and 15
years after baseline. The age-adjusted rate of metabolic syndrome
was ten per 1000 person-years; 14% of the sample developed
metabolic syndrome. After adjustment for age, race and sex, rela-
tive risk was elevated among participants with higher BMI, and
BMI was the only characteristic that was a significant predictor of
metabolic syndrome across race–sex groups. Risk for metabolic
syndrome increased 23% per 4.5 kg of weight gained (95% CI
20–27%).
The prevalence of metabolic syndrome is increasing among US
adults (Ford et al., 2004). Men and women aged at least 20 years
from the National Health and Nutrition Examination Survey con-
ducted between 1988 and 1994 (n = 6436) were compared with
1677 participants from the 1999–2000 survey. Using the NCEP
definition of metabolic syndrome, age-adjusted prevalence
increased from 24.1% to 27.0% (p = 0.088). The increase was sta-
tistically significant for women, and increases in high blood pres-
sure, waist circumference and hypertriglyceridaemia accounted for
much of it.
Individuals with schizophrenia appear to be at significant risk
of developing metabolic syndrome. The Clinical Antipsychotic
Trials of Intervention Effectiveness (CATIE) programme (Stroup

et al., 2003), which included a large sample of 1493 patients with
schizophrenia, confirmed a substantial metabolic burden in this
population (Stroup, 2004). At baseline, 42% of subjects entering
the programme were obese, 64% met criteria for hyperlipidaemia,
37% met criteria for hypertension and 12% had evidence of dia-
betes mellitus (Stroup, 2004). Formal criteria for metabolic syn-
drome were met by 41% of participants (McEvoy et al., 2005).
This finding is consistent with the observations from an ongoing
US clinical trial of adjunctive topiramate treatment for schizoaf-
fective disorder (bipolar type) (n = 33), where the baseline point
prevalence of the metabolic syndrome using NCEP criteria was
42% (Basu et al., 2004). Even higher prevalence rates were found
in a cross-sectional study in 48 outpatients with schizophrenia
(Kato et al., 2004), where the prevalence of metabolic syndrome
was 63% in all patients, 41% in non-Hispanic patients, 74% in
Hispanic patients, 70% in Cuban Americans and 88% in other
Hispanic subgroups. The authors concluded that patients with
schizophrenia have a threefold greater risk of developing meta-
bolic syndrome than the general population, and that Hispanic
schizophrenia populations have a significantly higher prevalence
of metabolic syndrome than non-Hispanic populations. An
increased waist circumference was the strongest clinical correlate
with metabolic syndrome in this sample.
In one non-US sample of psychiatric patients, the prevalence of
metabolic syndrome appeared somewhat lower. In this UK study,
metabolic parameters were measured in 103 diagnostically hetero-
geneous psychiatric outpatients (Mackin et al., 2005). Only 8% of
patients fulfilled criteria for metabolic syndrome. In contrast,
when NCEP criteria were applied to 35 Finnish outpatients with
long-term schizophrenia, metabolic syndrome was found in 37%
(Heiskanen et al., 2003). This finding was similar to that from a
study of Canadian patients with schizophrenia or schizoaffective
disorder (n = 240), where prevalence rates for the metabolic syn-
drome (42.6% of men and 48.5% of women) were approximately
two-times higher than the published rates in the US adult popu-
lation, and where the metabolic syndrome appeared to occur at a
younger age than in the general population (Cohn et al., 2004).
Psychological factors impacting the risk of metabolic syn-
drome were examined in a population-based cohort of 425 women
who were followed for an average of 7.4 years (Raikkonen et al.,
2002). Women who exhibited high levels of depression, tension
and anger at baseline, and who had an increase in anger during the
follow-up, had an elevated risk for developing the metabolic syn-
drome during follow-up. The metabolic syndrome at baseline also
predicted increasing anger and anxiety 7.4 years later. The authors
concluded that, in women, psychological risk factors affect the
development of the metabolic syndrome, and that the association
between anger and the metabolic syndrome is reciprocal.
Among patients with schizophrenia, this high prevalence of
metabolic syndrome has been attributed to a number of additional
risk factors, including poor dietary choices (McCreadie, 2003) and
the consumption of a greater quantity of food (Strassnig et al.,
2003). The potential impact of antipsychotic treatment will be dis-
cussed later in this review.
Metabolic Syndrome and Cardiovascular Disease 87
Correlation with cardiovascular risk
For the most part, it appears that metabolic syndrome predicts car-
diovascular disease. It has been known for some time from the
Framingham Heart Study that age-adjusted cardiovascular events
are linearly related to hypertension, and that the risk is higher at
each point for patients who have impaired glucose tolerance
(Kannel et al., 1991). Because metabolic syndrome is more
common among patients with schizophrenia than the general
population, this may explain the increased risk of death due to car-
diovascular illness seen in patients with schizophrenia. Among
3623 patients with schizophrenia in Alberta, Canada, 20% of the
301 deaths were attributed to cardiovascular disease, resulting in a
Standardized Mortality Ratio (SMR, number of deaths observed
divided by the number of deaths expected) of 1.4 (Newman and
Bland, 1991). Similarly, among 370 patients with schizophrenia in
Southhampton, UK, cardiovascular disease resulted in 18% of the
79 deaths and a SMR of 1.9 (Brown et al., 2000).
Population-based prospective cohorts have examined the
association of the metabolic syndrome with cardiovascular and
overall mortality. In the Kuopio Ischaemic Heart Disease Risk
Factor Study (Lakka et al., 2002), 1209 Finnish men, aged 42–60
years at baseline (during 1984–1989), who were initially free from
cardiovascular disease, cancer or diabetes, were followed-up
through to December 1998. Death rates due to coronary heart
disease, cardiovascular disease, and any cause were compared
among men with metabolic syndrome and those without, using
NCEP and WHO definitions. Mortality was higher for those with
metabolic syndrome, with relative risks of 3.77 (95% CI
1.74–8.17), 3.55 (95% CI 1.96–6.43) and 2.43 (95% CI
1.64–3.61) for coronary heart disease, cardiovascular disease and
all-causes, respectively. This is consistent with the findings from
the Atherosclerosis Risk in Communities Study (McNeill et al.,
2005) where the association between the NCEP definition of the
metabolic syndrome and cardiovascular disease was tested among
12,089 black and white middle-aged individuals. The metabolic
syndrome was present in 23% of individuals without diabetes or
prevalent cardiovascular disease at baseline. Over an average of
11 years of follow-up, men and women with the metabolic syn-
drome were one-and-a-half and two times more likely to develop
coronary heart disease than control subjects. Similar associations
were found between the metabolic syndrome and incident
ischaemic stroke. Hazard ratios increased with the number of asso-
ciated components of the metabolic syndrome compared with no
components (adjusted for age, race, study site, LDL-cholesterol
level and smoking). Attempts to quantify which of the components
of the NCEP definition were most relevant for cardiovascular
disease among a cohort of 3128 patients undergoing angiography
have suggested that a high fasting glucose and low HDL-choles-
terol have the highest odds ratios (1.90, 95% CI 1.63–2.23; 1.38,
95% CI 1.18–1.62, respectively), with hypertriglyceridaemia,
hypertension and a high BMI not being statistically significant,
even though the presence of the metabolic syndrome per se was
(odds 1.30, 95% CI 1.10–1.55) (Anderson et al., 2004). According
to the WHO criteria, microalbuminuria also confers a strong risk
of cardiovascular death (Isomaa et al., 2001), but it is not yet clear
88 Metabolic Syndrome and Cardiovascular Disease
how predictive the specific cluster of high fasting glucose, low
HDL-cholesterol, and microalbuminuria might be in terms of car-
diovascular disease risk.
For patients who are older and already have diabetes, the
Casale Monferrato Study (Bruno et al., 2004) demonstrated that
the WHO definition of the metabolic syndrome was not a predictor
of 11-year all-cause and cardiovascular mortality. Results were
based on 685 deaths in 10 890 person-years of observations. The
mean age of the subjects was 68.9 years, and 56% were at least 65
years old at recruitment. The prevalence of the metabolic syn-
drome was high (76%). However, more than a twofold higher car-
diovascular risk, independent of conventional risk factors, was
evident in diabetic subjects with only one component of the syn-
drome compared with those with diabetes only (hazard ratio 2.92,
95% CI 1.16–7.33). The authors concluded that categorizing type
2 diabetic subjects as having or not having the metabolic syn-
drome did not provide further prediction of all-cause and cardio-
vascular mortality compared with the knowledge of its single
components.
Role of C-reactive protein as a predictor
C-reactive protein (CRP) is a marker for inflammatory processes.
It appears to independently predict cardiovascular disease, and can
stratify risk in those with metabolic syndrome or diabetes, as seen
in a cohort of 3873 patients from the National Health and Nutri-
tion Examination Survey of 1999–2000 (Malik et al., 2005). Odds
were highest for those with diabetes and high CRP (7.73, 95% CI
3.99–14.95), compared with 3.21 (95% CI 1.27–8.09) for those
with diabetes and low CRP or 3.33 (95% CI 1.80–6.16) for those
with metabolic syndrome but high CRP. Similarly, in a prospec-
tive cohort study of 746 American men aged 46–81 years who
were free of cardiovascular disease (Schulze et al., 2004), CRP
was significantly associated with an increased risk of cardiovascu-
lar events (relative risk for 3rd quartile levels of CRP was 2.52
[95% CI 1.31–4.86], and for the 4th quartile 2.62 [95% CI
1.29–5.32], after adjustment for age, physical activity, alcohol
intake, family history of coronary heart disease, elevated blood
pressure history, elevated cholesterol history, aspirin use,
smoking, fasting status, BMI, fibrinogen, creatinine, HbA1c and
non-HDL-cholesterol).
In addition to its relationship with cardiovascular risk, the rela-
tionship between CRP and insulin resistance has also been studied.
In a cross-sectional analysis of 5959 non-diabetic adults aged at
least 20 years who participated in the Third National Health and
Nutrition Examination Survey (1988–1994), higher homeostasis
model assessment (HOMA) values were observed when clinically
elevated CRP was present (Chen et al., 2004), even after adjust-
ment for age, race, education, physical activity, smoking, alcohol,
non-steroidal anti-inflammatory drug use, blood pressure, BMI,
waist circumference, serum total cholesterol and triglycerides. In a
study in southwestern France involving 597 men and 556 women
(Marques-Vidal et al., 2002), the prevalence of insulin resistance
syndrome (defined by an elevated HOMA and/or use of antidia-
betic medication and/or elevated fasting blood glucose, as well as
at least two of: (1) elevated BMI or waist–hip ratio, (2) hyperten-
sion or treatment for same, or (3) dyslipidemia or treatment for
same) was 23% for men and 12% for women. After adjusting for
age, alcohol, tobacco and menopause, subjects with insulin resist-
ance syndrome were found to have significantly higher CRP
levels.
CRP enhanced the prognostic utility of the metabolic syndrome
in the West of Scotland Coronary Prevention Study (Sattar et al.,
2003). A modified version of the NCEP definition of metabolic
syndrome was used in this study, where BMI replaced waist cir-
cumference as a criterion. Data were available for 6447 men to
predict coronary heart disease, and for 5974 men to predict new-
onset diabetes. Over almost 5 years of follow-up, the presence of
elevated CRP conferred additional risk, over and above the pres-
ence or absence of metabolic syndrome. However, in another
sample of 3037 (1681 women) in the Framingham Offspring
Study (Rutter et al., 2004), using both CRP and metabolic syn-
drome was no better for estimating cardiovascular risk than either
measure alone, even though both measures were independent of
each other.
Contribution of second-generation
antipsychotics
Treatment of schizophrenia invariably requires the use of antipsy-
chotics, usually over many years. Among 240 patients with schiz-
ophrenia in Toronto, Canada, with a mean length of illness from
first hospitalization of 19.4 years, the prevalence of metabolic syn-
drome was 42.6% in men and 48.5% in women (Cohn et al.,
2004). Compared with a reference population from the Canadian
Heart Health Survey (MacLean et al., 1992), Framingham 10-year
risk of myocardial infarction was greater in the male patients. The
authors recommended routine evaluation of coronary heart disease
risk factors, especially metabolic syndrome and cigarette smoking
(74% of the men and 66% of the women smoked, compared to the
national sample where the smoking rates were 30% and 28%,
respectively). Of all the components of the metabolic syndrome,
statistically significant differences in prevalence were seen for ele-
vated BMI, waist circumference, triglycerides and HDL-
cholesterol among the patients compared to the reference
population. Rates of hypertension were similar between both
groups. Unfortunately, the cross-sectional study design limited the
ability to separate the relative contribution of medication to car-
diovascular risk. However, fasting plasma triglycerides differed
among the antipsychotic groups (mean of 2.60, 2.22, 1.89 and
1.83 mol/l for clozapine, olanzapine, risperidone and typical
antipsychotics, respectively). Framingham risks and metabolic
syndrome risks did not differ between antipsychotic groups.
In a sample of 48 individuals with schizophrenia in Florida
(Kato et al., 2004), those with metabolic syndrome had statisti-
cally significantly elevated waist circumference and HDL-choles-
terol, after controlling for age, gender, race and ethnicity. No
association was found between metabolic syndrome and anti-
psychotic medication, however, the design of the study (small
sample size and lack of a control group) and the composition of

the sample (half of the patients were taking clozapine) precluded
meaningful analysis of this issue.
Metabolic syndrome was found in 13 out of 35 Finnish outpa-
tients with long-term schizophrenia (Heiskanen et al., 2003). In
order of frequency, the prevalence of the different components of
the metabolic syndrome were elevated waist girth (68% of men,
75% of women), HDL-cholesterol (58% in men, 25% of women),
elevated fasting blood glucose (46%), elevated serum triglycerides
(31%) and hypertension (26%). No associations were found
between metabolic syndrome and the different antipsychotics
used, although an inverse relationship with dose was reported. As
with the study by Kato et al. (2004), the evaluation of inter-med-
ication differences was hampered by study design (small sample
size and lack of a control group) and the composition of the
sample (60% were using clozapine).
In a sample of 103 diagnostically heterogeneous psychiatric
outpatients in the north of England (Mackin et al., 2005), only
eight met WHO criteria for metabolic syndrome (three receiving
olanzapine, two receiving clozapine, two receiving quetiapine and
one receiving risperidone), all of whom were among the 83 taking
second-generation antipsychotics either alone or with first-
generation antipsychotics. Pair-wise comparisons suggested that
BMI and HbA1c were higher among patients receiving quetiapine
(n = 11) than patients receiving olanzapine (n = 32), and that
triglycerides were higher for those receiving clozapine (n = 8) than
for those receiving amisulpiride (n = 5) or risperidone (n = 13), but
the small sample sizes and the lack of correction for the multiplicity
of statistical analyses, make it difficult to interpret these findings.
In the absence of specific studies examining quantitative differ-
ences among the second-generation antipsychotics in relation to
risk of metabolic syndrome, studies assessing individual com-
ponents of the syndrome may be reviewed. An influential report
by a multidisciplinary consensus panel (ADA et al., 2004) noted
that such studies have consistently shown an increased risk for
diabetes and a worsening lipid profile in patients treated with
clozapine or olanzapine compared with patients receiving treat-
ment with first-generation antipsychotics, but that the risk in
patients taking risperidone and quetiapine is less clear. Others
have commented on the evidence and have disagreed, particularly
in relation to the risk of diabetes associated with second-genera-
tion antipsychotics (Citrome and Volavka, 2004; Citrome and
Volavka, in press). A recent review examined the quantity and
quality of the evidence supporting the notion that there are meas-
urable differences in propensity for weight gain among the
second-generation antipsychotics and assigned it to the ‘level 1’
category of quality (Marder et al., 2004). In contrast, the quality of
evidence for differential effects between specific antipsychotics on
the risk of diabetes and hyperlipidaemia was categorized as ‘level
2’, with the accompanying narrative suggesting that, ‘identifying
any of the agents as causally associated . . . would be premature’
for diabetes, and that there was ‘insufficient data . . . about relative
risk . . . with different antipsychotics’ for worsening lipid profile. It
is noteworthy that although changes in fasting plasma glucose
were not correlated with weight change in one double-blind, ran-
domized clinical trial comparing clozapine, olanzapine, risperi-
done and haloperidol, changes in total cholesterol were
Metabolic Syndrome and Cardiovascular Disease 89
(Lindenmayer et al., 2003), suggesting that weight change may be
a key factor in serum lipid alterations associated with antipsy-
chotic use (Meyer and Koro, 2004). There is no evidence to
support a differential effect of antipsychotics on the risk of hyper-
tension (Cohn et al., 2004), and no studies of microalbuminuria
and antipsychotics have been published.
The best predictors for the development of metabolic syndrome
in non-psychiatric samples have been measures of abdominal
obesity (Palaniappan et al., 2004; Carnethon et al., 2004). Thus,
the metabolic syndrome component with the strongest evidence
for a differential effect among second-generation antipsychotics is
also the component that is most predictive of metabolic syndrome.
This highlights the importance of aggressive management of
abdominal obesity. However, the issue of the ‘metabolically
obese’ remains, since metabolic syndrome can occur in those who
are not considered clinically overweight. Moreover, there is
renewed controversy over the actual health risk of being over-
weight per se, since being overweight was not associated with
excess mortality in a recent study that used data from National
Health and Nutrition Examination Surveys (Flegal et al., 2005).
The authors of this study noted that the impact of obesity on mor-
tality might have decreased over time because of improvements in
public health and medical care. Indeed, in an examination of 40-
year trends in cardiovascular disease risk factors by BMI group
among US adults aged 20–74 years using the National Health and
Nutrition Examination Surveys, the prevalence of all risk factors
except diabetes decreased over time for all BMI groups (Gregg et
al., 2005). Compared with obese individuals in 1960–1962, obese
individuals in 1999–2000 had a 21-percentage-point lower preva-
lence of high cholesterol (39% in 1960–1962 compared with 18%
in 1999–2000), an 18-percentage-point lower prevalence of high
blood pressure (from 42% to 24%), and a 12-percentage-point
lower smoking prevalence (from 32% to 20%). Changes in risk
factors were accompanied by increases in lipid-lowering and anti-
hypertensive medication use, particularly among obese persons. In
essence, although obese individuals still had higher risk factor
levels than lean individuals, the levels of these risk factors were
much lower than in previous decades. This decrease in risk factors
for cardiovascular disease (Gregg et al., 2005), and the observed
decrease in the impact of obesity on mortality (Flegal et al., 2005)
may not apply to patients with major mental disorders who do not
access medical care and who may have multiple additional risk
factors. Nevertheless, these data are encouraging since they
demonstrate that a measurable positive impact on health outcomes
is achievable through the use of preventative measures, ongoing
monitoring, and effective management.
Cardiovascular risk reduction
For patients with schizophrenia, lifestyle factors can have a major
impact on cardiovascular risk. In one survey involving 103 outpa-
tients with schizophrenia in Scotland (McCreadie et al., 2003),
compared with the general population, fewer schizophrenia
patients consumed acceptable levels of certain foodstuffs import-
ant in a balanced diet (e.g. fruit, vegetables, milk). In addition to
90 Metabolic Syndrome and Cardiovascular Disease
this relatively unhealthy diet, 70% of patients were smokers, and
86% of the women and 70% of the men were overweight or obese.
The mean 10-year Framingham risk of coronary heart disease was
10.5% in men and 7% in women, compared with the reference
population risks of 6.4% and 4.1%, respectively. Reduction of car-
diovascular risk in the schizophrenia population will require
special attention to these modifiable risk factors. As discussed
earlier, BMI and weight gain are important risk factors for the
metabolic syndrome, with risk increasing by 23% per 4.5 kg of
weight gained (Carnethon et al., 2004). Regular physical activity
may counter this risk (relative risk 0.49, 95% CI 0.34–0.70) (Car-
nethon et al., 2004), but attention to overall caloric intake is
crucial. Even modest weight loss is associated with increased life
expectancy, and may be associated with reductions in other car-
diovascular risk factors such as high blood pressure, glucose,
HbA1c and lipids (Lean et al., 1990; McCarron et al., 1997).
Treatment of the metabolic syndrome
The presence of the metabolic syndrome requires active inter-
vention in order to reduce the risk of cardiovascular disease or
death. Guidelines are in constant flux, with the lower limit of
abnormal fasting glucose and the target levels of HDL-cholesterol
both currently under review. Agreement does exist that all com-
ponents of the metabolic syndrome need to be targeted (NCEP,
2002). Atherogenic dyslipidaemia requires correction, including
elevated triglycerides, low HDL-cholesterol, and the reduction of
small, dense LDL-cholesterol particles; LDL-cholesterol reduction
alone does not result in full benefit. Hypertension requires treat-
ment. Prophylactic aspirin for a prothrombotic state should be
given. Correcting insulin resistance involves weight reduction and
increasing physical activity. Unfortunately, drugs that decrease
insulin resistance (in the absence of diabetes) have not been
proven to reduce risk of coronary heart disease, but this remains
an active area of research (Davidson, 2003b). Needless to say, the
presence of diabetes requires aggressive monitoring and manage-
ment of plasma glucose levels.
The benefits of a combination of intensified integrated behavi-
our modification and targeted polypharmacy addressing hypergly-
caemia, hypertension, dyslipidaemia and microalbuminuria can be
significant, as described in a open, parallel study (n = 160; mean
follow-up 7.8 years) conducted at the Steno Diabetes Center in
Denmark, examining cardiovascular disease in patients with type
2 diabetes mellitus and microalbuminuria (Gaede et al., 2003;
Pedersen and Gaede, 2003). In this study, 44% of patients in the
conventional treatment group had a cardiovascular event com-
pared with 24% in the intensive treatment group; thus, a relative
risk reduction of about 50% was observed (hazard ratio 0.47, 95%
CI 0.24–0.73). The decline in HbA1c values, blood pressure,
serum cholesterol and triglyceride levels measured after an
overnight fast, and urinary albumin excretion rate were all signifi-
cantly greater in the intensive-therapy group than in the conven-
tional-therapy group.
Ongoing monitoring for patients with
schizophrenia
Decreasing risk of cardiovascular disease among patients with
schizophrenia will require monitoring of all components of the
metabolic syndrome: abdominal obesity, lipids (triglycerides and
HDL-cholesterol), blood pressure, glucose and, perhaps, microal-
buminuria. Unfortunately, just as there are inconsistent definitions
of the metabolic syndrome, there are inconsistent guidelines for
monitoring. One of the first to be developed were the so-called
‘Mount Sinai Guidelines’ based on a meeting held 17–18 October
2002 at the Mount Sinai School of Medicine in New York City
(Marder et al., 2002; Marder et al., 2004). Monitoring of BMI and
waist circumference is recommended in this guideline at every
visit for the first 6 months, and quarterly thereafter. Fasting plasma
glucose is recommended at baseline, then 4 months later, then
yearly. A full lipid profile is recommended at baseline and at least
every 2 years when LDL-cholesterol is normal, otherwise every 6
months if LDL-cholesterol is over 130 mg/dL (3.367 mmol/L).
Unfortunately, these guidelines do not include blood pressure as
part of the metabolic monitoring package.
The American Psychiatric Association’s broad guidelines for
the treatment of schizophrenia (Lehman et al., 2004) recommend a
BMI and a fasting plasma glucose level at the same intervals as
the Mount Sinai guidelines, but omit the recommendation for
measuring waist circumference. Blood pressure is included, but
only ‘as clinically indicated, particularly as medication doses are
titrated’. A lipid profile is recommended at baseline, and then at
least every 5 years.
Perhaps the most complete set of monitoring recommendations
can be found in a report of a consensus development conference
conducted by members of the American Diabetes Association, the
American Psychiatric Association, the American Association of
Clinical Endocrinologists and the North American Association for
the Study of Obesity on 19–21 November 2003 (ADA et al.,
2004). BMI is recommended at baseline and then at weeks 4, 8
and 12, and then quarterly. Waist circumference is recommended
at baseline and then annually. Blood pressure is recommended at
baseline, at 12 weeks, and then annually. Fasting plasma glucose
is recommended at baseline, at 12 weeks, and then annually. A
lipid profile is recommended at baseline, at 12 weeks, and then
every 5 years. These guidelines are the recommended minimum
requirements for monitoring. If multiple risk factors are present,
closer scrutiny of metabolic parameters should be considered. The
addition of cardiovascular risk factors such as microalbuminuria
and CRP in future guidelines is anticipated.
Worryingly, monitoring is still not the norm in psychiatric
practice. Seventy-nine percent of 300 respondents to a psychia-
trists’ telephone survey in the USA indicated that waist circumfer-
ence is measured in few or no patients, although 62% of
psychiatrists indicated that they obtain weight measurements for
all or most of their patients (Newcomer et al., 2004). Only 34% of
respondents indicated they obtain blood pressure measurements
for most or all of their patients, with 43% obtaining glucose levels
and 29% obtaining lipid levels for most or all of their patients. In a
written survey of 258 psychiatrists from the states of Georgia,

Iowa and Ohio, only 43% indicated that personal and family
history, and height and weight, were easily obtainable (Buckley et
al., in press); 42% indicated that waist circumference was difficult
to obtain or unobtainable. Further educational efforts are clearly
desirable.
Conclusions
Metabolic syndrome provides a means to identify individuals at
risk of developing diabetes mellitus and/or cardiovascular disease.
No matter what definition of metabolic syndrome is used, the
prevalence of this syndrome is increasing over time, and patients
with major mental health disorders such as schizophrenia are more
prone to developing metabolic disorder than the general popu-
lation. Although obesity is one component of the metabolic syn-
drome, it is possible to have normal weight and have the metabolic
syndrome, the so-called state of being ‘metabolically obese’. The
cardiovascular consequences of having the metabolic syndrome
are considerable and include a reduced life expectancy. C-reactive
protein may assist in assessing cardiovascular risk among patients
with metabolic syndrome. All components of the metabolic syn-
drome need to be monitored on a regular basis and several guide-
lines exist to assist the clinician in doing so.
Although prevention of the development of metabolic syn-
drome is desirable, active treatment may ultimately be required to
treat abnormalities in lipids, blood pressure, and glucose, and to
address the prothrombotic state. Although antipsychotics differ in
their propensity for weight gain, the differential impact this may
have on attributable risk of developing metabolic syndrome has
not been adequately determined. Until it is, careful monitoring for
the metabolic syndrome is recommended in all patients receiving
antipsychotics, with increased vigilance in the presence of exces-
sive weight gain.
Acknowledgements
The material in this review was presented at a consensus panel
meeting held in Dublin, Ireland, 14–15 April, 2005, which was
sponsored by Eli Lilly and Company.
Declaration of interest
Leslie Citrome, M D, MPH, is a consultant for, has received hono-
raria from, or has conducted clinical research supported by the
following: Abbott Laboratories, AstraZeneca Pharmaceuticals,
Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline,
Janssen Pharmaceuticals, Novartis Pharmaceuticals, Pfizer Inc,
and Repligen Corp.
References
American Diabetes Association; American Psychiatric Association;
American Association of Clinical Endocrinologists; North American
Association for the Study of Obesity (2004) Consensus development
Metabolic Syndrome and Cardiovascular Disease 91
conference on antipsychotic drugs and obesity and diabetes. Diabetes
Care 27: 596–601
Anand S (2002) The metabolic syndrome in Canada. Presentation on
CMEonDiabetes.com. http://www.cmeondiabetes.com/pub/the.meta-
bolic.syndrome.in.canada.php Accessed May 2, 2005
Anderson JL, Horne B D, Jones H U, Reyna S P, Carlquist J F, Bair T L,
Pearson R R, Lappe D L, Muhlestein JB; Intermountain Heart Collabo-
rative (IHC) Study (2004) Which features of the metabolic syndrome
predict the prevalence and clinical outcomes of angiographic coronary
artery disease? Cardiology 101: 185–193
Anuurad E, Shiwaku K, Nogi A, Kitajima K, Enkhmaa B, Shimono K,
Yamane Y (2003) The new BMI criteria for asians by the regional
office for the western pacific region of WHO are suitable for screening
of overweight to prevent metabolic syndrome in elder Japanese
workers. J Occup Health 45: 335–343
Basu R, Brar J S, Chengappa K N, John V, Parepally H, Gershon S,
Schlicht P, Kupfer DJ (2004) The prevalence of the metabolic syn-
drome in patients with schizoaffective disorder–bipolar subtype.
Bipolar Disord 6: 314–318
Bloomgarden ZT (2004) Definitions of the insulin resistance syndrome:
the 1st World Congress on the Insulin Resistance Syndrome. Diabetes
Care 27: 824–830
Brown S, Inskip H, Barraclough B (2000) Causes of the excess mortality
of schizophrenia. Br J Psychiatry 177: 212–217
Bruno G, Merletti F, Biggeri A, Bargero G, Ferrero S, Runzo C, Prina
Cerai S, Pagano G, Cavallo-Perin P; Casale Monferrato Study (2004)
Metabolic syndrome as a predictor of all-cause and cardiovascular
mortality in type 2 diabetes: the Casale Monferrato Study. Diabetes
Care 27: 2689–2694
Buckley P F, Miller D D, Singer B, Arena J, Stirewalt EM (in press) Clini-
cians’ appreciation of the metabolic adverse effects of antipsychotic
medications. Schizophrenia Research
Carnethon M R, Loria C M, Hill J O, Sidney S, Savage P J, Liu K; Coro-
nary Artery Risk Development in Young Adults study (2004) Risk
factors for the metabolic syndrome: the Coronary Artery Risk Devel-
opment in Young Adults (CARDIA) study, 1985–2001. Diabetes Care
27: 2707–2715
Chen J, Wildman R P, Hamm L L, Muntner P, Reynolds K, Whelton P K,
He J; Third National Health and Nutrition Examination Survey (2004)
Association between inflammation and insulin resistance in U.S. non-
diabetic adults: results from the Third National Health and Nutrition
Examination Survey. Diabetes Care 27: 2960–2965
Citrome L, Volavka J (2004) Consensus development conference on
antipsychotic drugs and obesity and diabetes: response to consensus
statement. Diabetes Care 27: 2087–2088
Citrome L, Volavka J (2005) Consensus development conference on
antipsychotic drugs and obesity and diabetes: response to consensus
statement. Journal of Clinical Psychiatry 66: 1073–1074
Citrome L, Blonde L, Damatarca C (2005) Metabolic Issues in Patients
With Severe Mental Illness. Southern Medical Journal 98: 714–720
Cohn T, Prud’homme D, Streiner D, Kameh H, Remington G (2004) Char-
acterizing coronary heart disease risk in chronic schizophrenia: high
prevalence of the metabolic syndrome. Can J Psychiatry 49: 753–760
Davidson MB (2003a) Metabolic syndrome/insulin resistance
syndrome/pre-diabetes: new section in diabetes care. Diabetes Care 26:
3179
Davidson MB (2003b) Is treatment of insulin resistance beneficial
independent of glycemia? Diabetes Care 26: 3184–3186
Flegal K M, Carroll M D, Ogden C L, Johnson CL (2002) Prevalence and
trends in obesity among US adults, 1999–2000. JAMA 288:
1723–1727
92 Metabolic Syndrome and Cardiovascular Disease
Flegal K M, Graubard B I, Williamson D F, Gail MH (2005) Excess
deaths associated with underweight, overweight, and obesity. JAMA
293: 1861–1867
Ford E S, Giles WH (2003) A comparison of the prevalence of the meta-
bolic syndrome using two proposed definitions. Diabetes Care 26:
575–581
Ford E S, Giles W H, Dietz WH (2002) Prevalence of the metabolic syn-
drome among US adults: findings from the third National Health and
Nutrition Examination Survey. JAMA 287: 356–359
Ford E S, Giles W H, Mokdad AH (2004) Increasing prevalence of the
metabolic syndrome among US adults. Diabetes Care 27: 2444–2449
Gaede P, Vedel P, Larsen N, Jensen G V, Parving H H, Pedersen O (2003)
Multifactorial intervention and cardiovascular disease in patients with
type 2 diabetes. N Engl J Med 348: 383–393
Gregg E W, Cheng Y J, Cadwell B L, Imperatore G, Williams D E, Flegal
K M, Narayan K M, Williamson DF (2005) Secular trends in cardio-
vascular disease risk factors according to body mass index in US
adults. JAMA 293: 1868–1874
Grundy S M, Brewer HB Jr, Cleeman J I, Smith SC Jr, Lenfant C; Ameri-
can Heart Association; National Heart, Lung, and Blood Institute
(2004) Definition of metabolic syndrome: Report of the National
Heart, Lung, and Blood Institute/American Heart Association con-
ference on scientific issues related to definition. Circulation 109:
433–438
Heiskanen T, Niskanen L, Lyytikainen R, Saarinen P I, Hintikka J (2003)
Metabolic syndrome in patients with schizophrenia. J Clin Psychiatry
64: 575–579
Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen M
R, Groop L (2001) Cardiovascular morbidity and mortality associated
with the metabolic syndrome. Diabetes Care 24: 683–689
Kanauchi M, Kanauchi K, Hashimoto T, Saito Y (2004) Metabolic syn-
drome and new category ‘pre-hypertension’ in a Japanese population.
Curr Med Res Opin 20: 1365–1370
Kannel W B, Wilson P W, Zhang TJ (1991) The epidemiology of impaired
glucose tolerance and hypertension. Am Heart J 121: 1268–1273
Kato M M, Currier M B, Gomez C M, Hall L, Gonzalez-Blanco M (2004)
Prevalence of metabolic syndrome in hispanic and non-hispanic
patients with schizophrenia. Prim Care Companion J Clin Psychiatry 6:
74–77
Katzmarzyk PT (2002) The Canadian obesity epidemic, 1985–1998.
CMAJ 166: 1039–1040
Lakka H M, Laaksonen D E, Lakka T A, Niskanen L K, Kumpusalo E,
Tuomilehto J, Salonen JT (2002) The metabolic syndrome and total
and cardiovascular disease mortality in middle-aged men. JAMA 288:
2709–2716
Lean M E, Powrie J K, Anderson A S, Garthwaite PH (1990) Obesity,
weight loss and prognosis in type 2 diabetes. Diabet Med 7: 228–233
Lehman A F, Lieberman J A, Dixon L B, McGlashan T H, Miller A L,
Perkins D O, Kreyenbuhl J; American Psychiatric Association; Steer-
ing Committee on Practice Guidelines (2004) Practice guideline for the
treatment of patients with schizophrenia, second edition. Am J Psychi-
atry 161(2 Suppl): 1–56
Liao Y, Kwon S, Shaughnessy S, Wallace P, Hutto A, Jenkins A J, Klein
R L, Garvey WT (2004) Critical evaluation of adult treatment panel III
criteria in identifying insulin resistance with dyslipidemia. Diabetes
Care 27: 978–983
Lindenmayer J P, Czobor P, Volavka J, Citrome L, Sheitman B, McEvoy J
P, Cooper T B, Chakos M, Lieberman JA (2003) Changes in glucose
and cholesterol levels in patients with schizophrenia treated with
typical or atypical antipsychotics. Am J Psychiatry 160: 290–296
Lorenzo C, Okoloise M, Williams K, Stern M P, Haffner SM; San Antonio
Heart Study (2003) The metabolic syndrome as predictor of type 2 dia-
betes: the San Antonio Heart Study. Diabetes Care 26: 3153–3159
Mackin P, Watkinson H M, Young AH (2005) Prevalence of obesity,
glucose homeostasis disorders and metabolic syndrome in psychiatric
patients taking typical or atypical antipsychotic drugs: a cross-sectional
study. Diabetologia 48: 215–221
MacLean D R, Petrasovits A, Nargundkar M, Connelly P W, MacLeod E,
Edwards A, Hessel P (1992) Canadian heart health surveys: a profile of
cardiovascular risk. Survey methods and data analysis. Canadian Heart
Health Surveys Research Group. CMAJ 146: 1969–1974
McCarron D A, Oparil S, Chait A, Haynes R B, Kris-Etherton P, Stern J S,
Resnick L M, Clark S, Morris C D, Hatton D C, Metz J A, McMahon
M, Holcomb S, Snyder G W, Pi-Sunyer FX (1997) Nutritional man-
agement of cardiovascular risk factors. A randomized clinical trial.
Arch Intern Med 157: 169–177
McCreadie RG; Scottish Schizophrenia Lifestyle Group (2003) Diet,
smoking and cardiovascular risk in people with schizophrenia: descrip-
tive study. Br J Psychiatry 183: 534–539
McEvoy J P, Meyer J M, Goff D C, Nasrallah H A, Davis S M, Sullivan L,
Meltzer H Y, Hsiao J, Stroup T S, Lieberman J A (2005) Prevalence of
the metabolic syndrome in patients with schizophrenia: baseline results
from the Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE) schizophrenia trial and comparison with national estimates
from NHANES III. Schizophrenia Research (in press)
McNeill A M, Rosamond W D, Girman C J, Golden S H, Schmidt M I,
East H E, Ballantyne C M, Heiss G (2005) The metabolic syndrome
and 11-year risk of incident cardiovascular disease in the atherosclero-
sis risk in communities study. Diabetes Care 28: 385–390
Malik S, Wong N D, Franklin S, Pio J, Fairchild C, Chen R (2005) Cardio-
vascular disease in U.S. patients with metabolic syndrome, diabetes,
and elevated C-reactive protein. Diabetes Care 28: 690–693
Marder S R, Essock S M, Miller A L, Buchanan R W, Davis J M, Kane J
M, Lieberman J, Schooler NR (2002) The Mount Sinai conference on
the pharmacotherapy of schizophrenia. Schizophr Bull 28: 5–16
Marder S R, Essock S M, Miller A L, Buchanan R W, Casey D E, Davis J
M, Kane J M, Lieberman J A, Schooler N R, Covell N, Stroup S,
Weissman E M, Wirshing D A, Hall C S, Pogach L, Pi-Sunyer X,
Bigger JT Jr, Friedman A, Kleinberg D, Yevich S J, Davis B, Shon S
(2004) Physical health monitoring of patients with schizophrenia. Am J
Psychiatry 161: 1334–1349
Marques-Vidal P, Mazoyer E, Bongard V, Gourdy P, Ruidavets J B,
Drouet L, Ferrieres J (2002) Prevalence of insulin resistance syndrome
in southwestern France and its relationship with inflammatory and
hemostatic markers. Diabetes Care 25: 1371–1377
Meigs JB (2004) Metabolic syndrome: in search of a clinical role. Diabetes
Care 27: 2761–2763
Meyer J M, Koro CE (2004) The effects of antipsychotic therapy on serum
lipids: a comprehensive review. Schizophr Res 70: 1–17
National Cholesterol Education Program (NCEP) Expert Panel on Detec-
tion, Evaluation, and Treatment of High Blood Cholesterol in Adults
(2001) Executive Summary of The Third Report of The National Cho-
lesterol Education Program (NCEP) Expert Panel on Detection, Evalu-
ation, And Treatment of High Blood Cholesterol In Adults (Adult
Treatment Panel III). JAMA 285: 2486–2497
National Cholesterol Education Program (NCEP) Expert Panel on Detec-
tion, Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) (2002) Third Report of the National Cho-
lesterol Education Program (NCEP) Expert Panel on Detection, Evalu-
ation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III) final report. Circulation 106: 3143–3421
Newcomer J W, Nasrallah H A, Loebel AD (2004) The atypical antipsy-

chotic therapy and metabolic issues national survey: practice patterns
and knowledge of psychiatrists. J Clin Psychopharmacol 24 (Suppl 1):
S1–6
Newman S C, Bland RC (1991) Mortality in a cohort of patients with
schizophrenia: a record linkage study. Can J Psychiatry 36: 239–245
Ota T, Takamura T, Hirai N, Kobayashi K (2002) Preobesity in World
Health Organization classification involves the metabolic syndrome in
Japanese. Diabetes Care 25: 1252–1253
Palaniappan L, Carnethon M R, Wang Y, Hanley A J, Fortmann S P,
Haffner S M, Wagenknecht L; Insulin Resistance Atherosclerosis
Study (2004) Predictors of the incident metabolic syndrome in adults:
the Insulin Resistance Atherosclerosis Study. Diabetes Care 27:
788–793
Pedersen O, Gaede P (2003) Intensified multifactorial intervention and car-
diovascular outcome in type 2 diabetes: the Steno-2 study. Metabolism
52 (8 Suppl 1): 19–23
Raikkonen K, Matthews K A, Kuller LH (2002) The relationship between
psychological risk attributes and the metabolic syndrome in healthy
women: antecedent or consequence? Metabolism 51: 1573–1577
Rutter M K, Meigs J B, Sullivan L M, D’Agostino RB Sr, Wilson PW
(2004) C-reactive protein, the metabolic syndrome, and prediction of
cardiovascular events in the Framingham Offspring Study. Circulation
110: 380–385
Sattar N, Gaw A, Scherbakova O, Ford I, O’Reilly D S, Haffner S M, Isles
C, Macfarlane P W, Packard C J, Cobbe S M, Shepherd J (2003) Meta-
bolic syndrome with and without C-reactive protein as a predictor of
coronary heart disease and diabetes in the West of Scotland Coronary
Prevention Study. Circulation 108: 414–419
Schulze M B, Rimm E B, Li T, Rifai N, Stampfer M J, Hu F B (2004) C-
Metabolic Syndrome and Cardiovascular Disease 93
reactive protein and incident cardiovascular events among men with
diabetes. Diabetes Care 27: 889–894
Stern M P, Williams K, Gonzalez-Villalpando C, Hunt K J, Haffner S M
(2004) Does the metabolic syndrome improve identification of indi-
viduals at risk of type 2 diabetes and/or cardiovascular disease? Dia-
betes Care 27: 2676–2681
St-Onge M P, Janssen I, Heymsfield S B (2004) Metabolic syndrome in
normal-weight Americans: new definition of the metabolically obese,
normal-weight individual. Diabetes Care 27: 2222–2228
Strassnig M, Brar J S, Ganguli R (2003) Nutritional assessment of patients
with schizophrenia: a preliminary study. Schizophr Bull 29: 393–397
Stroup TS (2004) Antipsychotic drug treatment of schizophrenia: update
on the CATIE trial. In: NCDEU Abstracts from the 44th Annual
Meeting, June 1–4, 2004, Phoenix, Arizona. Department of Health and
Human Services, National Institutes of Health, National Institute of
Mental Health, Bethesda, MD
Stroup T S, McEvoy J P, Swartz M S, Byerly M J, Glick I D, Canive J M,
McGee M F, Simpson G M, Stevens M C, Lieberman JA (2003) The
National Institute of Mental Health Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE) project: schizophrenia trial design
and protocol development. Schizophrenia Bulletin 29: 15–31
Tan C E, Ma S, Wai D, Chew S K, Tai ES (2004) Can we apply the
National Cholesterol Education Program Adult Treatment Panel defini-
tion of the metabolic syndrome to Asians? Diabetes Care 27:
1182–1186
United States Department of Health and Human Services, Centers for
Disease Control and Prevention (2003) National Diabetes Fact Sheet,
United States. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2003.pdf
Accessed May 7, 2004