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ONLINE
FIRST
Systematic
Review of Early Cardiometabolic Outcomes of the First Treated
Episode of Psychosis

Debra
L. Foley, PhD; Katherine I. Morley, PhD

Arch Gen
Psychiatry. Published online February 7, 2011.
doi:10.1001/archgenpsychiatry.2011.2

ABSTRACT

Context
The increased mortality associated with schizophrenia is
largely due to cardiovascular disease. Treatment with
antipsychotics is associated with weight gain and changes
in other cardiovascular risk factors. Early
identification of modifiable cardiovascular risk factors
is a clinical imperative but prospective longitudinal
studies of the early cardiometabolic adverse effects of
antipsychotic drug treatment other than weight gain have
not been previously reviewed.

Objectives  To assess the methods and reporting of
cardiometabolic outcome studies of the first treated
episode of psychosis, review key findings, and suggest
directions for future research.

Data Sources  PsycINFO, MEDLINE, and Scopus from
January 1990 to June 2010.

Study Selection  Subjects were experiencing their
first treated episode of psychosis. Subjects were
antipsychotic naive or had been exposed to antipsychotics
for a short known period at the beginning of the study.
Cardiometabolic indices were assessed. Studies used a
longitudinal design.

Data Extraction  Sixty-four articles were identified
describing 53 independent studies; 25 studies met
inclusion criteria and were retained for detailed
review.

Data Synthesis  Consolidated Standards of Reporting
Trials and Strengthening the Reporting of Observational
Studies in Epidemiology checklists were used to assess
the methods and reporting of studies. A qualitative
review of findings was conducted.

Conclusions  Two key hypotheses were identified based
on this review: (1) in general, there is no difference in
cardiovascular risk assessed by weight or metabolic
indices between individuals with an untreated first
episode of psychosis and healthy controls and (2)
cardiovascular risk increases after first exposure to any
antipsychotic drug. A rank order of drugs can be derived
but there is no evidence of significant class differences.
Recommended directions for future research include
assessing the effect on cardiometabolic outcomes of
medication adherence and dosage effects, determining the
therapeutic window for antipsychotic use in adults and
youth, and testing for moderation of outcomes by
demographic factors, including sex and age, and clinical
and genetic factors.

INTRODUCTION

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Introduction

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Methods

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Results

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References

Twenty-five
years after diagnosis, individuals with schizophrenia
have a mortality risk that is 3 times that of the general
population.1
Although risk of suicide is increased 18-fold over 25 years,1
the very low base rate for suicide in the wider community
means that the major cause of mortality and morbidity
among individuals with schizophrenia is actually natural
causes, predominantly cardiovascular disease.1-2
Antipsychotic drugs, such as clozapine, can save lives by
reducing the impulsiveness and aggression that can lead
to suicide3-4
but they can also alter risk for cardiovascular disease
by causing weight gain5-6
and possibly hypertension and lipid and glucose
abnormalities.7
The risk for cardiovascular disease appears to be
increasing among individuals with schizophrenia,1
creating an ever-widening gap between the life expectancy
of the seriously mentally ill and the broader
community.8
Determining if antipsychotic drugs reduce or increase
overall mortality associated with schizophrenia or other
psychoses is therefore a pressing issue9-10
and the identification of, and intervention directed at,
modifiable risk factors for cardiovascular disease among
the seriously mentally ill, a clinical imperative.

Research is needed to understand the nature and magnitude of
the cardiovascular risk factors associated with
schizophrenia and other psychoses in the early phase of
illness to track the effects of different drug treatments
for psychosis on key risk factors for cardiovascular
disease. Distinguishing pretreatment status from
treatment effects is important for understanding the
source of cardiovascular disease associated with psychosis
and to inform decisions regarding medication review and
other interventions. This distinction can only be made at
the very beginning of treatment in patients with a first
episode of psychosis who have not previously been exposed
to antipsychotic drugs or who have been exposed for a
short known period.11
First-episode psychosis is an intermediate diagnosis used
in the early phase of psychotic illness until the
clinical picture stabilizes.12
Most first episodes of psychosis will eventually be
diagnosed as schizophrenia in younger cohorts, or as
schizophrenia, bipolar disorder, or major depression with
psychotic features in samples unselected for age at
onset.13

The aims of this report are to:

Identify prospective longitudinal treatment studies of the
first episode of psychosis that include assessment of
cardiometabolic outcomes. These include body weight and
central obesity and associated biomarkers,
hyperglycemia and hyperinsulinemia, dyslipidemia,
hypertension, and inflammatory markers (Table).

Summarize the methods and quality of reporting of
identified studies.

Conduct a review of the early cardiometabolic outcomes of
treated psychosis and report key findings.

Suggest directions for future research.

View
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Table.
Cardiometabolic Indices Assessed by the Studies
Reviewed Herein and Their Association With
Cardiovascular Outcomes

METHODS

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DATA
SOURCES

Two search strings were used to identify studies: ["first
episode psychosis" AND metabolism] and [psychosis AND
naive AND "glucose OR insulin OR cholesterol OR
triglycerides OR blood pressure OR weight"]. The search
was limited to English-language publications and was
conducted using MEDLINE (via PubMed), PsycINFO, and
Scopus for the period from January 1, 1990, through June
15, 2010. The reference lists of identified articles were
also hand searched.

STUDY
SELECTION

Studies were included if (1) subjects had a first episode of
psychosis; (2) subjects were antipsychotic drug naive or
only recently exposed to antipsychotics for a short known
period at the initiation of the study; and (3) a
prospective longitudinal study design was implemented.
File audits, cohort studies, and drug trials (blind or
open) were all eligible. Medical record file audits were
considered only if they used data from clinics that
conducted routine monitoring of all patients.

DATA
EXTRACTION

Items from the Consolidated Standards of Reporting Trials
(CONSORT)14-15
and Strengthening the Reporting of Observational Studies
in Epidemiology (STROBE)16-17
checklists were used to assess the methods and quality of
reporting (eTable
1). We added 4 additional fields—industry
sponsorship, assessment of medication compliance,
follow-up psychiatric diagnosis, and if tests for
differences in cardiometabolic outcomes across different
antipsychotics were conducted.

RESULTS

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PROSPECTIVE
LONGITUDINAL TREATMENT STUDIES OF THE FIRST EPISODE OF
PSYCHOSIS

Sixty-four articles were identified describing 53
independent studies; 25 studies met inclusion criteria
and were retained for detailed review (eTable
1). Studies were excluded because they did not
consist solely of patients with first-episode psychosis
(n = 21), patients were not antipsychotic drug
naive at entry to the study and recent brief exposure was
not explicitly specified (n = 5), or exposure
was not brief (ie, at least 6 months)
(n = 2).

METHODS AND
QUALITY OF REPORTING

Industry
Sponsorship

Ten studies received support from the pharmaceutical
industry (eTable
1).

Study Design
and Hypotheses

Studies reviewed comprised 10 randomized trials, 5
nonrandomized trials, and 10 observational cohort studies
(eTable
1). One randomized trial, 1 nonrandomized trial, and
4 cohort studies included healthy controls to conduct a
cross-sectional case-control comparison of baseline
cardiometabolic indices.18-24
Cardiometabolic outcomes (predominantly weight) were a
primary outcome measure in 16 studies18-21,23-34;
the primary outcome was treatment efficacy or all-cause
medication discontinuation, with cardiometabolic measures
a secondary outcome, in the remaining studies (eTable
2).

Sample
Ascertainment and Subject Participation

Two studies described in detail the population from which
subjects were ascertained and both appear to have
ascertained samples representative of the broader
population of patients.35-36
All studies provided information on eligibility criteria.
Four randomized trials, 1 nonrandomized trial, and 4
cohort studies excluded subjects who used recreational
drugs,28
had recent alcohol or drug abuse,37
or a substance use disorder.18-20,25,
33,
36,
38
The drugs were not specified. Six studies excluded individuals
with any cardiometabolic abnormality at baseline.18-19,25,
28,
30-31
Only 2 studies reported the number of potential subjects
who met eligibility criteria. Four studies reported the
percentage of eligible individuals approached who
subsequently consented to participate in the study (eTable
1) (for Addington et al,27
no participation rate is recorded because it was a
retrospective medical file audit study). All others
reported that their sample consisted of all consecutive
admissions at 1 or more treatment centers.

Drug-Naive
Status and Medication

Patients were either antipsychotic naive or had been exposed
to antipsychotics for between 9 days and 16 weeks. All
studies described the medication administered, but only 4
formally assessed medication compliance, using pill
counts,35,
39
prescription counts,20
or patient report.40

Selection of
Control Subjects

Eight studies included controls (eTable
1). Controls were recruited from hospital
staff,19,
24
universities, and the general community21,
24
and an anonymous workplace health screening program.18
The other studies provided no information on how controls
were recruited. No study provided any information on how
many controls were initially approached or any
differences between control participants and
nonparticipants in the study. All but 1 study21
attempted to match controls to cases on at least some pertinent
characteristics such as age, sex, and ethnicity.

Sample Size and
Follow-up

Sample size varied (n = 9-555) but most studies
were small. Only 4 studies ascertained more than 200
patients. One study provided an explicit description of
how subjects were followed up for postbaseline
assessments.28
For 3 studies, it could be inferred that follow-up of
subjects was routinely conducted because subjects
appeared to have been inpatients for the duration of the
study.30-31,39
Others did not provide any information on how subjects
were tracked through the course of the study, how and
where follow-up assessments were conducted, and methods
used to try to find subjects lost to follow-up. Nine
studies provided information about the reasons that
follow-up assessments could not be conducted21,
23,
30-31,35-36,40-42
(simply stating that patients were discharged from the
hospital or dropped out of the study was not considered
sufficient). The average follow-up time across studies
was 31.7 weeks (median, 52 weeks) but ranged from 4
weeks34
to 2.5 years23
(3 years including the additional follow-up study by
Addington et al43).

Analytical
Methods Including Missing Data Handling

Subgroup analyses or tests of interaction were generally not
well described or justified. The methods used for handling
missing data were described in only 6 studies. For 3
others, it could be inferred that a complete case
analysis was conducted.27,
29,
40

Subject
Characteristics

Four studies did not provide information on diagnoses,21,
26-27,33
and 1 provided incomplete information.29
All studies provided some demographic information on
subjects, such as proportion of males and females,
average age, socioeconomic status, and ethnicity. Most
studies did not tabulate the number of participants with
missing data for each variable, making it difficult to
determine numbers of subjects in different analyses.

Tested for Drug
Differences

Nineteen studies administered multiple antipsychotics.18-21,23-24,27-29,32-36,38,
40-42,44
Nine studies analyzed data for all drugs combined.19,
21,
23,
27,
29,
32-34,44
Ten studies tested for drug differences in
cardiometabolic outcomes.18,
20,
24,
28,
35-36,38,
40-42
Six studies administered a single antipsychotic25-26,30-31,37,
45;
5 administered olanzapine,25-26,30-31,45
some to test if the mode of administration45
or adjunct treatments minimized weight gain.30-31

Case-Control
Comparisons

Seven studies tested if patients were different from
controls at baseline with regard to weight and fat
distribution and diet; indices of diabetes risk; and
biochemical indices such as triglyceride, cholesterol,
and cortisol levels (eTable
1). Four studies recruited patients who were
antipsychotic naive18-19,24,
46:
1 included patients within 72 hours of first
exposure,22
1 included patients with up to 2 weeks' lifetime exposure
but no more than 3 doses in the month prior to
recruitment,20
and another recruited patients with up to 16 weeks of
recent exposure.21

RESEARCH
FINDINGS

Case-Control
Findings

At baseline, patients had a higher waist to hip ratio than
controls in 3 studies,18-19,24
a higher saturated fat intake,24
and, in a study that matched on body mass index (BMI), 3
times more intra-abdominal fat,24
but there was no elevation of intra-abdominal fat in
another study that did not report matching.19
There were no other significant weight-related
differences. At baseline, patients did not have more
total body fat,24
abdominal subcutaneous fat,19,
24
unsaturated fat intake,24
or a higher weight,19,
21,
46
BMI,19-21,24,
46
or waist circumference46
than controls.

Patients had a higher prevalence of prediabetes (elevated
fasting glucose21
or insulin19
level) than controls in 2 studies but 1 of these included
patients exposed to antipsychotics for up to 16
weeks.21
Another study reported a 10-fold higher prevalence of
diabetes in patients (5%) than controls (0.5%),22
which may be largely independent of weight or low-density
lipoprotein (LDL) cholesterol given that the relevant
controls were significantly more likely to have elevated
LDL cholesterol levels and to be overweight or obese (52%
vs 27%, in their corrected Table 1) compared with
patients. Patients did not differ from controls on
trigylceride21;
total, LDL,22
or high-density lipoprotein (HDL) cholesterol21-22;
insulin21;
adiponectin; leptin; interleukin 6; vascular cell
adhesion molecule 1; or E-selectin21
levels. One study found an elevated waist to hip ratio
and elevated fasting insulin level relative to controls
only in female patients.19

Two studies used controls to test if change over time was
due to factors other than treatment.20,
46
One study matched hospitalized cases and controls by sex,
age, exercise and diet (basal metabolic rate), race, and
socioeconomic status to match for possible confounders of
natural weight gain over time.46
Concomitant drugs that could potentially affect weight
were not permitted. Patients had significantly elevated
weight (4 kg) and BMI (2 kg) after 6 weeks of
double-blind, randomized treatment with haloperidol,
risperidone, or olanzapine compared with controls after 6
weeks of unmedicated follow-up. After 12 months of treatment
with haloperidol, risperidone, olanzapine, or
perphenazine, cases had a significantly greater increase
in BMI (2 kg) than controls matched only for age.20

To control for progressive weight gain in cases over time,
independent of medication, 1 study included a second
control group of patients (n = 7) who refused
antipsychotic drug treatment for longitudinal comparison
with treated patients and healthy controls.20
The mean weight gain was 17 kg across 1 year for olanzapine,
8 kg for risperidone, 4 kg for haloperidol, 1 kg for
perphenazine, 1 kg for patients who refused
antipsychotics, and 1 kg for age- and sex-matched
controls with no history of psychosis.

Change in
Cardiometabolic Risk Factors After Treatment With
Antipsychotics

Studies that administered multiple antipsychotics but
analyzed data for all drugs combined19,
21,
23,
27,
29,
32-34,44
found that changes in weight, BMI, and waist
circumference were evident after 1 month.34
There was a significant increase in interleukin 12 after
6 weeks47
and a significant increase in subcutaneous and
intra-abdominal fat, a 3-fold increase in leptin level,
and a significant increase in total and LDL cholesterol,
triglyceride, and nonfasting glucose levels after 10
weeks.19
Total body weight increased by 10% to 12% after 6 to 12
months.27,
29
Most of that weight change occurred in the first 6
months. At baseline, 36% to 42% were overweight or
obese21,
27
(like the broader community); after 6 months, 58% to 71%
were overweight or obese.21,
27

There was a significant change in total,21,
29,
44
LDL,21,
44
and HDL cholesterol,29
triglyceride,29,
44
fasting insulin and glucose, leptin, E-selectin, and
adiponectin levels by 6 months.21
Weight gain continued for at least 3 years.43
Those who had taken antipsychotics continuously over 2.5
years had nonsignificantly more weight gain (13 kg) than
those who had not (7 kg).23
Genotype may also play a role. The wild-type variant of
the 5HT2C receptor gene regulatory region was associated
with significantly more weight gain after 10 weeks taking
risperidone or chlorpromazine than the –759 C/T
polymorphism in a Han Chinese cohort.32
This finding was replicated in a Spanish cohort treated with
a different combination of antipsychotics and in the
subset of those given olanzapine.33

In studies that administered multiple antipsychotics and
tested for differences in cardiometabolic outcomes across
drugs,18,
20,
24,
28,
35-36,38,
40-42
the combination of drugs studied and the follow-up
interval varied (eTable
1), which is important because the trajectory of
weight gain varies across different drugs. We therefore
summarize results by follow-up point to better show the
pattern of findings that emerges across studies.

By 6 to 8
Weeks.  Weight gain was significant. The
average weight gain after 6 to 8 weeks taking olanzapine
was 5 to 6 kg,18,
26,
45
which was significantly higher than the average weight
gained while taking risperidone (4 kg) or haloperidol (3
kg).18
In another study, means were not reported but the rank
order of weight gain by drug administered was the
same.36
There was a significant increase in fasting and
postprandial blood glucose levels and the incidence of
diabetes after 6 weeks in male patients.39
The largest effects were seen for olanzapine, then
risperidone and haloperidol. At 8 weeks, there was a
significant increase in insulin level, insulin
resistance, and glucose, cholesterol, triglyceride, and C
peptide levels across clozapine, olanzapine, risperidone,
and sulpiride combined but no significant difference
between drugs.28

By 3 to 4
Months.  Olanzapine was associated with
significantly more weight gain (7-9 kg)26,
41,
48
than haloperidol (3-4 kg)41,
48
but not risperidone (6 kg).48
Risperidone was associated with significantly more weight
gain than haloperidol (5 kg vs 3 kg).38
Other results were less consistent. A significant
increase in cholesterol and fasting insulin levels was
found after 3 to 4 months taking olanzapine in 1
study26
but not another.25
No significant increase was found in fasting
triglyceride, glucose,26
or leptin25
levels but there was a significant increase in absolute
fat mass; percentage of body fat and waist to hip ratio,
suggesting central deposition of body fat; and C peptide
level while taking olanzapine.25

By 6
Months.  Gain in intra-abdominal fat was
nonsignificantly higher with risperidone (27
cm2) than olanzapine (18 cm2).24

By 1
Year.  There was no significant difference in
weight gain across different antipsychotics.20,
35,
38,
40,
48
Two studies did not report pairwise drug comparisons,
just 4- and 5-way comparisons.20,
40
The rank and range of average weight gain reported after
1 year taking antipsychotics for each drug across
informative studies is olanzapine, 11 to 14 to 17
kg20,
40,
48;
amisulpride, 10 kg40;
clozapine, 10 kg35;
quetiapine fumarate, 10 kg40;
risperidone, 8 to 9 kg20,
48
and at 2 years, 7 kg38;
haloperidol, 4 to 7 to 11 kg20,
40,
48
and at 2 years, 6 kg38;
chlorpromazine, 6 kg35;
ziprasidone hydrochloride, 5 kg40;
and perphenazine, 1 kg.20

This ranking of antipsychotics was reflected in other
weight-related changes, such as 4-kg or more weight
increase,36
7% or more weight increase,42,
46
increasing BMI,41,
48
and the incidence of metabolic syndrome,49
but not for intra-abdominal fat.24
Orally disintegrating tablets of olanzapine were
associated with significantly less weight gain than
standard tablets,45
as was adjunctive reboxetine31
but not fluoxetine.30

At 12 months, there was a significant increase in insulin
level, insulin resistance, and total and LDL cholesterol,
triglyceride, leptin, and ghrelin levels,40,
50-51
an elevation in fasting glucose level in 1 study40
but not in 2 others,35,
50
and weight gain significantly correlated with insulin and
leptin levels.51
No significant differences were found across haloperidol,
olanzapine, or risperdione.51
No significant differences were found across haloperidol,
amisulpride, olanzapine, quetiapine, or
ziprasidone.40
A comparison of olanzapine, risperidone, and quetiapine
in another of the larger samples did find significant
differences at 12 months: olanzapine and quetiapine were
associated with a greater elevation in triglyceride level
and systolic blood pressure than risperidone; olanzapine
was associated with a greater elevation in diastolic
blood pressure than risperidone; quetiapine was
associated with a greater elevation in cholesterol level
than risperidone; and olanzapine was associated with a
greater reduction in HDL cholesterol level than quetiapine
or risperidone.42
This is consistent with the earlier-mentioned ranking for
weight, with olanzapine over quetiapine over risperidone.

Baseline
Predictors of Cardiometabolic Outcomes

Lower pretreatment BMI,20,
44,
46
younger age,20,
44
triglyceride level,44
more negative symptoms,20
and more co-medications and antidepressants20
predicted weight gain after antipsychotic treatment. In 1
study, women (but not men) starting with a normal BMI
gained a significantly higher percentage of body weight
(mean, 18%) than those starting with an overweight BMI
(mean, 2%).27

COMMENT

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Drawing
definitive conclusions about the impact of antipsychotics
on cardiovascular risk factors in patients with a first
episode of treated psychosis is not currently possible.
Some drug comparisons are entirely lacking, and others
appear underpowered. Sample sizes varied widely but most
were small. Only 4 studies ascertained more than 200
patients. Most studies do not describe their patient or
control samples well enough to gauge representativeness.
Medication compliance is rarely assessed and never
explicitly factored into analyses, even in formal
treatment trials. Dropout rates in the longer trials were
as high as 80% to 90%,41,
52
which limits conclusions about longer-term outcomes. Given
the sparseness of cardiometabolic outcome data beyond 1
year, a commonly used method for handling missing data
(last observation carried forward) may underestimate
weight gain and associated parameters in patients
compliant with antipsychotic use for much longer than
average periods by as much as 50%.52

The results of the studies reviewed herein point toward 2
important hypotheses that need further research:

In general, there is no difference in cardiometabolic
indices between patients and controls prior to
treatment with antipsychotic drugs. Caveat: Prior to
first exposure to antipsychotics, patients may have a
higher waist to hip ratio and more intra-abdominal fat
relative to BMI than controls but adequate control matching
may be required to detect these early differences.

Risk for cardiovascular disease, indexed by weight
and other metabolic indices, increases after
first exposure to any antipsychotic. Caveat: After 1
year of antipsychotic drug treatment, a rank order of
drugs can be derived across all studies reviewed herein
but there is no evidence of significant differences
between first- and second-generation antipsychotics.
Weight gain after 1 year taking risperidone, for
example, was very similar to weight gain after 1 year
taking haloperidol or chlorpromazine. Variance in
adverse cardiometabolic effects within each class
indexes the most meaningful source of variance. Weight
gain while taking olanzapine, for example, was much
higher than weight gain while taking ziprasidone.

SUGGESTIONS FOR
FUTURE DIRECTIONS

Weight gain may be the most visible of the adverse
cardiometabolic effects of antipsychotic drugs but
tracking less visible risk factors is just as important.
Elevated LDL cholesterol level is the main target for
primary prevention of heart disease2
but it is not clear whether changes in LDL or HDL
cholesterol, triglyceride, or serum glucose levels or
insulin resistance in the first treated episode of
psychosis are independent of weight changes. More
research in this area is needed to determine which
cardiometabolic indices are most strongly affected by
which antipsychotics and what the long-term consequences
of this are.

As many as 39% of patients are nonadherent and 20%
inadequately adherent53
in their first year of antipsychotic drug treatment but
many studies do not assess or analyze medication compliance.
Assessment of serum levels of antipsychotics is important
because compliance with a prescription does not ensure a
therapeutic dose and that is ultimately the point of
tracking adherence with prescribed medication in relation
to outcomes. Some antipsychotics do not even have a known
therapeutic window, especially for youth.54
This is an important unsolved problem. Dosage effects on
the efficacy of antipsychotics for psychotic symptom reduction
and the emergence or exacerbation of cardiometabolic risk
factors, and their relationship, should be tested.

Comorbidity, sex, age, and genetic makeup may all affect
treatment efficacy and adverse effects. Exclusion
criteria in drug trials often include substance abuse and
depression or other medical conditions, even minor
cardiometabolic abnormalities. Recreational drug use,
drug abuse, and depression are all common in cohorts of
patients with a first treated episode of psychosis55-57
and increase risk for cardiovascular disease,58-59
but we do not know if they moderate cardiovascular risk
during treatment with antipsychotics.

The age distribution in cohorts of patients with a first
treated episode of psychosis varies by sex because of sex
differences in the age at onset of psychosis.13
Patients with first-episode psychosis are composed of
younger men and older women unless artificially
constrained to ascertain a specific age range via a youth
service. This means that the prevalence of schizophrenia
in first-episode cohorts will be much higher in youth and
young adults than in those unselected for age.13
Tests for sex differences should therefore control for
age effects60
and all studies should report any age limits on
ascertainment and intake/outcome diagnosis. Diagnosis is
important because large population-based studies have
shown that different psychosis subtypes index partly distinct
risk factors,61
which may prove to be related to comorbidity with
physical disease. There is no a priori reason to assume
that treatment effects are unrelated to risk factors for
psychosis or cardiovascular disease.

Women may be more sensitive to the effects of
antipsychotics60
and their increased risk for central obesity may be evident
early.19
After 3 to 6 months of treatment, women had waist circumference
measures in the high-risk range.29
Hypoadiponectinemia induced by visceral fat accumulation
may be a strong risk factor for metabolic and
cardiovascular diseases and some cancers.62
Central obesity early in the course of treated illness
may therefore predict later physical disease. Efforts to
evaluate interventions that target emerging central
obesity, especially in women, should be a clinical
research priority.

Adoption of both the CONSORT guidelines for randomized
controlled trials and the STROBE guidelines for
observational (cohort) studies will increase the accuracy
of reporting and interpretation of future studies of
cardiometabolic outcomes of the first treated episode of
psychosis. Beyond the implementation of these guidelines
we recommend future studies:

Provide a more detailed characterization of the primary
exposure—medication—by assessing and analyzing
medication compliance by identifying the therapeutic
window for antipsychotic drugs in adults and youth and
by evaluating dosage effects.

Undertake a comprehensive assessment of
cardiometabolic risk factors following, at the
very least, recommended monitoring
guidelines.63
Long-term follow-up will be required to accurately
document the emergence of some outcomes, such as
diabetes.

Examine whether cardiovascular outcomes are
moderated by (1) demographic characteristics (sex
and age at a minimum); (2) clinical
characteristics; and (3) genetic factors.

CLINICAL
IMPLICATIONS

Individuals treated with antipsychotics should be assessed
before (or very soon after) first exposure to
antipsychotics to determine baseline cardiovascular risk.
Regular monitoring is then recommended using consensus
guidelines.63
Any clinically significant changes should be dealt with
following recommended protocols and referral to a primary
care physician or appropriate specialist.64
Information from monitoring should guide the selection
(and switching) of antipsychotic agents,63
but in practice, regular monitoring is rarely
conducted.65
We have found that general nurses can conduct monitoring
in a first-episode psychosis service,66
but in other settings, and outside of the rigorous
protocols of research studies, cardiometabolic monitoring
is still not routinely implemented.67
This is an important failure of care.

LIMITATIONS

There are many unresolved issues. Contrary to expectations,
in all but 1 of the largest studies,42
cardiometabolic outcomes were not significantly different
across different antipsychotics at study end points. This
may reflect low power to detect true differences given
currently attainable sample sizes relative to the number
of antipsychotics administered. A recent meta-analysis of
weight gain following first exposure to antipsychotics in
the absence of any concomitant medications that may affect
weight did not find any significant differences across
antipsychotics5
because, the authors concluded, there were insufficient data.
Different second-generation antipsychotics are associated
with significantly different cardiometabolic profiles in
samples that are not restricted to the first treated
episode.68
Olanzapine causes more weight gain than all other
second-generation antipsychotics except clozapine.
Clozapine causes more weight gain than risperidone,
risperidone more than amisulpride, and sertindole more
than risperidone. Olanzapine elevates cholesterol level
more than aripiprazole, risperidone, and ziprasidone but
not amisulpride, clozapine, and quetiapine. Quetiapine
elevates cholesterol level more than risperidone and
ziprasidone. Olanzapine elevates blood glucose level more
than amisulpride, aripiprazole, quetiapine, risperidone,
and ziprasidone but not clozapine. Key unanswered
questions concern the strength of the association between
antipsychotic exposure and adverse cardiometabolic
effects for each antipsychotic, which can only be
estimated with previously antipsychotic-naive patients,
the timing of the emergence of these effects, and their
trajectory, not if they eventually occur. An observed
temporal relationship does not prove a causal relationship
exists, and lifestyle factors associated with psychosis
may play a part, but systematic differences in the
pattern and timing of the adverse cardiometabolic
outcomes of different antipsychotics in randomized trials
are consistent with a causal link. Possible modifiers of
the observed association, its effect size and trajectory,
are important to evaluate because treatment is correlated
with length and severity of illness. Longitudinal
investigation of patients who refuse antipsychotics or
become noncompliant is therefore required to test if risk
is concentrated in those who are compliant with their
antipsychotic medication.

AUTHOR
INFORMATION

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Introduction

•

Methods

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Results

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Comment

•

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References

Correspondence:
Debra L. Foley, PhD, Orygen Youth Health Research Centre,
35 Poplar Rd, Parkville, VIC 3052, Australia (dfoley{at}unimelb.edu.au

).

Submitted for Publication: June 28, 2010; final revision
received November 3, 2010; accepted December 16,
2010.

Published Online: February 7, 2011.
doi:10.1001/archgenpsychiatry.2011.2

Financial Disclosure: None reported.

Funding/Support: Dr Foley was supported by the Colonial
Foundation (Australia) and is a recipient of grant
G09M4402 from the Heart Foundation (Australia). Dr Morley
was supported by Public Health Fellowship 520452 from the
Australian National Health and Medical Research
Council.

Author
Affiliations: Applied Genetics and Biostatistics, Orygen Youth
Health Research Centre (Dr Foley), and Centres for Youth Mental
Health (Dr Foley) and Molecular, Environmental, Genetic, and
Analytic Epidemiology, School of Population Health (Dr Morley), the
University of Melbourne, Parkville, Victoria, Australia; and
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,
Hinxton, Cambridge, England (Dr Morley).

REFERENCES

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