Is antipsychotic polypharmacy associated with metabolic syndrome even after adjustment for lifestyle effects?: a cross-sectional study
Is antipsychotic polypharmacy associated with metabolic syndrome even after adjustment for lifestyle effects?: a cross-sectional study
Background: Although the validity and safety of antipsychotic polypharmacy remains unclear, it is commonplace in the treatment of schizophrenia. This study aimed to investigate the degree that antipsychotic polypharmacy contributed to metabolic syndrome in outpatients with schizophrenia, after adjustment for the effects of lifestyle. Methods: A cross-sectional survey was carried out between April 2007 and October 2007 at Yamanashi Prefectural KITA hospital in Japan. 334 patients consented to this cross-sectional study. We measured the components consisting metabolic syndrome, and interviewed the participants about their lifestyle. We classified metabolic syndrome into four groups according to the severity of metabolic disturbance: the metabolic syndrome; the premetabolic syndrome; the visceral fat obesity; and the normal group. We used multinomial logistic regression models to assess the association of metabolic syndrome with antipsychotic polypharmacy, adjusting for lifestyle. Results: Seventy-four (22.2%) patients were in the metabolic syndrome group, 61 (18.3%) patients were in the premetabolic syndrome group, and 41 (12.3%) patients were in visceral fat obesity group. Antipsychotic polypharmacy was present in 167 (50.0%) patients. In multinomial logistic regression analyses, antipsychotic polypharmacy was significantly associated with the pre-metabolic syndrome group (adjusted odds ratio [AOR], 2.348; 95% confidence interval [CI], 1.181-4.668), but not with the metabolic syndrome group (AOR, 1.269; 95%CI, 0.679-2.371). Conclusions: These results suggest that antipsychotic polypharmacy, compared with monotherapy, may be independently associated with an increased risk of having pre-metabolic syndrome, even after adjusting for patients' lifestyle characteristics. As metabolic syndrome is associated with an increased risk of cardiovascular mortality, further studies are needed to clarify the validity and safety of antipsychotic polypharmacy.
Metabolic syndrome is a cluster of metabolic dysfunctions,
including central obesity, hypertension, glucose, and lipid
abnormalities. Those with the syndrome have a two- to
threefold increase in cardiovascular mortality and a
twofold increase in all-cause mortality . Patients with
schizophrenia are more likely to have metabolic syndrome
than the general population .
To date, a few research studies have reported an
association between antipsychotic polypharmacy and
1Yamanashi Prefectural KITA Hospital, 3314-13 Kamijominamiwari,
Asahimachi, Nerasaki-shi, Yamanashi, Japan
Full list of author information is available at the end of the article
metabolic syndrome [3,4]. Limited evidence currently
exists regarding the benefits of antipsychotic
polypharmacy, and antipsychotic monotherapy is consistently
recommended in the treatment of patients with
schizophrenia [5,6]. Antipsychotic polypharmacy is, however,
commonplace in the treatment of schizophrenia [7-11],
and has been reported to occur in a wide range
(1390%) of cases. In Japan, in particular, polypharmacy has
been reported to occur at a higher rate than in other
If antipsychotic polypharmacy, which is not
recommended, is associated with a greater risk of metabolic
syndrome, the spread of polypharmacy is a serious concern.
However, it remains unclear among earlier studies
whether antipsychotic polypharmacy is associated with
metabolic syndrome as a direct result of patients’
unhealthy lifestyle. Patients with schizophrenia are likely
to make poor dietary choices, have low rates of physical
activity, and smoke cigarettes , and their unhealthy
lifestyle is assumed to be associated with an increased risk
of metabolic syndrome. However, as little information is
available on the association between metabolic syndrome
and antipsychotic polypharmacy in conjunction with
patients’ lifestyle, further research is needed any such
In this cross-sectional study, we aimed to investigate
the relationships between antipsychotic polypharmacy
and metabolic syndrome in outpatients with
schizophrenia, with adjustment for the effects of lifestyle.
Participants who lived in the community and received
psychiatric outpatient treatment were recruited from
April 2007 to October 2007. The study inclusion criteria
were: regular attendance at Yamanashi Prefectural KITA
Hospital, Japan; an ICD-10 diagnosis of schizophrenia,
schizotypal and delusional disorders; and age 18 years or
During the study period, of all 599 patients who
fulfilled the inclusion criteria in this study, 399 consented
to participate in the study. As 65 of these patients did
not complete the questionnaire, data from 334 patients
were used in the analysis.
The study design was approved by the Ethics
Committees of Yamanashi Prefectural KITA Hospital. Written
informed consent was obtained from all participants.
Assessment in this study consisted of sociodemographics
(age, gender), duration of psychiatric treatment, family
history of lifestyle-related disease, metabolic syndrome,
prescribed antipsychotics, and participants’ lifestyle. In
addition, psychiatrists in charge of the participants
assessed the patients on the Global Assessment of
Functioning (GAF) scale.
Rather than using the discrete diagnostic category of
metabolic syndrome, we divided metabolic syndrome
into four groups based on severity of metabolic
disturbance (metabolic syndrome, pre-metabolic syndrome,
visceral fat obesity and normal), since metabolic
syndrome is continuously disturbed in nature . In
accordance with the diagnostic criteria proposed by the
Japanese Committee of the Metabolic Syndrome
Diagnostic Criteria , metabolic syndrome was defined as
visceral fat obesity (abdominal circumference: ≥85 cm for
males, ≥90 cm for females) and at least two of the
following three criteria: elevated blood glucose (fasting glucose
level ≥110 mg/dL), lipid abnormalities (triglycerides ≥150
mg/dL and/or high-density lipoprotein (HDL) cholesterol
<40 mg/dL), and elevated blood pressure (systolic blood
pressure ≥130 mmHg and/or diastolic blood pressure
≥85 mmHg). Current treatment with diabetes,
lipidlowering, or antihypertensive medication fulfilled the
criterion for elevated blood glucose, lipid abnormality, and
elevated blood pressure, respectively. Pre-metabolic
syndrome was defined as the presence of one of the above
three criteria in addition to visceral fat obesity.
We classified metabolic syndrome in the following
four groups: the normal group did not fulfill the criteria
of visceral fat obesity, the visceral fat obesity group
fulfilled only the criteria of visceral fat obesity, the
premetabolic syndrome group was defined by the presence
of only one of the three criteria above in addition to
visceral fat obesity, and the metabolic syndrome group
was defined by the presence of at least two of the three
criteria above in addition to visceral fat obesity.
Participants were given written instructions to fast overnight
on the day before assessment, and asked to confirm
their fasting status before blood samples were taken. A
single venous blood sample was withdrawn and analyzed
for glucose, triglycerides, and HDL cholesterol. Nurses
measured abdominal circumference and blood pressure.
We investigated prescribed antipsychotics from patient
charts on the day we measured the participant’s
metabolic syndrome parameters. All dosages of antipsychotic
drugs were converted into chlorpromazine equivalents
 in order to estimate the total daily
In this study, polypharmacy was defined as the
concomitant use of two or more antipsychotics, while
monotherapy was defined as the use of only one antipsychotic.
Antipsychotic treatment in Japan was subject to special
conditions during the study period. First, clozapine had
not been launched at this time. Second, olanzapine and
quetiapine were contraindicated for patients with
diabetes or a history of diabetes because it was reported that
some patients that were treated with olanzapine and
quetiapine developed severe hyperglycemia and diabetic
Assessment of participants’ lifestyle
We assessed the participants’ dietary habits, physical
activity, and smoking habits. With regards to dietary
habits, these were assessed by an originally designed
selfreporting questionnaire that consisted of the following
four items, which have been used in earlier studies: snack
eating (Do you eat snacks?), intake of fatty foods (Do you
eat fatty foods?), preference for a high-salt diet (Do you
put soy sauce or Worcestershire sauce on your food?),
and consumption of soft drinks (Do you drink soft
drinks?) [17,18]. Each item was scored on a 4-point scale
(1 = never, 2 = rarely, 3 = sometimes, 4 = always).
To assess the participants’ physical activity, we used
the Exercise and Physical Activity Guide for Health
Promotion 2006 . In this guide, physical activity consists
of exercise and non-exercise activities (e.g., walking,
cleaning the floors, and walking up and down stairs).
The units used to express the intensity and quantity of
physical activity are “MET” and “MET × hour”,
respectively. MET is calculated as energy expenditure (oxygen
uptake, mL/kg/min) during a specific physical activity
divided by sitting/resting energy expenditure. Defining
the MET of sitting/resting as 1, that of normal walking,
for example, is 3. The unit “MET × hour” (expressed as
“Ex” for Exercise (Ekusasaizu in Japanese)) was
calculated by multiplying the MET by the duration of the
activity (hour). The goal for physical activity was set at
23 Ex or more per week, with 3 MET of physical activity
set as the minimum (cut off).
Using the Compendium of Physical Activities , we
interviewed participants about their exercise and
nonexercise activities with more than 3 MET in the one
week prior to the study day, and calculated the quantity
of their physical activity.
Participants’ smoking habits were rated as 1 (= 21 or
more cigarettes per day), 2 (= 6 to 20), 3 (= 1 to 5), or 4
(= no cigarette).
Analyses of variance, chi-square tests, and Kruskal-Wallis
tests were used to compare demographic, treatment and
clinical variables in the classification of metabolic
To examine the effects of antipsychotic polypharmacy
on metabolic syndrome, we conducted multinomial
logistic regression analyses, with the classification of
metabolic syndrome as the dependent variable. For the
analyses, we entered the variables whose p-values were
less than 0.1 in univariate tests into the model. A p
value of <0.05 was considered statistically significant.
Data were analyzed using SPSS 14.0 J for Windows.
Characteristics, lifestyle, and antipsychotic treatment of
participants (Table 1)
The mean age of the 334 participants was 44.2 years,
and 42.8% were female. The mean GAF score was 53.5,
48.8% had a family history of lifestyle-related disease,
and the mean duration of psychiatric treatment was 18.2
years. The mean value of physical activity was 22.4 Ex,
and the mean score for smoking habit was 3.0.
The mean dose in chlorpromazine equivalents was 596.6
mg/day, and 35.0% received olanzapine and quetiapine.
One hundred six (31.7%) patients received two
antipsychotics, 48 (14.4%) patients were on three antipsychotics, and
13 (3.9%) patients were on four antipsychotics. According
to the definition in this study that polypharmacy was
the concomitant use of two or more antipsychotics, 167
participants (50.0%) were receiving antipsychotic
Category of metabolic syndrome
Of the 334 participants, 176 (52.7%) fulfilled the visceral
fat obesity criteria, 92 (27.5%) fulfilled the elevated blood
glucose criteria, 138 (41.3%) fulfilled the lipid abnormality
criteria, and 105 (31.4%) fulfilled the elevated blood
pressure criteria. Seventy-four (22.2%) patients were in the
metabolic syndrome group, 61 (18.3%) patients were in
the pre-metabolic syndrome group, 41 (12.3%) patients
were in the visceral fat obesity group, and 158 (47.3%)
were in the normal group. The characteristics, lifestyle and
antipsychotic treatment in each group are summarized in
Table 1. The rate of polypharmacy in the groups of
metabolic syndrome, pre-metabolic syndrome, visceral fat
obesity and normal were 52.7%, 63.9%, 61.0%, and 40.5%,
Compared to the monotherapy group, the
polypharmacy group was more likely to fulfil the visceral fat
obesity criterion (61.7% vs. 43.7%, p = 0.0014) and the
elevated blood glucose criterion (32.9% vs. 22.2%, p =
0.037), and less likely to fulfil the elevated blood pressure
criterion (26.3% vs. 36.5%, p = 0.045). The prevalence of
the metabolic syndrome group in monotherapy and
polypharmacy showed no significant difference (23.4% vs.
21.0%, p = 0.60). However, the polypharmacy group was
more likely to be the pre-metabolic syndrome group
(46.7% vs. 34.1%, p = 0.019).
Multinomial logistic regression analyses (Table 2)
Multinomial logistic regression analyses revealed that
the metabolic syndrome group was associated with
being male, longer duration of psychiatric treatment,
and heavier smoking habit. The pre-metabolic syndrome
group was associated with being male and antipsychotic
polypharmacy. The visceral fat obesity group was
associated with being male and higher antipsychotic total
Thus, overall, antipsychotic polypharmacy was not
related to the severity of symptoms in the metabolic
syndrome group but was related to the severity of
symptoms in the pre-metabolic syndrome group.
Our study shows that antipsychotic polypharmacy is not
correlated with metabolic syndrome but is correlated
Table 1 Characteristics, lifestyle and antipsychotic treatment in total participants and four groups
Physical activity, mean (SD), Ex
with the wider range of the syndrome when adjusting
for the effects of lifestyle in outpatients with
schizophrenia. These findings indicate that antipsychotic
polypharmacy contributes in part to metabolic syndrome.
It remains unclear why antipsychotic polypharmacy is
correlated with metabolic disturbance. Earlier studies
suggested that various receptors effects, such as H1, D2,
5HT1A, 5-HT2C, a2, and M3, might contribute to metabolic
disturbance . We speculate that the complex
receptorbinding profiles of antipsychotic polypharmacy might be
one of the causes of metabolic disturbance.
Among earlier studies, the association between
metabolic syndrome and antipsychotic polypharmacy was not
certain. For example, Correll et al.  observed that
patients who receive antipsychotic polypharmacy had
significantly higher rates of metabolic syndrome in
visceral fat obesity
Table 2 Multinomial logistic regression analyses
The dependent variable has four categories: normal, visceral fat obesity, pre-metabolic, and metabolic syndrome. The latter three categories are compared with
the normal category.
AOR: adjusted odds ratio, CI: confidence interval
Nagelkere’s R square = 0.26.
univariate analyses, but antipsychotic polypharmacy was
not independently associated with metabolic syndrome
in logistic regression analyses which accounted for
demographic and clinical variables. They speculated that
antipsychotic polypharmacy was not a primary factor for
metabolic syndrome, and that factors related to
antipsychotic polypharmacy, such as inactivity, contributed to
the risk of metabolic syndrome.
Physical activity was not associated with metabolic
syndrome of any severity in this study. We infer that the
association between metabolic syndrome and
antipsychotic polypharmacy is not certain because of the effect
of antipsychotic polypharmacy on lowering blood
pressure, rather than because of the effect of inactivity. It
was reported that polypharmacy was associated with a
significantly higher drop in systolic pressure than
monotherapy . This might be due to the effects of a
higher dose than that received during monotherapy or a
drug interaction which created dopaminergic and
noradrenergic deficiency conditions, such as Shy-Drager
syndrome. Similarly, in the present study, patients receiving
antipsychotic polypharmacy were less likely to fulfil the
criterion of elevated blood pressure. Consequently,
because antipsychotic polypharmacy tended not to be
associated with elevated blood pressure, which is one of
the three criteria for metabolic syndrome, polypharmacy
may not have been correlated with metabolic syndrome,
which needs to fulfil two or more of the three criteria,
but rather with pre-metabolic syndrome, which needs to
fulfil one or more of the criteria. We speculate that
antipsychotic polypharmacy is directly associated with
metabolic disturbance and increases the risk for metabolic
syndrome, but the effect on lowering blood pressure
masks the diagnosis of metabolic syndrome.
Another reason for our finding that polypharmacy
contributes in some way to metabolic syndrome is that
psychiatrists might be reluctant to prescribe additional
antipsychotics for patients with metabolic syndrome to
avoid worsening their metabolic profiles; however, for
patients with pre-metabolic syndrome, they might not
hesitate to prescribe additional antipsychotic.
Antipsychotic polypharmacy was not significantly
associated with the visceral fat obesity group. That may
be why the sample size in the group was small. We
speculate that the association between polypharmacy
and the visceral fat obesity may become significant if
the sample size is larger.
Among the lifestyle factors, smoking habit was
associated with prevalence of metabolic syndrome. It is
considered to be an important risk factor for metabolic
syndrome in the general population [22,23]. The
prevalence of smoking in schizophrenia greatly exceeds that
in the general population [24-26]. For the prevention of
metabolic syndrome, it is necessary to provide guidance
for lifestyle, such as smoking cessation advice, to
patients with schizophrenia, especially those receiving
The limitations of our study were a cross-sectional
design, moderate sample size, high rate of refusal to
participate in the study, and non-assessment of other
psychotropic drugs except antipsychotics. In addition, special
conditions were imposed on antipsychotic treatment in
Japan at the time of the study, that is, clozapine had not
yet been launched and olanzapine and quetiapine were
contraindicated for patients with diabetes or a history of
diabetes. Clozapine and olanzapine, in particular, are
known as high-risk drugs for metabolic syndrome .
Therefore, the above special conditions are likely to have
affected the results in this study.
Our study is the first attempt to clarify the relationship
between metabolic syndrome, antipsychotic
polypharmacy, and patients’ lifestyle. The findings indicate that
antipsychotic polypharmacy, compared with
monotherapy, may be independently associated with an increased
risk of having pre-metabolic syndrome, even after
adjusting for patients’ lifestyle characteristics. Despite
the fact that there is little evidence regarding the
efficacy of antipsychotic polypharmacy in schizophrenia
and that it is not recommended in its treatment of
schizophrenia, it has been common practice in the past. As
metabolic syndrome is associated with an increased risk
of cardiovascular mortality, further studies are needed to
clarify the validity and safety of antipsychotic
polypharmacy in this patient population.
The study was supported by the Research Grant for Nervous and Mental
Disorders from the Ministry of Health, Labour and Welfare.
FM participated in the design and the coordination of the study, performed
the statistical analyses and drafted the manuscript. KS conceived of the
study and participated in the design and the coordination of the study. YF,
RM, FK, MiK, HS and YaO participated in the design and the coordination of
the study. HI and YaO participated in the analytical plan, the interpretation
of the results, and assisted in drafting the manuscript.
MaK participated in the design of the study. HK assisted with the
interpretation of the results and helped draft the manuscript. All authors
read and approved the final manuscript.
The authors declare that they have no competing interests.
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