Acta Psychiatr Scand 2015: 132: 97–108 © 2015 John Wiley & Sons A/S.

John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
All rights reserved ACTA PSYCHIATRICA SCANDINAVICA
DOI: 10.1111/acps.12445

Clinical overview

Weight gain and obesity in schizophrenia:

epidemiology, pathobiology, and
management
Manu P, Dima L, Shulman M, Vancampfort D, De Hert M, Correll P. Manu1,2,3, L. Dima4,
CU. Weight gain and obesity in schizophrenia: epidemiology, M. Shulman1, D. Vancampfort5,
pathobiology, and management. M. De Hert6, C. U. Correll1,2,3
1
The Zucker Hillside Hospital, New York, NY, USA,
Objective: To review recent advances in the epidemiology, 2
Albert Einstein College of Medicine, New York, NY,
pathobiology, and management of weight gain and obesity in patients USA, 3Hofstra North Shore – LIJ School of Medicine,
with schizophrenia and to evaluate the extent to which they should Hempstead, NY, USA, 4Faculty of Medicine, Transilvania
influence guidelines for clinical practice. University, Brasov, Romania, 5KU Leuven Department of
Method: A Medline literature search was performed to identify clinical Rehabilitation Sciences, Leuven, Belgium and
6
and experimental studies published in 2005–2014 decade. University Psychiatric Centre KU Leuven, Kortenberg,
Results: Weight gain and obesity increase the risk of adult-onset Belgium
diabetes mellitus and cardiovascular disorders, non-adherence with
pharmacological interventions, quality of life, and psychiatric
readmissions. The etiology includes adverse effects of antipsychotics,
pretreatment/premorbid genetic vulnerabilities, psychosocial and
socioeconomic risk factors, and unhealthy lifestyle. Patients with
schizophrenia have higher intake of calories in the form of high-density
food and lower energy expenditure. The inverse relationship between
baseline body mass index and antipsychotic-induced weight gain is
probably due to previous antipsychotic exposure. In experimental
models, the second-generation antipsychotic olanzapine increased the
orexigenic stimulation of hypothalamic structures responsible for Key words: schizophrenia; weight gain; obesity;
energy homeostasis. pathobiology; management
Conclusion: The management of weight gain and obesity in patients Peter Manu, Medical Services, The Zucker Hillside
with schizophrenia centers on behavioural interventions using caloric Hospital, North Shore – LIJ Health System, 75-59 263rd
intake reduction, dietary restructuring, and moderate-intensity physical Street, Glen Oaks, New York, NY, USA.
E-mail: pmanu@nshs.edu
activity. The decision to switch antipsychotics to lower-liability
medications should be individualized, and metformin may be
considered for adjunctive therapy, given its favorable risk-benefit
profile. Accepted for publication April 27, 2015

Clinical recommendations
• Weight gain is greatest in patients with schizophrenia treated with the second-generation antipsychot-
ics clozapine and olanzapine.
• The antipsychotic-induced weight gain is inversely related to the baseline body mass index, a finding
that likely reflects prior antipsychotic exposure or regression to the mean.
• The management of weight gain and obesity in patients with schizophrenia requires frequent moni-
toring, early recognition, and multidisciplinary treatment. With the exception of metformin, pharma-
cological interventions to improve the cardiometabolic status are generally not recommended for
broad clinical usage.

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Manu et al.

Additional comments
• Stigma, negative discrimination, and low socioeconomic status hinder training, education and close
personal relationships and limit opportunities for achieving physical fitness and access to healthier
food.
• Poor illness self-management skills, deficits in executive function and memory, residual psychotic
symptoms, and substance misuse limit the effectiveness of behavioural intervention and weight reduc-
tion.
• The drugs associated with weight loss in patients with antipsychotic-induced weight gain are metfor-
min, d-fenfluramine, sibutramine, topiramate, and reboxitine. Treatment with amantadine, dextro-
amphetamine, famotidine, fluoxetine, fluvoxamine, nizatidine, orlistat, phenylpropanolamine, and
rosiglitazone was not superior to placebo.

Introduction ology, pathobiology, and management of weight

Weight gain and obesity are critical issues in
patients with schizophrenia. Both can adversely
affect the risk of adult-onset diabetes mellitus and
cardiovascular disorders, non-adherence with
pharmacological interventions, quality of life (1),
and psychiatric readmissions (2). Treatment with
second-generation antipsychotics is frequently
invoked as the cause of weight gain in schizophre-
nia, but the explanation is multifactorial and
includes pretreatment and premorbid genetic vul-
nerabilities, socioeconomic disadvantages, and
unhealthy lifestyle (3, 4). The need for early
detection of weight gain is great, because weight
gain occurs early during antipsychotic exposure
(5, 6).
The abnormal nutritional status (7) and ‘devel-
opmental’ obesity in schizophrenia (8) have been
described more than half-century ago. To date,
there are over 2600 papers indexed by Medline on
the topic of weight gain and obesity in schizophre-
nia, and the space constraints of this special issue
allows only a circumscribed update.
Aims of the study
To identify recent clinical and experimental data
that have advanced the understanding of obesity in
schizophrenia with regard to its genetic, neuro-
transmitter, hormonal, and psychosocial mecha-
nisms and to clarify the ways in which these data
contribute to a rational approach for the preven-
tion and management of weight gain in this patient
population.
Material and methods
For this narrative review, we performed a Medline
literature search to identify the most recent com-
prehensive descriptions of advances in the epidemi-
gain and obesity in the community. We then aimed
to find clinical and experimental studies published
in the last decade that investigated advances in
these areas in patients with schizophrenia and to
evaluate the extent to which they should influence
guidelines for clinical practice.
Results
Epidemiology
From 1980 to 2013, the proportion of adults with a
BMI ≥25 kg/m2 has increased worldwide from
29.8% to 38.0% in females and from 28.8% to
36.9% in males (9). In children and adolescents,
the prevalence of overweight and obesity has
increased by 47.1% in the same interval, which is
almost double the change (27.5%) recorded for
adults (9). In both developed and developing
countries, successive cohorts became heavier most
rapidly in the 20–40 years of age group (9). Long-
term trends were similar in countries that had low
and high rates of obesity in 1980, and no country
has shown a significant decrease in the past
33 years (9). Obesity contributes to the increased
morbidity for type 2 diabetes mellitus, coronary
artery disease, dyslipidemia, arterial hypertension,
stroke, sleep apnea, osteoarthritis, and some solid
tumors, and is associated with increased all-cause
mortality (10). In the United States, obese persons
incur 80% higher spending on prescription drugs
and 46% higher hospitalizations costs (10).
Compared with the general population, patients
with early-stage or previously untreated schizo-
phrenia and bipolar disorder have a substantially
higher risk to be classified as overweight
(BMI = 25–<30 kg/m2), obese (BMI ≥30 kg/m2),
or of having central obesity (waist circumference
>102 cm in men and >88 cm in women) (11, 12).

98

Individual antipsychotics have different weight
gain potentials (13–19). Among first-generation
antipsychotics, low-potency agents, such as chlor-
promazine and thioridazine, are associated with a
higher risk of weight gain than either mid-potency
or high-potency agents (4). Weight gain is greatest
with the second-generation antipsychotics, cloza-
pine, and olanzapine. Iloperidone, quetiapine, ris-
peridone, paliperidone, sertindole, and zotepine
confer an intermediate risk, whereas amisulpride,
aripiprazole, asenapine, lurasidone, and ziprasi-
done are generally associated with small increases
in body weight (4, 12, 13). A post hoc analysis of
4626 patients with schizophrenia, who had com-
pleted 3 years of naturalistic antipsychotic mono-
therapy with clozapine, olanzapine, quetiapine,
risperidone, amisulpride, and oral and depot first-
generation antipsychotics (20), indicated that the
mean weight gain was highest with olanzapine
(4.2 kg) and lowest with amilsulpride (1.8 kg).
Weight accrual was fastest during the first
6 months of treatment and, depending of the drug,
7–15% of patients moved from normal weight to
the overweight or obese status (20).
All antipsychotics are associated with notable
weight gain in antipsychotic-na€ıve and first-epi-
sode patients (6, 14, 21–24). For example, in a 12-
month trial involving patients with first-episode
schizophrenia who received antipsychotics consid-
ered body weight neutral (amisulpride, ziprasi-
done, and low-dose haloperidol), each drug was
associated with relevant weight gain (9.7, 4.8 and
6.3 kg respectively) (17). These findings are sup-
ported by a recent 3-year study of treatment with
quetiapine, ziprasidone, and aripiprazole in
patients with a first psychotic episode (25). The
proportion of patients gaining ≥7% baseline
weight was 23% for ziprasidone, 32% for quetia-
pine, and 45% for aripiprazole.
The greatest amount of weight gain associated
with antipsychotics in previously drug-naive
patients with schizophrenia occurs in the first few
months (4). For example, a meta-analysis reported
a mean weight gain of about 3.8 kg and a mean
gain in BMI of 1.2 kg/m2 within the first 12 weeks
of antipsychotic treatment in previously drug-
naive patients who were >15 years old (21). In
patients with schizophrenia and bipolar disorder
treated for ≥48 weeks with olanzapine, 64%, 32%,
and 12% of patients gained ≥7%, ≥15%, and ≥25%,
respectively, of their baseline body weight (26).
Subsets of patients treated with second-genera-
tion antipsychotics have a particularly rapid and
marked weight gain after exposure. In a retrospec-
tive analysis of 1191 patients diagnosed with
schizophrenia or schizoaffective disorder treated
Weight gain and obesity in schizophrenia
with olanzapine (27), approximately 15% of sub-
jects had a rapid change of ≥7% body weight dur-
ing the first 6 weeks of treatment, with a mean
weight gain of 1.8–3.2 kg (about 4% of the base-
line body weight) during the first 2 weeks. The
mean weight change in this subgroup was higher at
the end of the 52 weeks compared with subjects
with a slower or no weight increase at 6 weeks.
The rapid weight gainers were younger, had a
lower baseline BMI, and more likely to report
increased food craving (27).
Increasing evidence indicates that antipsychotics
have greater orexigenic weight gain potential in
children and adolescents than in adults (5, 17, 28)
and that young patients receiving antipsychotics
are at increased risk of being or becoming over-
weight or obese (5, 29–32). A recent comparison of
pooled long-term studies (median follow-
up = 201 days) of patients treated with olanzapine
indicated a mean weight gain of 4.8 kg in adults,
but 11.2 kg for adolescents (33). The proportion of
patients gaining ≥7% of their baseline weight was
55.4% among adults and 89.4% in patients
<18 years of age, a difference not solely explained
by ongoing growth in youth. Weight gain is highly
prevalent in youth receiving antipsychotics for aut-
ism spectrum disorders, possibly because they had
no or little previous antipsychotic exposure and
received antipsychotics at an earlier age than
patients treated for psychotic and bipolar disorders
(12, 34). Across 34 head-to-head and placebo-con-
trolled studies, involving 2719 young patients with
psychotic and bipolar disorders who received ola-
nzapine, clozapine, risperidone, quetiapine, or ari-
piprazole for between 3 weeks and 12 months
(with 79.4% of these studies lasting only
≤3 months), the average weight gained was 3.8–
16.2 kg with olanzapine, 0.9–9.5 kg with cloza-
pine, 1.9–7.2 kg with risperidone, 2.3–6.1 kg with
quetiapine, and 0–4.4 kg with aripiprazole (35).
A debate is continuing with regard to the inverse
relationship between baseline BMI and antipsy-
chotic-induced weight gain. A careful analysis of
data available in the early 2000s concluded that the
correlation reflected a regression to the mean, with
the greatest weight changes occurring in the
cohorts differing the most from the population
mean prior to treatment (36). A recent data mining
of the Worldwide Schizophrenia Outpatient
Health Outcomes studies concerning 4626 patients
completing 3 years of monotherapy with antipsy-
chotics found that the proportion of patients gain-
ing ≥7% of body weight was smaller with
increasing BMI (37). For example, in the cloza-
pine-treated subpopulation, significant weight gain
was observed in 14% of obese patients, but in 44%
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Manu et al.
of those in the underweight/normal weight group.
The corresponding frequencies were 16% and 52%
for risperidone, 22% and 42% for quetiapine, and
20% and 55% for olanzapine. The difference and
correlation were significantly weaker in patients
treated with oral (25% vs. 34%) or depot (26% vs.
39%) first-generation antipsychotics. Pooled longi-
tudinal data in patients treated with olanzapine
(mean modal dose = 13.3 mg/day) indicated that
the slowing in the rate of weight gain observed
after 2–4 months of treatment was greatest for
patients who were obese at baseline (38). The inter-
pretation of these data is hampered by the fact that
for approximately 90% of the patients entered in
the largest of these studies (37), the baseline BMI
may have reflected weight accrual during an earlier
exposure to one or more antipsychotic drugs
(Bushe CJ, Personal communication, December 1,
2014).
Pathobiology
Body weight and energy homeostasis. The significant
increase in the worldwide rates of overweight and
obese subpopulations has been related to changes
in diet composition, increased caloric intake, and
modifications of the gut microbiome (9). The most
basic explanation for weight gain leading to obes-
ity is a prolonged imbalance between energy
expenditure and caloric intake (39). In recent
years, the excess energy intake and its storage as
fat has been tied to sugary beverages and increased
availability of calorie-dense food (39).
The maintenance of energy homeostasis involves
central and peripheral mechanisms for regulation
of appetite and satiety, a process that involves
input from the gastrointestinal tract and the adi-
pose tissue. Digested food produces nutrients that
activate enteroendocrine cells to stimulate the
release of gut hormones (glucagon-like peptide 1,
peptide YY), which in turn act on the vagus nerve
and brainstem. The integration of the peripheral
signals takes place in the arcuate nucleus of the
hypothalamus, which contains anorexigenic pro-
opiomelanocortin (POMC) and orexigenic neuro-
peptide Y (NPY)/agouti-related peptide (AgRP)
neurons. Among gut hormones, ghrelin has an
orexigenic effect, while a direct effect of the GLP-1
on the hypothalamus reduces food intake (39).
Two adipokines, leptin and adiponectin, also play
a major role in regulating food intake by influenc-
ing the potent orexigenic effect of insulin. Leptin
suppresses insulin secretion in a negative feedback
loop (39–41), while adiponectin increases tissue
sensitivity to insulin (39). Despite excessive energy
storage, obese individuals continue to consume
100
large amounts of food, a fact attributed to the
non-homeostatic reward system, which appears to
rely on responses generated in the mesolimbic
structures through dopaminergic pathways (39).
Weight gain can be prevented by 150–250 min/
week of moderate-intensity endurance physical
activity, and additional resistance training will
increase the fat-free mass, but this level of energy
expenditure will induce only modest weight loss (42).
Dietary patterns and energy expenditure in
schizophrenia. Patients with schizophrenia con-
sume unhealthy food. A recent meta-analysis of 31
studies about dietary patterns identified a high
consumption of saturated fat and low intake of
fruit and dietary fiber (43). The unhealthy dietary
pattern has also been identified in subjects at high
risk for psychosis who had higher intake of satu-
rated fat and calories than healthy control subjects
(44). A detailed, controlled investigation indicated
that patients with schizophrenia had higher daily
intake of calories and protein per kilogram of body
weight, which was independent of BMI (45). The
contribution of carbohydrates to the total caloric
intake was greater in the schizophrenia group.
Compared with healthy control subjects, patients
consumed lower amounts of phytosterols, omega-
6, vitamin A, and alpha tocopherol. The nutri-
tional differences did not correlate with the type of
antipsychotic (45), an issue that requires further
investigation, given robust experimental evidence
that olanzapine increases the preference for high-
fat/high-sugar diet (46, 47).
The influence of antipsychotics on resting energy
expenditure has been addressed mostly in youth.
After 4 weeks of treatment with olanzapine, the
resting energy expenditure, which was very low
before and after treatment, did change significantly
(48). One-year treatment with olanzapine, risperi-
done, or quetiapine in adolescents led to an aver-
age increase in fat mass of 6.1 kg (49). Resting
energy expenditure/fat-free mass ratio, measured
with indirect calorimetry and bioelectrical imped-
ance, showed a significant increase and correlated
with the weight gain throughout the duration of
the follow-up. These findings suggest a drug-
induced hypometabolic state that may have an
adjuvant role in the increased appetite, caloric
intake, and weight accrual (49). The hypothesis is
supported by the fact that resting energy expendi-
ture/fat-free mass ratio is not significantly different
between non-obese and obese but otherwise
healthy youth (50). Data in adults are scarce, but
congruent with observations in adolescents, as
shown by a decrease in the resting energy expendi-
ture of 280 kcal/day in patients treated with cloza-

pine (51). However, once resting energy expendi-
ture is adjusted for fat-free mass, the energy expen-
diture at rest was similar for patients with
schizophrenia and healthy control subjects, sug-
gesting that differences in body composition and
an impaired capacity to use fat as a fuel may play a
significant role (52). A shift in net substrate oxida-
tion at rest away from fat oxidation toward glu-
cose oxidation could also contribute to weight gain
associated with antipsychotic medications (53).
Neurotransmitter and hormonal changes in schizophre-
nia. The importance of neurotransmitter and
hormonal effects in the weight accrual of patients
with schizophrenia has been studied mainly for
olanzapine. Leptin levels were similar in schizo-
phrenia patients and healthy control subjects
with comparable BMIs (40). An inverse associa-
tion was observed for baseline weight and leptin
levels with the extent of weight gained during 3–
6 months of antipsychotic monotherapy (41). In
contrast with the predictable leptin dynamic,
plasma AGRP levels did not decrease in patients
who gained weight on olanzapine, suggesting a
drug-mediated disruption of the hypothalamic
appetite control (54). Recent animal data also
indicated that olanzapine increased the orexigenic
NPY mRNA and decreased the anorexigenic
POMC in the arcuate nucleus (55) and upregulat-
ed ghrelin and ghrelin signaling, leading to
hyperphagia (56).
The contribution of adiponectin has not been
sufficiently elucidated. Plasma levels were inversely
correlated with BMI and significantly different
between patients receiving monotherapy with anti-
psychotics who were obese, overweight, or normal
weight (57, 58). The levels were lower in patients
treated with clozapine than in those receiving ola-
nzapine or risperidone. In a 3-month, prospective
study, adiponectin levels decreased in patients
treated with olanzapine, but increased in those
receiving risperidone, a differential effect not influ-
enced by the final BMI (59). These findings may
reflect a drug effect, given the results of a more
recent, well-controlled study of drug-na€ıve, normal
weight patients with schizophrenia, which indi-
cated that their adiponectin levels were signifi-
cantly higher than in overweight and obese, but
otherwise healthy control subjects (60).
Histaminergic transmission is involved in
energy homeostasis and also seems to be relevant
to antipsychotic-related weight gain, as the extent
of histamine H1 receptor (H1R) antagonism of
antipsychotics was the best predictor of the degree
of weight gain in clinical studies (61–63). By itself,
the affinity for the H1R classified correctly 15 of
Weight gain and obesity in schizophrenia
the 17 typical and atypical antipsychotics as to
their potential to produce weight gain (61).
Recent animal data strengthened this explanation,
indicating that the interaction between the hypo-
thalamic H1R and the AMP-activated protein
kinase (AMPK) signaling mediates, in a time-
dependent pattern, the hyperphagia and weight
gain induced by olanzapine (64). Expression of
H1R mRNA and the AMPK phosphorylation
were positively correlated with food intake during
the early, hyperphagic stage of antipsychotic-
induced weight gain. H1R blockade by AMPK
becomes a chronic state and explains the elevated
body weight maintenance. H1R agonists, such a
betahistine, inhibit olanzapine-related hyperpha-
gia in animal models (65) and in patients with
schizophrenia (66).
5-HT2c antagonism has been implicated in anti-
psychotic drug-related weight gain too, and most
second-generation antipsychotics, especially cloza-
pine and olanzapine, are potent 5-HT2c antago-
nists. All antipsychotics bind to and act either as
antagonists or partial agonists for D2 receptors,
and clinically, significant weight gain (≥7% of pre-
treatment values) can develop even with antipsy-
chotics that interact exclusively with D2 and/or D3
receptors, such as amisulpride (Kahn 2008), high-
lighting further the complex mechanisms of anti-
psychotic-related weight gain. Likewise, synergistic
effects between the blockade of D2 receptors and
5-HT2a or 5-HT2c receptors might play a key role
in triggering a cascade of events that lead to
increased energy intake and weight gain (3).
Genetic vulnerability. Data point toward a poten-
tial role of several genes in the weight gain induced
by antipsychotic drugs, including a-adrenergic
transmission, leptin receptor activity and signaling,
promelanin-concentrating hormone signaling,
including the melanocortin 4 receptor gene, and
cannabinoid receptor activity (3, 67). In patients of
European ancestry, weight gain produced during
treatment with clozapine and olanzapine had sig-
nificant genotypic and allelic associations with
functional polymorphisms in neuropeptide Y (68)
and the subunit genes coding the cellular energy
sensor AMP-activated protein kinase (69). Of great
interest are also findings indicating that variants of
genes controlling the dopamine D2 receptor and
serotonin 2C receptor correlate with weight gain in
individuals newly exposed to olanzapine (70). A
polymorphism of the ‘clock’ gene NR3C1,
involved in circadian regulation activity of gluco-
corticoid receptors, has been identified as a corre-
late of weight, waist circumference, and waist/hip
ration in patients with schizophrenia treated with
101
Manu et al.
antipsychotics, but the specificity of the finding is
debatable (71).
Recent work has also focused on exploring the
tumor necrosis factor (TNF) alpha gene. TNF-
alpha is considered one of the most reliable indica-
tors that inflammatory processes contribute to the
pathobiology of schizophrenia, bipolar disorder,
and depression (72). After controlling for non-
genetic factors, carriers of the 308 G polymor-
phism in this gene gained more weight during
8 years of clozapine treatment (73). However, the
findings were not confirmed in a larger study of
patients with schizophrenia treated for an average
of 4 years with clozapine, olanzapine, or risperi-
done (74).
Psychosocial factors. Psychosocial factors contrib-
ute to the etiology of obesity in schizophrenia by
restricting food choices and decreasing caloric
expenditure (75). Social isolation, low interest in
social achievement, and unmarried and unem-
ployed status are common in patients with schizo-
phrenia and lead to decreased levels of
participation in sports and other mainstream phys-
ical activities (75, 76). Negative discrimination and
stigma hinder training, education and close
personal relationship and, together with low socio-
economic status, may limit opportunities for
achieving physical fitness and access to healthier
food (75, 77). On the other hand, deficits in execu-
tive function and memory, residual psychotic
symptoms, poor illness self-management skills,
and substance misuse can interfere with the adop-
tion and thorough learning of new behaviours (75,
78).
Taken together, these data indicate that inter-
ventions aimed at the amelioration of obesity and
cardiovascular illness need to be as multipronged
and complex as the contributing psychosocial,
behavioural, and biological factors that make
obesity and cardiovascular illness more likely in
patients with severe mental illness, including
schizophrenia.
Management
General guidelines. The guidelines for the manage-
ment of overweight and obesity in adults have been
recently updated to match risk profiles for cardio-
vascular disorders with treatment benefits (10).
BMI and waist circumference must be measured at
least annually, and overweight and obese adults
should be informed of the relationship between ele-
vated BMI and the risk of cardiovascular disease,
type 2 diabetes, and all-cause mortality. Patients
with one or more risk factors (dyslipidemia, arte-
102
rial hypertension, or hyperglycemia) should be
informed that a sustained weight decrease of at
least 3%-5% will benefit their health. Changes that
create an energy deficit (intake < expenditure) are
required in all attempts to lose weight and can be
obtained by prescribing diets that (i) restrict high-
carbohydrates, high-fat, and low-fiber food, (ii)
create deficits of 500–759 kcal/day, or (iii) limit
total caloric intake to 1500–1800 kcal/day in males
and 1200–1500 kcal/day in females (10). The mac-
ronutrient composition is less important than the
caloric restriction (79), but low carbohydrate and
Mediterranean diets led to greater weight loss than
high-protein or low-glycemic index regimens (80).
Low-calorie diets should be avoided in pregnant or
lactating women and in patients with eating
disorders (79).
The adherence to diet and amount of weight lost
is enhanced by increased physical activity and par-
ticipation, for at least 6 months, in a comprehen-
sive lifestyle programme that should include
weekly high-intensity, on-site individual or group
sessions. Personalized feedback, delivered electron-
ically, is useful but should not replace face-to-face
interventions. For weight loss maintenance, recom-
mendations include monthly face-to-face interven-
tions, continuation of the reduced caloric intake,
and 200–300 min/week of physical activity (10).
Endurance activities are preferable, because resis-
tance training does not enhance weight loss (39).
For physically inactive patients, the exercise pro-
gramme may be started at a lower level, such as
walking 2–3 times/week for 30 min (79). Intensive
lifestyle interventions reduce body weight and car-
diovascular risk factors in the prime target group,
obese patients with type 2 diabetes (81). Bariatric
surgery should be considered for adults with BMI
>40 kg/m2 and for patients with obesity-related
morbidity with BMI ≥35 kg/m2 after dietary and
behavioural interventions.
The weight-lowering drugs approved for use in
the United States work by reducing appetite
through enhanced neurotransmission in the central
nervous system (i.e., the 5HT2C agonist lorcaserin,
phentermine/topiramate extended release, and nal-
trexone/bupropion) or by decreasing intestinal fat
absorption (orlistat) and should be used only as an
adjunct to lifestyle interventions (10, 82, 83). Orli-
stat is also approved for pediatric patients (84).
Compliance is reduced by gastrointestinal adverse
effects and increased risk of nephrolithiasis and
liver failure for orlistat; headache, dizziness, and
increased risk of serotonin syndrome for lorcaser-
in; and insomnia, irritability, anxiety, and distur-
bance of attention for phentermine/topiramate;
(82) and nausea, constipation, xerostomia, amne-

sia, seizures, and hepatotoxicity for naltrexone/
bupropion (82).
Among promising drugs awaiting completion of
regulatory trials are liraglutide, a glucagon-like
peptide-1 receptor agonist; and beloranib, a drug
that increases fat oxidation and lipolysis (83).
However, while these agents are approved for
weight loss in obese people in the general popula-
tion, only orlistat has been studied in randomized
trials in patients treated with antipsychotics, and
orlistat was not more effective than placebo (85).
While the majority of studies have been conducted
in adults, in pediatric obese patients, encouraging
data have emerged for metformin, exenatide, topi-
ramate, and zonisamide (84).
Initiating the discussion about weight gain
should be straightforward and use questions such
as ‘Do you have any concerns about your weight’
or ‘Do you think your body weight is making your
health problems worse’ (86). The patient’s readi-
ness and motivation to participate in a weight
reduction programme must be carefully explored
taking into account the barriers to behavioural
and lifestyle changes. The clinician may need to
consciously avoid confrontation and imposing
their authority or ideas, but instead rely on collab-
oration and enhanced patient autonomy (86).
Readiness can be tested by the question ‘Some peo-
ple don’t mind talking about their weight, others
don’t want to talk about it at all. How do you feel
about this?’ (86).
Non-pharmacological interventions. Strategies to
minimize or reverse cardiovascular and metabolic
adverse effects associated with antipsychotics
include foremost healthy lifestyle promotion
(Fig. 1a,b). Healthy lifestyle education, instruc-
tion, or intervention should always be used prior
to considering switching to lower-risk antipsychot-
ics for the sole reason of cardiometabolic risk sta-
bilization or adding medications that reduce
weight and/or reverse metabolic abnormalities (1,
22, 85, 87).
Psychiatrists should educate patients and those
most involved in their care about healthy lifestyle
behaviours and should use effective behavioural
interventions to motivate patients to make the
necessary changes, including smoking cessation,
adoption of a healthy diet, and regular physical
exercise (85, 88, 89). A meta-analysis of 17 con-
trolled studies reporting the effect of behavioural
interventions in 810 patients with schizophrenia
spectrum disorders indicated significant reductions
in weight ( 3.12 kg), BMI ( 0.94 kg/m2), waist
circumference ( 3.6 cm), and body fat ( 2.82%)
(1). The interventions were also remarkably suc-
Weight gain and obesity in schizophrenia
cessful in preventing further weight accrual, as an
increase ≥7% was observed in 61.3% of control
patients, but in only 29.7% of those receiving
behavioural treatment. Follow-up 3.6 months
after the intervention ended indicated enduring
benefits with regard to weight, but not BMI, sug-
gesting that behavioural interventions to prevent
or reduce weight gain should remain part of a
comprehensive treatment plan. The attenuation of
benefit over time was observed in a recently com-
pleted STRIDE trial, a controlled weight loss and
lifestyle intervention for individuals taking anti-
psychotic medications (90). Moderate caloric
reduction, a low-fat high-fiber diet, and at least
24 min of moderate-intensity physical activity/day
led to a 4.4 kg more weight loss than in the con-
trol group after 6 months, but only 2.6 kg after
1 year. In a recent trial of a behavioural weight
loss intervention in 291 persons with serious men-
tal illness, of whom 58.1% had schizophrenia or
schizoaffective disorder, the mean difference in
weight was 3.2 kg at 18 months compared with
a control group (75). The goals for the interven-
tion group were moderate-intensity aerobic exer-
cise, choosing healthy snacks, and smaller
portions, at least five daily servings of vegetables
and fruits, avoid junk food and sugar-sweetened
beverages, which were reinforced throughout the
trial by targeting deficits in memory and executive
function (75).
Switching or adding antipsychotics. Antipsychotic
switching to a lower-risk agent is another evidence-
based approach to addressing antipsychotic-
related weight gain and metabolic abnormalities
(Fig. 1a,b). However, the decision to switch anti-
psychotics should consider the patient’s entire psy-
chiatric and physical condition and the
pharmacological profiles of current and proposed
drugs (91). In the largest randomized controlled
efficacy trial in schizophrenia to date confirmed
that weight gain was not associated with clinically
relevant efficacy advantages and that switching to
agents that were associated with weight loss was
associated with similar efficacy outcomes as
switching to more weight gain-promoting agents
(92).
Older switch studies indicated that replacing a
high weight gain propensity antipsychotic with a
lower-risk antipsychotic (93–97) or switching from
antipsychotic polypharmacy to antipsychotic
monotherapy (98) is associated with statistically
and clinically relevant weight loss, mostly associ-
ated with metabolic improvements. For example,
in a head-to head prospective, open-label, 12-
month switch trial, ziprasidone (40–160 mg/day)
103
Manu et al.

(a)

Baseline:
4 week visit: 12 week visit:
Check body weight, BMI, waist 8 week visit:
Check weight and blood pressure,
circumference, blood Gauge clinical Gauge clinical
response, and repeat every 3 months.
pressure, fasting glucose and response,
Weight Check Check, fasting glucose and lipids,
lipids, HgA1c, and start lowest Weight Check
HbA1c, and repeat annually*
risk agent at lowest effective
dose

Do observed
Stop
clinical benefits No antipsychotic or
outweigh risks
switch to lower
of metabolic
risk agent.
side effects

Yes
Educate and
aggressively
manage risk
No >7% weight Yes Patient No
Continue to factors, consider
gain or motivated
monitor as referral to
metabolic to lose
above medical
complications weight?
specialist,
continue to
monitor as above
Yes
*Repeat more frequently if significant Weight loss
weight gain or symptoms/ signs of intervention- see
diabetes onset (polyuria, polydipsia) table 1b (75)

(b)

Antipsychotic-induced weight gain:

BMI 25–<30 with metabolic
complications
OR BMI >30 Hyper- Dys- Dys-
tension? lipidemia? glycemia?

No
Yes
No BMI Yes Address
over abnormalities and/or
40? refer to specialist

Insufficient Insufficient Insufficient Consider

response* Refer for supported or response* Start evidence based response* combination
Reinforce after 3–6 structured behavior after 6 months adjunctive after 3–6 therapy
t or referral
healthy months modification, nutritional pharmacotherapy for months for bariatric
lifestyle consult antipsychotic induced
surgery if indicated
education and (tailored to patient and weight gain (ie
due to obesity
instruction. stepped according to risk metformin or topiramate)
related
factor levels) **
complications.
Sufficient Sufficient
response response

Figure 1. (a) Suggested algorithm for

* Response defined as weight loss of
>5% and improvement in cardiovascular
Continue to monitor as in risk factors (lipids, glucose, HbA1C)
figure 1a ** If on clozapine, adjunctive use of
aripiprazole is also an option
cardiometabolic monitoring of patients
treated with antipsychotics. (b)
Suggested algorithm for managing
antipsychotic-related weight gain.

led to a decrease in BMI from 35.1 to 32.8 kg/m2, with placebo and a concomitant decrease in choles-
while aripiprazole (5–30 mg/day) decreased the terol and triglyceride levels (100).
BMI from 35.1 to only 34.9 (99). The absence of a
control group continuing their prestudy antipsy- Pharmacological treatment of antipsychotic-related
chotic, lack of standardized psychosocial support weight gain. When switching to a lower-risk anti-
during the intervention, and statistical processing psychotic is not an option, medications can also be
that ignored the duration of prior antipsychotic added to counteract antipsychotic-related cardio-
treatment complicates interpretation of this study. metabolic adverse events (Fig. 1a,b). In a meta-
Aripiprazole and ziprasidone received the most analysis of pharmacological strategies in patients
intense scrutiny for their role in attenuating anti- with any diagnosis who had gained weight with an-
psychotic-related weight gain. A recent meta- tipsychotics, only 5 of 15 studied drugs were asso-
analysis of three studies of adjunctive aripiprazole ciated with greater weight loss than placebo:
indicated a 2.13 kg mean difference compared metformin ( 2.94 Kg), d-fenfluramine ( 2.60 kg),

104

sibutramine ( 2.56 kg), topiramate ( 2.52 kg)
and reboxitine ( 1.90 kg) (85, 87). Treatment with
amantadine, dextroamphetamine, famotidine, flu-
oxetine, fluvoxamine, nizatidine, orlistat, phenyl-
propanolamine, and rosiglitazone was not superior
to placebo (85, 87). The results were confirmed by
a recent meta-analysis of 40 trials of 19 unique
pharmacological interventions restricted to
patients with schizophrenia spectrum disorders.
Again, metformin was the most effective drug
( 3.17 kg weight loss) compared with placebo
(100). There is no clear evidence that prevention,
that is, metformin given together with a newly
started antipsychotic, is more effective than inter-
vention after the weight gain has occurred (101).
Discussion
Weight gain and obesity in patients with schizo-
phrenia and other mental disorders are associ-
ated with a host of adverse physical and
psychiatric outcomes. Therefore, body weight
and related metabolic indices need to be moni-
tored routinely and targeted as part of a compre-
hensive and integrated care programme. As
severely mentally ill patients seek out or receive
less optimal care than the general population
(102) despite their higher risk for adverse physi-
cal outcomes (102, 103), mental healthcare pro-
viders should take on at least the orchestration
of integrated education, assessment, and care.
Nevertheless, it is also important to consider that
antipsychotics are currently the only medication
class with evidence for effective treatment of psy-
chosis (104). Moreover, in nationwide database
studies, patients with schizophrenia not receiving
antipsychotics had the highest all-cause mortality
(105, 106). Furthermore, other medications,
including mood stabilizers and antidepressants,
often used in patients with schizophrenia, can
also lead to weight gain, and adversely affect
lipid and glucose metabolism (107), and antipsy-
chotics have diverging weight gain and metabolic
risk potentials (4, 102). These differences should
be considered when making treatment choices
(91). Ideally, a treatment algorithm should start
with healthy lifestyle education/instruction and
lower cardiometabolic risk antipsychotics, and
only consider higher risk agents when it has
become clear that the physically safer medication
is not sufficiently effective or tolerated. Psychiat-
ric care providers should aim for balancing acute
and long-term efficacy as well as tolerability, and
engage other medical specialists as needed to
improve the overall well-being of patients with
schizophrenia.
Weight gain and obesity in schizophrenia
Declaration of interest
Dr. De Hert has been a consultant for, received grant and/or
research support and honoraria from, and been on the speak-
ers’ bureaus and/or advisory boards of Janssen-Cilag, Lund-
beck, and Takeda. Dr. Correll has been a consultant and/or
advisor to or has received honoraria from: AbbVie, Alkermes,
Bristol-Myers Squibb, Eli Lilly, Genentech, Gerson Lehrman
Group, IntraCellular Therapies, Janssen/J&J, Lundbeck,
MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva,
Roche, Sunovion, Supernus, and Takeda. He has received
grant support from the American Academy of Child and Ado-
lescent Psychiatry BMS, Janssen/J&J, National Institute of
Mental Health (NIMH), Novo Nordisk A/S, Otsuka, Takeda
and the Thrasher Foundation. Drs. Manu, Dima, Shulman,
and Vancampfort have nothing to declare.
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