General Hospital Psychiatry 78 (2022) 58–67

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General Hospital Psychiatry

journal homepage: www.elsevier.com/locate/genhospsych

Review article

A systematic review of licensed weight-loss medications in treating

antipsychotic-induced weight gain and obesity in schizophrenia
and psychosis
Kenn Lee a, *, Seri Abraham a, b, c, Robert Cleaver a
a
Liaison Mental Health Service, Royal Oldham Hospital, Pennine Care NHS Foundation Trust, United Kingdom
b
School of Psychiatry, Health Education England North West, United Kingdom
c
Manchester Metropolitan University, United Kingdom

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Schizophrenia and antipsychotic use are associated with clinically significant weight gain and
Antipsychotic subsequent increased mortality. Despite weight loss medications (WLMs) licensed by regulatory bodies (FDA,
Weight gain EMA, and MHRA) being available, current psychiatric guidelines recommend off-label alternatives, which differ
Obesity
from non-psychiatric guidelines for obesity.
Schizophrenia
Weight-loss medication
Objective: Evaluate the efficacy of licensed WLMs on treating antipsychotic-induced weight gain (AIWG) and
obesity in schizophrenia and psychosis (OSP).
Method: A literature search was conducted using Medline, EMBASE, PsycINFO and Cochrane Library online
databases for human studies using licensed WLMs to treat AIWG and OSP.
Results: Three RCTs (two liraglutide, one naltrexone-bupropion), one unpublished open-label trial (naltrexone-
bupropion), and seven observational studies (five liraglutide, one semaglutide, one multiple WLMs) were
identified. Results for liraglutide showed statistically significant improvement in weight, BMI, waist circum­
ference, HbA1c, cholesterol, and LDL readings on meta-analysis. Evidence was mixed for naltrexone-bupropion
with no detailed studies conducted for setmelanotide, or stimulants.
Conclusion: Evidence is strongest for liraglutide compared to other licensed WLMs. The findings, particularly the
inclusion of human trial data, provide evidence for liraglutide use in treating AIWG and OSP, which would better
align psychiatric practice with non-psychiatric practices around obesity. The findings also identify continued
literature gaps regarding other licensed WLMs.

1. Introduction significant as there is an increasing trend of second-generation anti­

Schizophrenia and psychosis are severe mental illnesses associated
with increased mortality [1–4], affecting approximately 24 million
people worldwide [5,6]. Life expectancy is 64.7 years, with an estimated
average 14.5 years of potential life lost [7], and the mortality gap is
increasing when compared against the general population [1,8,9]. While
causes are multifactorial, cardiometabolic risk factors such as cardio­
vascular disease and obesity are recognised major contributors
[1,2,10,11]. The pathophysiology is complex though use of second-
generation antipsychotics, particularly olanzapine and clozapine, are
recognised to directly worsen cardiometabolic risk factors and
antipsychotic-induced weight gain (AIWG) [12–14]. This effect is
psychotic use – not just for schizophrenia in adults, but in children and
non-psychotic mental illness [15–18].
The prevalence of obesity and other modifiable cardiometabolic risk
factors (e.g. smoking, type-2 diabetes mellitus (T2DM), hypertension,
dyslipidaemia, metabolic syndrome) are higher in individuals with
schizophrenia; with relative risks for each factor ranging between 1.5
and 5 compared to the general population [19]. Such factors, as well as
presence of mental illness and second-generation antipsychotic use, are
known to each be independently predictive of developing acute coro­
nary syndrome and stroke [10,20]; contributing to the early deaths seen
in schizophrenia.
One potential mechanism through which schizophrenia leads to

* Corresponding author.
E-mail address: kennlee@nhs.net (K. Lee).

https://doi.org/10.1016/j.genhosppsych.2022.07.006
Received 14 March 2022; Received in revised form 24 June 2022; Accepted 12 July 2022
Available online 14 July 2022
0163-8343/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
K. Lee et al.
development of cardiometabolic risk factors is through inflammatory
pathways. Acute and chronic psychosis have both been associated with
elevation of several inflammatory markers, including tumour necrosis
factor alpha, interleukin-6, interleukin-1-beta, and soluble interleukin-2
receptor [21]. These have also been associated with acute coronary
syndrome, metabolic syndrome, obesity, insulin resistance, and T2DM
[22–24]. Additionally, second-generation antipsychotics may further
increase risk through antagonism of histamine-1 [25], serotonin [26],
and dopamine-2 [27] receptors at the hypothalamus; interfering with
glucose, lipid, and appetite regulation [28]. They have also been shown
to interfere with monoaminergic systems, leading to increases in
appetite-promoting neuropeptide-Y and agouti-related protein and de­
creases in appetite-suppressing proopiomelanocortin [29].
Attention has been given to obesity and cardiometabolic risk factors,
both for individuals with schizophrenia and in mental illness more
broadly, to improve prognosis. In the United Kingdom (UK), this
included national public health policy and strategy, such as including
“physical health in people with mental illness” as a specific recommenda­
tion for the National Health Service England's Five-Year Plan [30] and
“improving physical healthcare to reduce premature mortality in people with
serious mental illness” being a performance indicator in the Commis­
sioning for Quality and Innovation payment framework for the National
Health Service England in 2017/2018 and 2018/2019 [31].
2. Background
Guidelines have been published on managing AIWG and obesity in
schizophrenia and psychosis (OSP) by several psychiatric and psycho­
pharmacological bodies [32–34]. While broadly in consensus and
aligned with non-psychiatric guidelines [35–37] for obesity (recognising
the potential long-term harm of poorly controlled cardiometabolic risk
factors and using a stepwise approach beginning with conservative in­
terventions (e.g. lifestyle changes, diet, exercise) before escalating to
pharmacological treatment and then bariatric surgery), they however
differ in which medications are used for pharmacological treatment.
The Maudsley [34] and British Association of Psychopharmacology
[33] treatment algorithms explicitly identify off-label metformin as first-
line options when treating AIWG and OSP in nondiabetics, with the
latter citing a lack of human data to support recommending licensed
options. Similarly, the American Psychiatric Association guidelines [32]
discuss and advocate off-label metformin.
In contrast, the National Institute for Health and Clinical Excellence
(NICE) [37], Endocrine Society [35], and American College of Cardiol­
ogy [36] uniformly recommend using only licensed medications for
weight management and did not consider off-label options such as
metformin. Specifically, NICE and the Endocrine Society recommend
orlistat or liraglutide, with the latter also recommending lorcaserin
(withdrawn from market), phentermine, and phentermine-topiramate as
options. NICE is also developing guidelines around treating obesity with
semaglutide [38]. The Endocrine Society explicitly recommends against
off-label medications.
As such, by favouring unlicensed WLMs, psychiatric practice de­
viates from those of cardiologists and endocrinologists in managing
obesity and cardiometabolic risk factors. This potentially exposes the
psychiatrist to increased civil liability [39]. There could be challenges to
informed consent if licensed treatments were not discussed or if patients
were not informed that the medication being proposed deviated from
cardiological and endocrinological recommendations and practices. The
latter could also expose the psychiatrist to malpractice lawsuits if the
patient alleges harm, as treating obesity with off-label medications does
not appear to be condoned by the respective medication manufacturers
or the relevant medical specialists (cardiology, endocrinology), with
explicit advice against so by the latter group [35].
Furthermore, this practice also potentially conflicts with General
Medical Council recommendations against prescribing unlicensed
medicines and to only do so when “there is no suitably licensed medicine”
59
General Hospital Psychiatry 78 (2022) 58–67
that meets the patient's needs [40]. Such recommendations should
particularly apply in psychiatry as people with mental illness are a
vulnerable population and may also be taking medication involuntarily
(e.g. if under a treatment order or via court order due to lacking ca­
pacity). Hence, it makes sense that the supervising doctor must be clear
when justifying their medication choices, especially when the medica­
tions are unlicensed for the particular use.
There are several licensed WLMs currently approved in the UK, Eu­
ropean Union (EU), or the United States (US) for weight management
[41,42]. These are orlistat, liraglutide, semaglutide, naltrexone-
bupropion, phentermine-topiramate, setmelanotide, phentermine,
diethylpropion, phendimetrazaine, and benzphetamine. Their class and
approval status have been summarised in Appendix A.
A potential reason for the discrepancy between psychiatric and non-
psychiatric guidelines is a lack of human data specific to patients with
mental illness at the time of the psychiatric guidelines' publication [33]
and new developments in the field such as the approval of new medi­
cations. Consequently, a review of the available evidence would be
beneficial, either to update these guidelines or to reaffirm that off-label
prescribing remains the most suitable option.
3. Methods
The systematic review was conducted based on a protocol registered
with PROSPERO [43] in accordance to guidelines set by the Preferred
Reporting Items for Systematic Reviews and Meta-analyses [44].
3.1. Selection criteria
All controlled studies, and observational studies involving more than
one participant, were included in the systematic review, provided they
involved adult participants (aged ≥18 years) with a diagnosis of a
psychotic disorder (e.g. schizophrenia, schizoaffective disorder, first
episode psychosis) and were medicated with a licensed WLM to treat
AIWG or OSP.
To qualify as a licensed WLM, it must be a currently available,
prescription-only medication approved for long-term weight manage­
ment in nondiabetics in the UK, US, or EU by the respective region's
regulatory body; namely Medicines and Healthcare Products Regulatory
Agency (MHRA), the Food and Drug Administration (FDA), and European
Medicines Agency (EMA) respectively. These were identified to be orli­
stat, liraglutide, semaglutide, phentermine-topiramate, naltrexone-
buopropion, setmelanotide, phentermine, diethylpropion, phendime­
trazaine, and benzphetamine. Medications that have since been with­
drawn from these markets – such as lorcaserin [45] and rimonabant [46]
– have been excluded from this review.
Additionally, only studies published between 1 January 2000 and 15
June 2022 were selected for review. With respect to orlistat specifically,
studies were limited only to those published on or after 1 January 2015
as studies prior to this date would have been already considered when
previously published guidelines were developed.
Not included in the review were case reports, qualitative studies,
studies solely involving established T2DM, studies on WLMs that have
been withdrawn from market (e.g. lorcaserin, rimonabant), studies
solely on unapproved WLMs (e.g. metformin, exenatide), animal studies,
and non-English articles.
3.2. Search strategy
Two researchers independently conducted literature searches using
Ovid MEDLINE, EMBASE, PsycINFO, and Cochrane Library databases
using a combination of search terms: “obesity”, “weight loss, “weight
gain”, or “prediabetes” (or similar); “antipsychotic” (or similar), “olan­
zapine”, “risperidone”, “clozapine”, “quetiapine”, “schizophrenia”, or
“psychosis”; and individual medications using their non-proprietary and
introductory trade names. Due to the number of search terms, separate
K. Lee et al.
searches were conducted using the above databases for each medication.
To identify grey literature, a separate search was conducted using the
same search terms via Google Scholar. The first 5 pages for each medi­
cation were reviewed for relevant articles (50 results per medication).
3.3. Outcomes and statistical analysis
The primary outcome of interest is change in weight following
treatment, including both direct measures of weight (e.g. absolute
weight loss), indirect measures (e.g. percentage weight loss), and
derived measures (e.g. body mass index (BMI), proportion achieving
≥5% weight loss). Other outcomes included are other cardiometabolic
risk factors (e.g. blood pressure, development of T2DM) and reported
adverse outcomes. The results are categorised by medication type, with
each medication type reviewed separately. Due to their different phar­
macology and mechanisms of action, it was decided that combining
their results would be inappropriate.
Meta-analysis and sensitivity analysis of RCT results was performed
where appropriate using Review Manager (RevMan)®, version 5.4.1
[47]. For continuous measures, simple unstandardised mean difference
was used following initial conversion into a common unit [48]. A funnel
plot would have been conducted to assess for publication bias only if
sufficient studies could be included (n ≥ 10, [49]). Grading of results
was completed using the GRADE approach [50], with loss of quality
commented on.
4. Results
4.1. General findings
411 articles were initially identified through the literature search
and a further 500 articles reviewed through the grey literature search; of
which 11 were found to meet criteria. Excluded articles were on the
basis of being duplicates, not meeting criteria (e.g. only involving di­
abetics, animal studies), or described protocols without containing re­
sults. One study on phentermine was excluded due to poor quality. No
article found was excluded solely for being unavailable in English.
The articles selected varied in typology (three randomised control
trials (RCTs), one open-label trial (OLT), seven observational studies);
the characteristics of which are summarised in Table 1. Three were
available only as abstracts [51–53] and one was an unpublished trial
that had been discontinued [54].
Typically, articles focused on individual WLMs. However, an obser­
vational study by Tham, et al. [55] was unique in including multiple
WLMs and evaluating them collectively. The study was divided into
three phases, with participants divided between liraglutide, topiramate,
and naltrexone-bupropion groups at baseline. Participants who did not
respond to treatment were offered a second WLM (liraglutide, top­
iramate, or phentermine) at three months, and non-responders with
depression were further offered phentermine at six months.
In total, eight articles included liraglutide, three included
naltrexone-bupropion, and one included semaglutide. Orlistat, setme­
lanotide, and central nervous system stimulants aside from phentermine
were not included in any of the identified articles. Only Tham, et al. [55]
included a phentermine-topiramate combination therapy though this
was not separately analysed from the other phentermine combinations
used in the study.
A variety of weight-related parameters were used to investigate the
efficacy of WLMs. Changes in weight, body mass index (BMI), and waist
circumference were the commonest measures used. However, due to
differences in methodology, the exact manner these were reported
varied from article to article. The main findings and conclusions of the
articles are summarised in Table 2.
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General Hospital Psychiatry 78 (2022) 58–67
4.2. Liraglutide
Although eight articles were identified on liraglutide, it should be
noted that two were by the same authors [51,59] using similar – but not
identical – criteria, methodology, and data and so may represent find­
ings of a single dataset and will be evaluated as such.
Of particular interest were two RCTs by Larsen et al. [57] and
Whicher et al. [56]. Both solely included patients with psychosis
(schizophrenia, schizoaffective disorder, first episode psychosis)
receiving antipsychotic treatment (primarily second-generation anti­
psychotics with only two participants on a first-generation antipsychotic
(zuclopenthixol decanoate)) and used placebo as controls. Where they
differed however were in their selectivity (Larsen, et al. [57] limited
their recruitment to patients with schizophrenia, treatment with olan­
zapine or clozapine, and excluded those with established T2DM or
normal glucose tolerance tests), duration (16 weeks vs 6 months), and
maximum treatment dose (1.8 mg/day vs 3.0 mg/day).
Meta-analysis of the estimated effect size on the cardiometabolic risk
factor parameters measured in the two RCTs. From the 131 participants
included, we found statistically significant (p-value <.05) differences
that favoured liraglutide treatment over placebo for changes in weight,
BMI, waist circumference, glycated haemoglobin (HbA1c), total
cholesterol, and low-density lipid (LDL) readings but not for systolic
blood pressure. These have been summarised in Table 3, with their
respective forest plots included in Appendix B. Due to the number of
RCTs included, sensitivity analysis was limited to comparing the results
with those using fixed effect models, with the results being mostly
unchanged.
The RCT by Larsen et al. [57] also found statistically significant
improvement in prediabetes status after 16 weeks of liraglutide (mean
difference (MD): 9.2%, (95% CI: 2.6 to 32.7), p-value <.001). However,
this was not sustained once treatment was discontinued as there was no
statistical difference in the odds ratio (OR) between the liraglutide and
placebo groups for developing T2DM when followed-up after one year
when compared to baseline (OR 2.76 (95% CI: 0.93 to 8.21), p-value
0.07) [60]. Nonetheless, the same study did find that changes in weight
(MD: − 3.81 kg, (95% CI: − 7.3 to − 0.2), p-value <.04) and BMI (MD:
-1.6 (95% CI: − 2.8 to − 0.3), p-value <.02) were partially sustained at
follow-up when compared to baseline despite liraglutide having been
discontinued. Other cardiometabolic risk factors (waist circumference,
systolic blood pressure, HbA1c, fasting glucose, total cholesterol, LDL)
however had returned to baseline levels.
These findings are supported by other observational studies
[51,52,58,59]; all of which found liraglutide beneficial as previously
summarised in Table 2. Likewise, Tham et al. [55] found that its lir­
aglutide monotherapy subset of subjects (n = 87) averaged a reduction
in weight of 10.9 ± 5.2% (p-value <.001) and waist circumference of
11.4 ± 5.2 cm (p-value <.01) after 52 weeks.
Also notable was an observational study by Maccora et al. of between
94 [51] and 100 [59] subjects also found no statistical difference in
response to liraglutide between its mental illness, eating disorder, and
non-mental-illness groups. This finding indicates liraglutide may behave
similarly in people with mental illness and those without, and that data
from general population may be applicable to those with mental illness.
In terms of adverse outcomes, nausea and gastrointestinal effects
were the ones most frequently reported [55–57,59]. However, due to
differences in reporting methods, they could not be combined for further
analysis. Larsen et al. [57] found statistically significantly higher rates of
nausea (62.0% vs 32.0%; p-value = .008) and orthostatic hypotension
(8.2% vs 0.0%; p-value = .04) in its intervention group compared to its
control group. Similarly, Whicher et al., 2021 found that gastrointestinal
symptoms accounted for 72% of the reported adverse events in its
intervention group. Nausea was reported in 37.5% of subjects in Lee
et al. [58]; 28% of subjects in Maccora et al. [59]; and 83.9% of lir­
aglutide subjects in Tham et al. [55]. However, where commented on,
no significant deterioration in mental illness was reported [55,57,59].
 Table 1

K. Lee et al.
Study and participant characteristics.
Study Study design Country Setting Intervention / Exposure Control / Number of participants Inclusion population Study
Comparator(s) duration
Intervention / Control /
Exposure Comparator

Liraglutide
Age 18–75 yrs.; Schizophrenia,
Whicher et al., schizoaffective disorder or first-episode
RCT UK Community Liraglutide up to 3.0 mg per day Placebo 24 23 6 months
2021 [56] psychosis diagnosis; BMI ≥30 kg/m2 or ≥
27 kg/m2 w/ weight-related consequences
Age 18–65 yrs.; Schizophrenia-spectrum
Larsen et al., 2017 diagnosis (excluding schizoaffective
RCT Denmark Community Liraglutide 1.2–1.8 mg per day Placebo 47 50 16 weeks
[57] disorder); Stable on olanzapine or
clozapine; Prediabetes
Retrospective
Lee SE et al., 2021 Schizophrenia or bipolar disorder
observational China Community Liraglutide 3.0 mg per day None 16 – 16 weeks
[58] diagnosis; Obesity diagnosis
study
Age 19–75 yrs.; BMI ≥30 kg/m2 or ≥ 27 kg/
21 in binge eating
Prospective, Psychiatric disorder (schizophrenia, Binge eating m2 w/ dyslipidemia/ hypertension/ type 2
Maccora et al., disorder group; 49
observational Italy Community bipolar disorder, major depressive disorder, No 30 diabetes mellitus; Previously failed lifestyle 6 months
2020 [59] in no psychiatric
study disorder) psychiatric disorder interventions; Treatment with liraglutide
disorder group
up to 3.0 mg/day
19 in binge eating Age 19–75 yrs.; BMI 29–68 kg/m2;
Maccora et al., Prospective, Severe psychiatric disorder Binge eating
disorder group, 48 Treatment with liraglutide up to 3.0 mg/
2018 (abstract observational Italy Community (schizophrenia, bipolar disorder, major disorder, No 27 6 months
in no psychiatric day; Previously failed multiple lifestyle
only) [51] study depressive disorder) psychiatric disorder
disorder group interventions
Prospective,
Svensson et al., Previous treatment with liraglutide Previous treatment Previous participation in previous RCT
observational Denmark Community 41 46 68 weeks
2019 [60] 1.2–1.8 mg per day with placebo (Larsen et al., 2017)
study
61

Schizophrenia, bipolar disorder or major

Prospective,
Di Volo et al., depressive disorder diagnosis; Obesity
observational Italy Community Liraglutide 0.6–3.0 mg per day None 8 – 60 days
2016 [52] diagnosis; Previously failed multiple
study
standardised lifestyle interventions
Naltrexone-bupropion
Male; Age 18–65 yrs.; Schizophrenia
Naltrexone and bupropion combination diagnosis; Stable antipsychotic treatment;
Lyu et al., 2018
RCT China Inpatient (naltrexone 25 mg per day, bupropion Placebo 11 10 Smoker ≥10 cigarettes/day; BMI >28 kg/ 24 weeks
[61]
300 mg per day) m2 or > 27 kg/m2 w/ dyslipidemia or waist
circumference > 90 cm
Age 18–75 yrs., Schizophrenia/
Schizoaffective disorder/ mood stabilised
Yale University, Bupropion extended release (ER) and Bupropion ER and
bipolar disorder, BMI ≥28 kg/m2, Stable
(unpublished, naltrexone combination (bupropion ER placebo combination
Phase 2, OLT USA Community 3 2 antipsychotic dose, Stable symptoms >2 16 weeks
last updated up to 450 mg per day, naltrexone 37 mg (Bupropion ER up to
months, >7% total body weight increase
2019) [54] per day) 450 mg per day)
with antipsychotic use within 1st year of
illness

General Hospital Psychiatry 78 (2022) 58–67

Semaglutide
Prasad et al., 2022 Retrospective, Patients with AIWG; Non-response (<5%
(abstract only) observational Canada Unspecified Semaglutide up to 2 mg per week None 12 – weight loss) to maximally tolerated 6 months
[53] study metformin (1–2 g per day) after 3 months
Multiple medications
Liraglutide 0.6–3.0 mg per day, or
Age ≥ 18 yrs.; diagnosed mental illness; 1+
topiramate 12.5–100 mg per day, or
Prospective, psychotropic medication; BMI ≥28 kg/m2;
Tham et al., 2021 naltrexone-bupropion (naltrexone
observational Australia Community None 244 – 2+ cardiometabolic risk factors 52 weeks
[55] 12.5–37.5 mg and bupropion 75–300 mg
study (hypertension, abdominal obesity, insulin
per day), or combination of the above,
resistance, lipid profile abnormalities)
+/− phentermine 15 mg per day
K. Lee et al. General Hospital Psychiatry 78 (2022) 58–67

Table 2
Study results and conclusions.
Study Intervention Weight-loss related parameter Result p-Value Conclusion

Liraglutide
Mean difference in weight change
− 6.0 (− 10.8 to
between arms at endpoint, kg (95% 0.015
− 1.36)
CI)
Mean difference in weight change
− 4.6 (− 8.4 to
between arms at endpoint, % (95% 0.021
− 0.7)
CI)
Mean difference in BMI change
− 1.76 (− 3.31 to
between arms at endpoint, kg/m2 0.028
− 0.20)
Whicher et al., Liraglutide up to 3.0 mg per day vs (95%CI) Liraglutide was effective in treating
2021 [56] placebo Mean difference in waist obesity in OSP
− 7.2 (− 12.3 to
circumference change between arms 0.008
− 2.1)
at endpoint, cm (95%CI)
Mean difference in HbA1c change
− 3.6 (− 5.9 to
between arms at endpoint, mmol/ 0.003
− 1.3)
mol (95%CI)
Mean difference in fasting plasma
− 0.6 (− 1.3 to
glucose change at endpoint, mmol/L 0.081
0.1)
(95%CI)
Estimated difference in weight
− 5.3 (− 7.0 to
change between arms at endpoint, <0.001
− 0.3.7)
kg (95%CI)
Estimated difference in BMI change
− 1.8 (− 2.4 to
between arms at endpoint, kg/m2 <0.001
− 1.3)
(95%CI)
Estimated difference in waist
− 4.1 (− 6.0 to
circumference change between arms <0.001
− 2.3)
at endpoint, cm (95%CI) Liraglutide was effective in treating OSP
Larsen et al., 2017 Liraglutide 1.2–1.8 mg per day vs
Estimated difference in prediabetes in concomitant olanzapine or clozapine
[57] placebo
status between arms at endpoint, % 9.2 (2.6 to 32.7) <0.001 in prediabetes
(95%CI)
Estimated difference in HbA1c
− 0.2 (− 0.3 to
change between arms at endpoint, % <0.001
0.1)
(95%CI)
Estimated difference in fasting
plasma glucose level change 0.90 (0.88 to
<0.001
between arms at endpoint, relative 0.95)
change (95%CI)
Mean body weight change at − 4.3 (− 6.6 to
<0.001
endpoint, kg (95%CI) − 2.0)
110.17 ± 15.78
Mean waist circumference change at
from 103.65 ± 0.005
endpoint, cm ± SD
13.03
30.99 ± 4.42
Mean BMI change at endpoint, kg/
from 32.14 ± 0.002
Lee SE et al., 2021 m2 ± SD Liraglutide was effective in reducing
Liraglutide 3.0 mg per day 3.55
[58] body weight in AIWG
97.36 ± 11.56
Mean plasma glucose level change
from 108.63 ± 0.013
at endpoint, mg/dL ± SD
15.99
Mean HbA1c change at endpoint, % 5.40 ± 0.25 from
0.056
± SD 5.61 ± 0.38
Proportion ≥ 5% weight loss at
50 –
endpoint, %
Weight loss in psychiatric disorder Patients with schizophrenia, bipolar
Liraglutide 0.6–3.0 mg per day in 3.7 ± 2.7
group at 1 month, kg ± SD disorder, or major depressive disorder
patients with psychiatric disorders
Maccora et al., Weight loss in psychiatric disorder were successful in reducing weight with
(schizophrenia, bipolar disorder, major 5.9 ± 5.2 0.04
2020 [59] group at 3 months, kg ± SD liraglutide, and this response did not
depressive disorder) vs binge eating
Weight loss in psychiatric disorder differ when compared to the
disorder vs no mental illness 7.9 ± 6.4
group at 6 months, kg ± SD comparison groups
Proportion > 5% weight loss in Patients with schizophrenia, bipolar
psychiatric disorder group at 3 37 – disorder, or major depressive disorder
Maccora et al., Severe psychiatric disorder
months, % were successful in reducing weight with
2018 (abstract (schizophrenia, bipolar disorder, major
Proportion > 5% weight loss in liraglutide, and this response did not
only) [51] depressive disorder)
psychiatric disorder group at 6 57 – differ when compared to the
months, % comparison groups
Estimated difference in weight
change between arms at follow-up
1.5 (− 1.8 to 4.7) 0.38
compared to end of original RCT, kg
Weight reduction following treatment
(95% CI)
Svensson et al., Previous treatment with liraglutide with liraglutide was partially sustained
Estimated difference in BMI change
2019 [60] 1.2–1.8 mg per day vs placebo on follow-up after treatment was
between arms at follow-up
0.2 (− 1.0 to 1.4) 0.73 discontinued
compared to end of original RCT,
kg/m2 (95% CI)
1.2 (− 1.8 to 3.2) 0.43
(continued on next page)

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K. Lee et al. General Hospital Psychiatry 78 (2022) 58–67

Table 2 (continued )
Study Intervention Weight-loss related parameter Result p-Value Conclusion

Estimated difference in waist

circumference change between arms
at follow-up compared to end of
original RCT compared to end of
original RCT, cm (95% CI)
Estimated difference in
development to T2DM between 3.31 (1.05 to
0.06
arms at follow-up compared to end 10.43)
of original RCT, odds ratio (95% CI)
Estimated difference in HbA1c
change between arms at follow-up
3.6 (1.5 to 5.6) 0.0005
compared to end of original RCT,
mmol/mol (95% CI)
Estimated difference in fasting
plasma glucose level change
1.13 (1.06 to
between arms at follow-up 0.0005
1.21)
compared to end of original RCT,
relative change (95% CI)
Estimated difference in weight
− 3.81 (− 7.3 to
change between arms at follow-up 0.04
− 0.2)
compared to baseline, kg (95% CI)
Estimated difference in BMI change
between arms at follow-up − 1.6 (− 2.8 to
0.02
compared to baseline, kg/m2 (95% − 0.3)
CI)
Estimated difference in waist
circumference change between arms
− 2.7 (− 6.0 to
at follow-up compared to end of 0.11
0.6)
original RCT compared to baseline
RCT, cm (95% CI)
Estimated difference in
development to T2DM between 2.76 (0.93 to
0.07
arms at follow-up compared to 8.21)
baseline, odds ratio (95% CI)
Estimated difference in HbA1c
change between arms at follow-up 1.3 (− 0.5 to 3.2) 0.16
compared to baseline, % (95% CI)
Estimated difference in fasting
plasma glucose level change
1.03 (0.79 to
between arms at follow-up 0.14
1.03)
compared to baseline, relative
change (95% CI)
Mean weight change after 30 days,
3.75 (5.075) –
Di Volo et al., 2016 kg (% body weight) Liraglutide was useful to treat obesity
Liraglutide 0.6–3.0 mg per day
[52] Mean weight change after 60 days, for people with mental illness
6 (5.933) –
kg (% body weight)
Naltrexone-bupropion
Treatment: 0.2
Body weight change between arms ± 5.3
0.779
at endpoint, kg ± SD Placebo: − 0.9 ±
3.1
Treatment: 0.0
BMI change between arms at ± 1.9
0.314
endpoint, kg/m2 ± SD Placebo: − 0.3 ±
Naltrexone and bupropion combination No weight loss was observed with
Lyu et al., 2018 1.1
(naltrexone 25 mg per day, bupropion naltrexone and bupropion combination
[61] Treatment: 0.5
300 mg per day) vs placebo in patients with schizophrenia
Fasting glucose change between ± 1.5
0.264
arms at endpoint, mmol/L ± SD Placebo: 1.0 ±
1.6
Treatment: 0.05
HbA1c change between arms at ± 0.6
0.385
endpoint, % ± SD Placebo: 0.4 ±
1.1
Treatment:
37.33 (5.81),
from 39.06
BMI at endpoint, kg/m2 (SD) (6.03) –
Bupropion extended release (ER) and
Yale University, Control: 30.65
naltrexone combination (bupropion ER
(unpublished, last (3.88), from Trial not completed by original
up to 450 mg per day, naltrexone 37 mg
updated 2019) 29.55 (0.07) researchers due to funding
per day) vs bupropion ER and placebo
[54] Treatment:
(bupropion ER up to 450 mg per day)
113.60 (11.24),
Weight at endpoint, kg (SD) from 118.78 –
(11.17)
Control: 91.25
(continued on next page)

63
K. Lee et al. General Hospital Psychiatry 78 (2022) 58–67

Table 2 (continued )
Study Intervention Weight-loss related parameter Result p-Value Conclusion

(27.64), from
87.25 (15.48)
Semaglutide
Prasad et al., 2022 Weight change at 3 months, kg − 4.88 ± 3.2 <0.05 Semaglutide may be effective in
(abstract only) Semaglutide up to 2 mg per week reducing AIWG in patients not
Weight change at 6 months, kg − 5.53 ± 5.58 0.02
[53] responding to metformin
Multiple medications
Weight change from baseline at
− 11.79 ± 6.13 <0.001
endpoint, kg
Liraglutide 0.6–3.0 mg per day, or Weight change from baseline at
12.3% <0.001
topiramate 12.5–100 mg per day, or endpoint, %
Tham et al., 2021 naltrexone-bupropion (naltrexone BMI change from baseline at WLM was effective to treat obesity for
− 3.88 ± 2.10 <0.001
[55] 12.5–37.5 mg and bupropion 75–300 mg endpoint, kg/m2 people with mental illness
per day), or combination of the above, Waist circumference change from
− 12.56 ± 6.35 <0.001
+/− phentermine 15 mg per day baseline at endpoint, cm
HbA1c change from baseline at
− 1.26 ± 0.56 <0.001
endpoint, %

Table 3
Summary of findings for pharmacological treatment with liraglutide compared with placebo.
Patients Individuals with AIWG or OSP

Intervention Liraglutide
Comparison Placebo
Number of participants 131 (62 in intervention group, 69 in placebo group)
Number of RCTs 2
Mean difference (95% GRADE
Outcomes Z P Comments
CI) assessment
− 5.29 (− 6.86 to ⊕ ⊕ ⊕⊕
Body weight, kg 6.58 <0.00001
− 3.71) High
⊕ ⊕ ⊕⊕
BMI, kg/m2 − 1.69 (− 2.99 to − 0.4) 2.56 0.01
High
⊕ ⊕ ⊕⊝ Graded down due to inconsistency in results (mean of one RCT falling outside
Waist circumference, cm − 4.8 (− 6.49 to − 3.11) 5.56 <0.00001
Medium 95% CI of total).
− 3.12 (− 4.13 to ⊕ ⊕ ⊕⊕
HbA1c, mmol/mol 6.10 <0.00001
− 2.12) High
Systolic blood pressure, mm ⊕ ⊕ ⊕⊝ Graded down due to inconsistency in results (mean of one RCT falling outside
− 1.38 (− 6.08 to 3.32) 0.58 0.56
Hg Medium 95% CI of total).
− 0.51 (− 0.71 to ⊕ ⊕ ⊕⊝ Graded down due to inconsistency in results (mean of one RCT falling outside
Total cholesterol, mmol/L 4.96 <0.00001
− 0.31) Medium 95% CI of total).
− 0.33 (− 0.48 to ⊕ ⊕ ⊕⊕
LDL, mmol/L 4.14 <0.00001
− 0.17) High

4.3. Naltrexone-bupropion
Lyu et al. [61] was notable as it was the only identified study that
took place in an inpatient setting and that recruited male subjects
exclusively. It also administered naltrexone-bupropion separately rather
than its combined preparation, though doses used were within the
treatment range of the combined preparation [62]. It had two objectives
– namely to investigate the efficacy of naltrexone-bupropion to promote
weight loss as well as smoking cessation amongst patients with schizo­
phrenia. The trial however found no statistically significant difference in
the change in body weight, BMI, fasting glucose, HbA1c, triglycerides,
high-density lipids, and LDL (p-value = .264 to 0.900).
An unpublished OLT by Yale University [54] yielded similar results.
Much like Lyu et al. [61], naltrexone and bupropion were administered
separately rather than in its combined preparation. It had originally
intended to recruit 40 subjects but was discontinued after having recruit
five (3 in naltrexone-bupropion group, 2 in placebo-bupropion group).
Consequently, further analysis had not been conducted. For complete­
ness, we had undertaken analysis of the data and found no statistically
significant changes in weight, BMI, and waist circumference, as included
in Appendix C.
These findings however differ from those by Tham et al. [55]. In the
naltrexone-bupropion subset of their subjects (n = 22), an average
reduction in weight of 10.9 ± 5.2% (p-value <.001) and waist
circumference of 7.9 ± 2.2 (p-value <.001) was observed after 52 weeks
of treatment.
4.4. Phentermine
Although not evaluated as monotherapy, Tham et al. [55] found that
phentermine combinations (liraglutide + phentermine, topiramate +
phentermine, liraglutide + topiramate + phentermine) collectively
showed the largest reduction in weight (15.8 ± 3.3%) and waist
circumference (16.4 ± 6.1 cm) when compared to the groups without
phentermine. However, no p-values were provided to determine if these
results were significant.
4.5. Semaglutide
Prasad et al. [53] found that their cohort – patients with AIWG who
did not initially respond to metformin – showed weight loss at three and
six months after being changed to semaglutide. However, the study
neither quantified how many responded to semaglutide nor explain the
meaning behind their results (i.e. if the figures represented means or
medians, standard deviations or variances, etc).

64
K. Lee et al.
5. Discussion
5.1. Current state and interpretation of the evidence
Except for liraglutide, we found limited human studies published on
treating AIWG or OSP with licensed WLM. This includes an absence of
new data on orlistat and an absence data for setmelanotide. The lack of
the latter may be explainable by its relatively recent authorisation for
weight management. The lack of human data contrasts with the general
population where multiple large RCTs for naltrexone-bupropion, phen­
termine-topiramate, and liraglutide have been published from the
period reviewed [63].
The RCTs we did find also typically involved fewer subjects (21 to 97
subjects vs 45 to 8910 subjects) and shorter durations (16 weeks to 6
months vs 20 to 121 weeks) than trials investigating the general popu­
lation [63]. This however may be unsurprising due the subject's nar­
rower focus and comparatively smaller target population, leading to
trials being smaller scale.
The evidence supporting naltrexone-bupropion was mixed. Only one
RCT was published, which showed no statistically significant results on
weight loss. This however contrasts with the observational study by
Tham et al. [55]. Lyu et al. [61] postulated their trial's small size (n =
31) resulted in it lacking the power to detect an effect. It is also possible
that the concurrent assessment of naltrexone-bupropion's smoking-
cessating properties in the RCT acted as a confounder as smoking
cessation can be associated with subsequent weight gain [64]. Similarly,
the inpatient setting and exclusion of females may also have been
confounders.
Likewise, the evidence around semaglutide was limited. Although
Prasad et al. [53] reported efficacy, its small size and presentation of
results made the findings difficult to interpret.
More evidence was found supporting liraglutide use. This includes
two RCTs, which had been a specific gap previously identified in the
literature [33]. Methodological heterogeneity however resulted in our
adopting a random effects model for meta-analysis, leading to wider
confidence intervals. Nonetheless, statistically significant reduction in
weight, BMI, and waist circumference – amongst other cardiometabolic
risk factors – were found as previously described. Particularly inter­
esting was how the results were comparable – and possibly superior – to
off-label metformin in terms of mean weight (− 5.29 kg (95% CI: − 6.86
to − 3.71) vs − 3.24 kg (95% CI: − 4.72 to − 1.76)) and BMI (− 1.69 kg/m2
(95% CI: − 2.99 to − 0.40) vs − 1.11 kg/m2 (95% CI: − 1.62 to 0.60)
change [65]. Additionally, the lack of difference in response to liraglu­
tide between the mental illness and non-mental-illness groups in Mac­
cora et al. [59] indicated that general population data for liraglutide
may also be applicable to people with mental illness.
Overall, these findings provide evidence to support using liraglutide
for AIWG and OSP treatment. This is meaningful as it in turn provides an
evidence base to better align their management by psychiatry with the
practices recommended by endocrinologists, cardiologists, and national
guidelines [35–37] when managing obesity; all of which favour licensed
WLMs – including liraglutide specifically – over off-label options.
5.2. Direction for future research
There remains a continued literature gap around using naltrexone-
bupropion and phentermine-topiramate, particularly in comparison to
the general population. Further research on these treatments so that
recommendations – be it for or against – can be made, particularly as
they are licensed medications for a condition with few available licensed
pharmacological options.
Further research on liraglutide would also be beneficial to better
evaluate replicability of results. This should ideally take a more uniform
protocol, ideally with involving larger numbers, over a longer duration,
and standardised means of measuring side effects and psychiatric
symptoms.
65
General Hospital Psychiatry 78 (2022) 58–67
It should also be recognised that liraglutide trial data is currently
only from RCTs conducted using predominantly White European par­
ticipants [56,57]; meaning further research in other demographic
groups may be beneficial to ascertain generalisability to these groups.
Other domains worth exploring include cost-benefit, tolerability, and
practicality of administering liraglutide. Liraglutide is currently more
expensive compared to presently used oral treatments such as orlistat
and off-label metformin, both of which are available in generic form. Its
higher price may consequently cause it to be financially prohibitive for
widescale use and/or otherwise limit access.
Similarly, factors like negative symptoms, lack of routine, and poor
concordance may cause daily subcutaneous injections of liraglutide to
be impractical. In that regard, the recently approved semaglutide may
be a research avenue of added interest for psychiatry. Unlike liraglutide,
it is a once-weekly injection comparable to some antipsychotic depots
[41]. It may thus be more easily integrated into existing service struc­
tures (e.g. depot clinics) and treatment plans. Particularly promising is
that other glucagon-like-peptide-1 receptor agonists (e.g. off-label exe­
natide) have also shown to be effective for AIWG [56,57,66,67]. It is
possible that other glucagon-like-peptide-1 receptor agonists could
provide an avenue of research for future treatment options, especially if
they receive authorisation as WLMs for nondiabetics.
6. Conclusion
Our review found that research was most available for liraglutide
compared to other licensed WLMs. Due to either lack or conflicting re­
sults for naltrexone-bupropion, phentermine-topiramate, setmelanotide,
and semaglutide, we are at this stage unable to make any recommen­
dations around their use in AIWG and OSP. Data was however stronger
for using liraglutide, which was found to reduce weight, BMI, waist
circumference, cholesterol, and LDLs on meta-analysis of two RCTs. This
is important as it is licensed for weight management and in line with
obesity management outside of psychiatry, in contrast to the off-label
medications currently used in psychiatry. Consequently, liraglutide –
as a licensed option – should be included when discussing pharmaco­
logical treatment of AIWG and OSP, and where an off-label treatment
was instead chosen, the rationale (e.g. costs, side effects, preference)
should be documented in the clinical notes in line with General Medical
Council guidelines around off-label prescribing.
Funding
This review was not funded. None of the authors received funding for
the preparation or production of this review.
Declaration of Competing Interest
There were no conflicts of interest for any of the authors involved in
the review.
Data availability
This is a systematic review. Data derived from results of included
studies. No access to raw data.
Acknowledgement
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.genhosppsych.2022.07.006.
K. Lee et al. General Hospital Psychiatry 78 (2022) 58–67

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