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Adjunctive α-lipoic acid reduces weight gain compared with placebo at 12

weeks in schizophrenic patients treated with atypical antipsychotics: a
double-blind randomized placebo-con...

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DOI: 10.1097/YIC.0000000000000132

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Adjunctive α-lipoic acid reduces weight gain compared with
placebo at 12 weeks in schizophrenic patients treated with
atypical antipsychotics: a double-blind randomized
placebo-controlled study
Nam Wook Kima,b, Yul-Mai Songe,f, Eosu Kimb,c, Hyun-Sang Chob,c,
Keun-Ah Cheona,b, Su Jin Kimg and Jin Young Parkb,d
α-Lipoic acid (ALA) has been reported to be effective in
reducing body weight in rodents and obese patients. Our
previous open trial showed that ALA may play a role in
reducing weight gain in patients with schizophrenia on
atypical antipsychotics. The present study evaluated the
efficacy of ALA in reducing weight and BMI in patients with
schizophrenia who had experienced significant weight gain
since taking atypical antipsychotics. In a 12-week, double-
blind randomized placebo-controlled study, 22 overweight
and clinically stable patients with schizophrenia were
randomly assigned to receive ALA or placebo. ALA was
administered at 600–1800 mg, as tolerated. Weight, BMI,
abdomen fat area measured by computed tomography, and
metabolic values were determined. Adverse effects were
also assessed to examine safety. Overall, 15 patients
completed 12 weeks of treatment. There was significant
weight loss and decreased visceral fat levels in the ALA
group compared with the placebo group. There were no
instances of psychopathologic aggravation or severe ALA-
associated adverse effects. ALA was effective in reducing
weight and abdominal obesity in patients with
Introduction
Weight gain and the related development of metabolic
syndrome are considered severe adverse effects of aty-
pical antipsychotics used to treat schizophrenia. These
adverse effects increase mortality and morbidity asso-
ciated with cardiovascular disease and diabetes (Osby
et al., 2000; Fontaine et al., 2001; Henderson et al., 2005;
Correll et al., 2009; Papanastasiou, 2012) and reduce drug
compliance, resulting in poor prognosis (Perkins, 2002;
Allison et al., 2003). Therefore, the prevention or the
management of atypical antipsychotic-induced weight
gain and metabolic abnormalities is a very important
issue.
Lifestyle modifications, such as regular exercise and diet,
have been shown to be effective and safe for reducing
increased weight caused by atypical antipsychotics (Wu
et al., 2008) when participants understand the program and
are motivated to modify their lifestyles. However, negative
symptoms of schizophrenia, such as avolition, anhedonia,
and social withdrawal, can make motivation difficult.
0268-1315 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Original article 1
schizophrenia who had experienced significant weight gain
since beginning an atypical antipsychotic regimen.
Moreover, ALA was well tolerated throughout this study. ALA
might play an important role as an adjunctive treatment in
decreasing obesity in patients who take atypical
antipsychotics. Int Clin Psychopharmacol 00:000–000
Copyright © 2016 Wolters Kluwer Health, Inc. All rights
reserved.
International Clinical Psychopharmacology 2016, 00:000–000
Keywords: α-lipoic acid, atypical antipsychotics, schizophrenia, visceral fat,
weight gain
a
Department of Psychiatry, Division of Child and Adolescent Psychiatry, bInstitute
of Behavioral Science in Medicine, cDepartment of Psychiatry, Severance
Hospital, dDepartment of Psychiatry, Gangnam Severance Hospital, Yonsei
University College of Medicine, eYonsei University College of Nursing,
f
Department of Education, National Center for Mental Health and gDepartment of
Family Medicine, Daehang Hospital, Seoul, South Korea
Correspondence to Jin Young Park, MD, PhD, Department of Psychiatry, College
of Medicine, Gangnam Severance Hospital, Yonsei University, 211 Eonju-ro,
Gangnam-gu, Seoul 06273, Republic of Korea
Tel: + 82 220 193 341; fax: + 82 234 624 304; e-mail: empathy@yuhs.ac
Received 9 December 2015 Accepted 18 April 2016
Several pharmacological management regimens have
been tested for their ability to antipsychotic-induced
weight gain, including orlistat, sibutramine, metformin,
and topiramate. Some of them have been suggested to be
effective (Werneke et al., 2002); however, potential
adverse effects of the drugs limit their clinical use and
require off-label prescriptions. Sibutramine, for example,
may increase the risk of serotonin syndrome in patients
taking serotonergic agents (Werneke et al., 2002). Such
neurotransmitter-modulating antiobesity agents may
have unpredictable, psychotomimetic effects (Kim et al.,
2008). Without a fat-restricted diet, orlistat may induce
flatulence or fecal incontinence (Werneke et al., 2002).
Moreover, their mechanisms are not specific to atypical
antipsychotic-induced hyperappetite (Kim et al., 2008).
Associations between 5′-adenosine monophosphate-
activated protein kinase (AMPK) and atypical
antipsychotic-induced weight gain have been reported
recently. Atypical antipsychotics were found to activate
AMPK in the rodent hypothalamus (Kim et al., 2007;
DOI: 10.1097/YIC.0000000000000132
 2 International Clinical Psychopharmacology 2016, Vol 00 No 00
Souza et al., 2012). AMPK plays a central role in energy
homeostasis complex signals of adipokines in peripheral
tissues and the hypothalamus (Kim et al., 2004; Kahn
et al., 2005). In the periphery, AMPK activation is asso-
ciated with decreased lipid formation and gluconeogen-
esis. Reciprocally, hypothalamic AMPK activation is
associated with increased food intake and weight gain.
Hypothalamic AMPK activity is suppressed by anorexi-
genic adipokines, such as leptin, and augmented by the
orexigenic agouti-related protein (Minokoshi et al., 2004;
Lee et al., 2005; Kola et al., 2006).
α-Lipoic acid (ALA) is an essential cofactor of mito-
chondrial respiratory enzymes (Packer et al., 1995) and
was shown to act as a powerful antioxidant that caused
weight loss in rodents (Kim et al., 2004; Seo et al., 2012)
and obese patients (Carbonelli et al., 2010; Koh et al.,
2011). The antiobesity effect of ALA is believed to be
mediated by suppressing hypothalamic AMPK activity
(Kim et al., 2004). Importantly, ALA can counteract the
weight gain mechanisms underlying atypical anti-
psychotics (Kim et al., 2007).
ALA is used widely as a supplement for antioxidants,
weight loss, to improve metabolic disturbances such as
lowering blood sugar, and so on. Moreover, it has been
approved for diabetic polyneuropathy (Duby et al., 2004;
Ziegler et al., 2006) in countries such as Germany and
Korea (Hahm et al., 2004), with ongoing multicenter trials
in Europe and North America, and is considered to be
safe. Medicinal use of ALA has not yet been approved by
the USA-FDA; it has been used as a herbal supplement
(Ziegler, 2004; Yadav et al., 2005; Ziegler et al., 2006; Koh
et al., 2011). It is available as an over-the-counter drug in
several countries, such as the USA, Germany, and Japan,
and can easily be purchased online (Rathmann et al.,
1998; Wold et al., 2005; Lee et al., 2006; Singh and Jialal,
2008). In this study, we prescribed ALA for weight loss
and to improve metabolic disturbances for schizophrenic
patients who take atypical antipsychotics. We previously
carried out a preliminary study of the efficacy of ALA in
reducing weight in a small number of patients with
schizophrenia on atypical antipsychotics in an open trial.
We observed significant weight loss and improved
metabolic profiles with a fixed ALA dose (1200 mg) over
12 weeks (Kim et al., 2008).
Here, we report the results of a pilot study to investigate
the efficacy and safety of ALA on weight and BMI in
schizophrenic patients who had gained weight since
beginning an atypical antipsychotic regimen. We carried
out a randomized, double-blind, placebo-control study to
investigate whether ALA use resulted in significant
weight loss or fat distribution changes compared with the
placebo control group. In addition, taking both the effi-
cacy and side effects of ALA into consideration, dosages
were adjusted for each patient (≤ 1800 mg).
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Methods
Participants
Chronic schizophrenic patients in the rehabilitation ward
of Gongju National Hospital participated. All participants
underwent a diagnostic evaluation using the Structured
Clinical Interview for the Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. (DSM-IV). They
had similar symptoms and levels of function as patients
treated in the outpatient clinic. These patients were
receiving medication doses for maintenance treatment;
the types and dosages of psychotropic medications were
very stable. The patients in the rehabilitation ward were
provided with various rehabilitation programs focused on
improving interpersonal relationships and daily life skills.
In the rehabilitation wards, patients could come and go
freely from 9 a.m. to 6 p.m., and the maximum hospita-
lization period was 1 year. The patients had similar life
patterns and diet plans.
The inclusion criteria were significant weight gain after
taking atypical antipsychotics (more than 10% weight
gain or current BMI ≥ 23 kg/m2), a regimen of one or two
atypical antipsychotics, no change in antipsychotic agents
during the study, and no change in dosage for 1 month
before study entry, a willingness to lose weight, and
currently not participating in weight-reduction programs.
The exclusion criteria were outpatient status, history of
medical illnesses (diabetes mellitus; an uncorrected
thyroid disorder; cardiovascular, cerebrovascular, liver, or
renal disease; or any serious and unstable medical ill-
ness), a family history of obesity, pregnancy, and the use
of any medication for weight reduction.
This study was carried out in accordance with the prin-
ciples described in the World Medical Association
declaration of Helsinki (1997). The study protocol and
the off-label use of ALA were approved by the Korean
FDA and the institutional review board of the Gongju
National Hospital. All participants provided written
informed consent.
Study design
A double-blind, placebo-controlled, randomized design
was used. Of the 26 patients who were assessed for
eligibility, 22 patients participated in the study. They
were assigned randomly to receive ALA or placebo for up
to 12 weeks. The ALA group included 10 participants
and the placebo group included 12 participants (Fig. 1).
In the study, a capsule containing 200 mg ALA or pla-
cebo was administered. ALA and placebo pills, which
were manufactured by the same company (Ildong
Pharmaceutical Company, Seoul, South Korea), appeared
identical and were served 30 min before each meal.
Neither research staff nor participants could distinguish
between the ALA and placebo pills. In the first week,
study medication was administered as 1200 mg/day of
ALA in divided doses (two capsules three times, for a
 ALA modulates atypical antipsychotic-induced weight gain Kim et al. 3

Fig. 1

26 assessed for eligibility

4 excluded:
declined to participate

22 randomized

ALA group Placebo group

(n = 10) (n = 12)

Drop out (n = 2)
-Exacerbation of symptom
-Dermatologic symptom

Referred for the first Referred for the first

follow-up (n = 8) follow-up (n = 12)

Drop out (n = 2)
Drop out due to discharge
-Newly diagnosed DM
(n = 1)
-Declined by patient

Referred for the second Referred for the second

follow-up (n = 7) follow-up (n = 10)

Drop out
due to discharge (n = 2)

Referred for the third Referred for the third

follow-up (n = 7) follow-up (n = 8)

Study flowchart. ALA, α-lipoic acid.

total of six capsules per day). If the effect was not suffi-
cient (weight loss < 1 kg/4 weeks), the study medication
was then increased to 1800 mg/day (three capsules three
times, total nine capsules per day). The maximum total
daily dose of ALA was 1800 mg/day. The mean dosages
of study medications were 1620.0 ± 289.83 mg in the ALA
group and 1650.0 ± 271.36 mg in the placebo group at
12 weeks (P = 0.805). We assessed the side effects of the
study medication in the following week and if well tol-
erated, the dosage was maintained. If the study drug was
considered to be associated with severe side effects, it
was decreased by 600 mg (Fig. 2).
Mood stabilizer administration was allowed if dosages
were unchanged for at least 1 month before entry. The
administration of concomitant medications, such as
anticholinergic agents or benzodiazepines, was allowed
on an as-needed basis. Participants were not placed on a
special diet or physical exercise program for weight
reduction.
Fifteen of 22 participants completed the 12-week study,
meaning that seven participants dropped out. Three
participants of the ALA group stopped their participation
because of exacerbation of pre-existing psychotic symp-
toms, dermatologic adverse effects, and discharges. Four
participants of the placebo group dropped out because of
diabetes, discharges, and patients’ declining to continue
participation (Fig. 1). We used last observation carried
forward to take into consideration the dropout rate and
the small sample size.
Outcome measures
Between-group changes in body weight and BMI over
12 weeks were considered the primary outcome. We
measured body weight and BMI after a fast from mid-
night and voiding at 9 a.m. at baseline and weeks 4, 8,
and 12. Glucose profile, lipid profile, and abdominal fat
area by fat computed tomography scan were measured at
baseline and 12 weeks. The glucose profile included
fasting glucose, insulin, glycated hemoglobin (HbA1c),
fasting total cholesterol, triglycerides, and free fatty acids.
Clinical assessment instruments included the Positive
and Negative Symptoms Scale (Kay et al., 1987), the
Hamilton Anxiety Scale (Hamilton, 1959), the
Montgomery–Åsberg Depression Rating Scale
(Montgomery et al., 1985), Clinical Global Impression
(both severity score and improvement scores) (Guy,
1976), the 36-Item Short Form (Hays et al., 1993), effi-
cacy of eating behavior and weight control (EEW) score

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 4 International Clinical Psychopharmacology 2016, Vol 00 No 00

Fig. 2

Dose up guideline Dose down guideline

YES
Weight loss ≥ 1 kg/4 weeks Maintain dose NO
If ALA adverse effects Maintain dose or consider increasing dose
are over moderate (reference: dose-up guideline)
severity
NO

YES
YES
Guideline for
Adverse effects of ALA Decrease dose 600 mg from previous dose
Adverse effects management
Severity: Moderate or Severe conservative management for adverse effects
severe
NO

Moderate
Add 600 mg to previous dose

Maintain the previous dose

Conservative management for adverse effects
Evaluation adverse effects after
NO
1 week Reevaluation adverse
effects after 2 weeks

YES
YES Decrease
Adverse effects of ALA Decreasing to previous dose Current dose > 600 mg
600 mg

NO
Maintain dose
Fix the dose until research Discontinuation
Maintain the increased dose end-point

Dosage adjustment guideline. ALA, α-lipoic acid.

(Lee, 1993), and the Rosenberg Self-Esteem Scale Results

(Rosenberg, 1965).
For the participants’ safety, side effects of the study
medications were monitored closely by self-report every
2 weeks, and laboratory blood tests were obtained at
screening, baseline, and weeks 4, 8, and 12.
Statistical analysis
Rank-based nonparametric longitudinal analysis was
used to compare changes in body weight and BMI
between groups. In the analysis, intent-to-treat analysis
included all randomization participants who received at
least one dose of study medication and for imputing the
missing data, the last observation carried forward method
was used.
We used Mann–Whitney U-tests to compare the clinical
and demographic characteristics between groups at
baseline and frequencies between groups.
Statistical significance was defined at a level of P-value
less than 0.05 and P-value less than 0.10 was considered a
statistical trend toward change. Statistical package for
social sciences v12.0 (SPSS Inc., Chicago, Illinois, USA)
and R (http://cran.r-project.org/web/packages/nparLD) were
used for the statistical analyses.
Baseline clinical characteristics
There were no significant differences between the two
groups in clinical and demographic characteristics,
including sex, age, dose equivalent, education year,
duration of illness, duration of antipsychotic use, and
duration of current atypical antipsychotic use. There
were no significant differences in anthropometric mea-
sures (height, weight, waist-to-hip ratio) glucose profile
(fasting glucose, insulin, and HbA1c), lipid profile (free
fatty acid, total cholesterol, and triglyceride), or the scores
of several psychiatric scales (Table 1).
Anthropometric measures
ALA had a significant effect on weight loss compared
with placebo. Nonparametric longitudinal analysis
showed a statistically significant time–group interaction
for weight (P = 0.023) and a trend for BMI (P = 0.065).
The mean (SD) weight loss at the 12-week endpoint was
1.34 (1.56) kg for the ALA group. However, the mean
weight increased by 0.74 (1.87) kg in the placebo group
over the same period (Fig. 3). On comparing body weight
changes over 12 weeks between the groups, there was a
significant change in body weight at week 12 (Table 2).
Although the patients in the placebo group continued to

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 ALA modulates atypical antipsychotic-induced weight gain Kim et al. 5

Table 1 Baseline clinical characteristics

Statistical comparison

ALA (N = 10) Placebo (N = 12) Z a

Pa
Demographic characteristics
Sex : male (female) 4 (6) 7 (5)
Age (mean ± SD) (female) 40.50 ± 6.65 40.08 ± 9.14 − 0.264 0.792
Dose equivalent (chlorpromazine, mg/day) 733.33 ± 463.48 1611.11 ± 1468.96 − 1.717 0.086
Education, (mean ± SD) (years) 13.20 ± 1.48 11.83 ± 2.41 − 1.344 0.179
Duration of illness (months) 188.80 ± 96.61 194.25 ± 100.93 − 0.593 0.553
Duration of antipsychotics (months) 188.40 ± 95.70 173.33 ± 76.06 − 0.132 0.895
Duration of AAPs (months) 86.90 ± 44.53 124.67 ± 80.82 − 1.055 0.291
Anthropometric measurements
Body weight (kg) 77.27 ± 14.43 73.14 ± 13.20 − 0.693 0.489
BMI (kg/m2) 29.05 ± 4.44 27.84 ± 4.50 − 0.759 0.448
Waist-to-hip ratio 0.99 ± 0.05 0.98 ± 0.07 − 1.058 0.29
Laboratory data
Fasting glucose measures
Glucose (mg/dl) 84.50 ± 13.53 79.50 ± 12.15 − 1.026 0.305
Insulin (µIU/ml) 9.66 ± 5.15 11.60 ± 8.92 − 0.066 0.947
HbA1c (%) 6.06 ± 0.56 5.93 ± 0.75 − 0.729 0.466
Fasting lipids
Free fatty acids (µEq/l) 577.80 ± 308.78 452.92 ± 243.95 − 1.055 0.291
Total cholesterol (mg/dl) 195.90 ± 33.19 201.42 ± 29.24 − 0.562 0.574
Triglyceride (mg/dl) 180.10 ± 101.21 180.67 ± 91.63 − 0.132 0.895
Fat CT (cm2)
Abdomen fat area 410.52 ± 156.40 402.29 ± 120.14 0 1
Visceral fat area 122.41 ± 39.04 114.23 ± 41.26 − 0.64 0.522
Subcutaneous fat area 288.11 ± 130.78 288.05 ± 87.85 − 0.497 0.619
Psychiatric scale
PANSS, positive 13.00 ± 6.63 14.92 ± 5.45 − 1.059 0.29
PANSS, negative 13.20 ± 6.50 16.67 ± 8.18 − 1.226 0.22
PANSS, general 30.90 ± 5.93 29.17 ± 5.64 − 0.398 0.691
HAM-A 5.20 ± 4.29 3.75 ± 2.83 − 0.729 0.466
MADRS 5.70 ± 3.40 3.92 ± 4.14 − 1.302 0.193
CGI-S 4.20 ± 0.42 4.42 ± 0.90 − 0.808 0.419
CGI-I 4.00 ± 0.00 4.00 ± 0.00 0 1
SF-36 score 60.60 ± 13.69 60.33 ± 16.99 − 0.066 0.947
EEW score 48.50 ± 6.01 48.75 ± 8.97 − 0.066 0.947
RSE score 17.90 ± 5.30 18.75 ± 4.92 − 0.463 0.643

There were no statistical differences in sex, age, dose equivalent, years of education, duration of illness, antipsychotics use, or atypical antipsychotics use.
AAP, atypical antipsychotics; ALA, α-lipoic acid; CGI-I, Clinical Global Impression Improvement Score; CGI-S, Clinical Global Impression Severity Score; CT, computed
tomography; EEW, efficacy of eating behavior and weight control; HAM-A, Hamilton Anxiety Scale; HbA1c, glycated hemoglobin; MADRS, Montgomery–Åsberg
Depression Rating Scale; PANSS, Positive and Negative Symptoms Scale; RSE, Rosenberg self-esteem; SF-36, 36-item short form.
a
Mann–Whitney U-test.

gain weight over 12 weeks, the patients in the ALA group
showed statistically significant weight loss over the trial
period (Fig. 3). Seven of the 10 participants in the ALA
group completed this study. Their mean (SD) weight loss
at the 12-week endpoint was 1.99 (1.42) kg. Eight of 12
participants in the placebo group completed this study
and their mean (SD) weight increased by 1.39 (1.81) kg
over the same period. The BMI changes over 12 weeks
between the two groups are shown in Table 2. Although
the mean BMI of the placebo group increased, that of the
ALA group decreased during the trial. However, the
difference between the two groups was not statistically
significant.
At the initial point of the study, the mean weight of the
ALA group was slightly higher than that of the placebo
group. However, the mean weight and other metabolic
profiles did not statistically differ between the two
groups. The baseline body weight and BMI were
adjusted statistically (Noguchi et al., 2012).
Laboratory measures
Glucose and lipid profile changes are shown in Table 3.
There was a significant difference over 12 weeks
between the groups for visceral fat area (P = 0.021). The
other measures were not statistically different between
the groups over 12 weeks.
Psychiatric measures
There was no significant change in the Positive and
Negative Symptoms Scale score in either group, sug-
gesting that psychotic symptoms were not aggravated
during the trial. Most scores on the other psychiatric
scales did not vary significantly during the trial (Table 4).
However, a significant tendency was observed in the
EEW score (P = 0.070). The EEW is a self-report on
dietary self-efficacy, with a higher score indicating more
self-efficacy for eating behavior.
Adverse effects and safety issues
The frequency of adverse effects was not different
between the two groups (P = 0.439). The most common

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 6 International Clinical Psychopharmacology 2016, Vol 00 No 00

Fig. 3 Table 3 Changes in laboratory data at 12 Weeks

kg ALA (N = 10) Placebo (N = 12) Time × groupa

2 ALA group (LOCF) Fasting glucose measures

Placebo group (LOCF) Glucose (mg/dl) 0.80 ± 7.48 0.08 ± 3.99 0.657
ALA group (observed data) Insulin (µIU/ml) 2.50 ± 3.96 − 1.09 ± 6.51 0.749
HbA1c − 0.13 ± 0.21 0.09 ± 0.37 0.177
1 Placebo group (observed data)
Fasting lipids
Free fatty acids − 14.40 ± 228.66 − 25.50 ± 176.77 0.371
(µEq/l)
0 Total cholesterol 13.90 ± 27.49 − 9.50 ± 30.13 0.086
∗ (mg/dl)
∗
Triglyceride (mg/dl) − 22.90 ± 67.24 1.25 ± 73.28 0.383
Fat CT (cm2)
−1 Abdomen fat area − 9.74 ± 36.34 2.82 ± 11.15 0.427
Visceral fat area+ − 7.98 ± 12.66 1.92 ± 7.72 0.021
Subcutaneous fat − 2.63 ± 34.93 1.80 ± 17.32 0.891
−2 area

ALA, α-lipoic acid; CT, computed tomography; HbA1c, glycated hemoglobin.

Week 0 Week 4 Week 8 Week 12 a
Rank-based nonparametric longitudinal analysis comparing the ALA and placebo
−3 groups.
+
P < 0.05.
Weight changes in the ALA and Placebo groups over 12 weeks. Mean
weight loss at 12 weeks in the ALA group and the placebo group. Data
are reported as mean ± SE.*P < 0.05 versus placebo. ALA, α-lipoic acid; Table 4 Changes in psychiatric scale scores at 12 weeks
LOCF, last observation carried forward.
ALA (N = 10) Placebo (N = 12) Time × groupa
PANSS, positive − 0.22 ± 3.90 − 2.34 ± 7.75 0.358
adverse effect in the ALA group was gastrointestinal PANSS, negative − 2.60 ± 7.17 0.08 ± 8.23 0.469
PANSS, general − 6.01 ± 7.89 − 5.50 ± 10.60 0.185
symptoms, but their frequency was not more than that of HAM-A − 2.60 ± 4.17 − 1.25 ± 2.60 0.600
the placebo groups. No severe side effects were reported MADRS − 2.40 ± 2.84 − 0.58 ± 4.03 0.124
in the trial. Although one case of skin eruption occurred CGI-S − 0.10 ± 0.57 − 0.25 ± 0.87 0.581
CGI-I − 0.30 ± 0.67 − 0.08 ± 0.67 0.448
in the ALA group, the participant stopped the medication SF-36 score 4.40 ± 11.53 3.00 ± 13.25 0.749
immediately (at week 4) and recovered soon thereafter. EEW score 0.50 ± 6.02 − 0.50 ± 6.17 0.070
RSE 1.00 ± 2.00 − 0.33 ± 2.90 0.121
The other dermatologic symptoms were mild (itching
sensation or pre-existing dermatitis) (Table 5). ALA, α-lipoic acid; CGI-I, Clinical Global Impression Improvement Score; CGI-S,
Clinical Global Impression Severity Score; EEW, efficacy of eating behavior and
weight control; HAM-A, Hamilton Anxiety Scale; MADRS, Montgomery–Åsberg
Depression Rating Scale; PANSS, Positive and Negative Symptoms Scale; RSE,
Discussion Rosenberg self esteem; SF-36, 36-item short form.
To our knowledge, this is the first randomized, double- a
Rank-based nonparametric longitudinal analysis in the ALA group compared with
blind, placebo-controlled study to investigate the efficacy the placebo group.

of ALA in patients with schizophrenia with antipsychotic-

induced weight gain.
Atypical antipsychotics are necessary to manage psycho-
tic symptoms in patients with schizophrenia. However,
the severe adverse metabolic effects of weight gain,
glucose intolerance, and hyperlipidemia have been
reported to increase morbidity and mortality in patients
with schizophrenia (Allison and Casey, 2001; Wirshing
et al., 2002; Smith et al., 2005). These harmful adverse
effects offset the beneficial effects of atypical anti-
psychotics in this group of patients. The mechanism of
antipsychotic-induced weight gain is not fully under-
stood, but it may be mediated by the activation of
hypothalamic AMPK (Kim et al., 2007). Several man-
agement regimens have been attempted to ameliorate

Table 2 Changes in body weight and BMI over 12 weeks

Measurement (mean ± SD) Analysisa

Baseline Week 4 Week 8 Week 12 Time × group 4 weeks × group 8 week × group 12 weeks × group
Body weight (kg)+
ALA 77.27 ± 14.43 76.87 ± 14.24 76.10 ± 14.03 75.93 ± 14.53 P = 0.023 0.260 0.121 0.012
Placebo 73.14 ± 13.20 73.03 ± 13.02 73.08 ± 13.17 73.88 ± 13.31
BMI (kg/m2)
ALA 29.05 ± 4.44 28.90 ± 4.55 28.62 ± 4.28 28.53 ± 4.46 P = 0.065
Placebo 27.84 ± 4.50 27.78 ± 4.20 27.71 ± 4.30 27.98 ± 4.37

ALA, α-lipoic acid.

a
Rank-based nonparametric longitudinal analysis comparing the ALA and placebo groups.
+
P < 0.05.

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Table 5 Reported adverse effects
ALA (N = 10) Placebo (N = 12)
Total number 9 12
Gastrointestinal side effects 6 7
Dermatologic side effects 3 3
Hypoglycemic side effects 0 2
ALA, α-lipoic acid.
atypical antipsychotic-induced weight gain, but their
effects were limited because of adverse effects (Taflinski
and Chojnacka, 2000) and nonspecific mechanisms
(Werneke et al., 2002).
ALA is known to exert an antiobesity effect by sup-
pressing hypothalamic AMPK activity in both rodents
(Kim et al., 2004) and obese patients (Koh et al., 2011).
This mechanism seems to counteract the possible
underlying mechanism of atypical antipsychotic-induced
weight gain. In our study, patients in the ALA group
showed reductions in body weight and BMI. In addition,
visceral fat area was significantly reduced. The anti-
obesity effects of ALA seemed to be proportional to the
time and dosage reported in previous studies (Koh et al.,
2011).
With respect to abdominal fat area measured by com-
puted tomography, the visceral but not subcutaneous
fat area was significantly reduced during this study
(Table 3). There is a strong correlation between
abdominal visceral fat and cardiovascular disease (Yusuf
et al., 2004; Canoy et al., 2007); visceral fat is associated
with metabolic abnormalities, such as insulin resistance
and atherogenic dyslipidemia (Patel and Abate, 2013;
Bastien et al., 2014). Moreover, visceral adipose tissue is a
major contributor to metabolic risk, whereas some
investigators have suggested that subcutaneous adipose
tissue may play a protective role (Fujimoto et al., 1994;
Matsuzawa et al., 1995; Banerji et al., 1999; McLaughlin
et al., 2011). Therefore, the reduction of visceral fat area
in the ALA group is a promising result considering the
association between metabolic syndrome and visceral fat.
The suppression of hypothalamic AMPK by ALA med-
ication may affect appetite increased induced by atypical
antipsychotics (Kim et al., 2004; Lee et al., 2005). The
higher EEW score in the ALA group suggests that these
patients were better able to control their eating behavior.
ALA medication reduced appetite and eating behavior
impulsivity. We interviewed the study participants and
nursing staff after the completion of the 12-week study.
Almost all of the participants in the ALA group reported
reduced appetite and confidence in controlling their
eating behavior, which is in line with the results of our
previous study (Kim et al., 2008).
In this study, the participants lived in the rehabilitation
ward and thus had similar life patterns and diets; hence,
many confounding factors were controlled. All patients
Copyright r 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
ALA modulates atypical antipsychotic-induced weight gain Kim et al. 7
were provided with the usual exercise and diet programs,
P-value which were not focused on particular individuals. In
0.439
addition, both psychotropic medication and ALA (or
placebo) medication were provided and checked by
nursing staff in the ward. In clinical trials for outpatients,
drug compliance is assessed by self-reports or the number
of leftover medications, making it more difficult to assess
compliance. The control of environment, diet, and
medication are the strengths of this study, despite the
small number of participants.
A relatively small number of participants was included,
and this may reduce confidence in the result. However,
despite the small sample size, positive results could be
observed in body weight and visceral fat area that could
suggest a strong effect on weight loss and reduction in
visceral fat. In addition, HbA1c and triglyceride levels
showed decreases, even if not significantly different from
the placebo in a small study. Further study using a large
sample size may find significant effects of ALA to these
variables.
ALA was generally well tolerated in this study as repor-
ted previously (Yadav et al., 2005; Ziegler et al., 2006; Koh
et al., 2011). There were no differences in the incidences
of adverse effects between the placebo and the ALA
groups (Table 5). The most common adverse effects
were gastrointestinal symptoms, including abdominal
pain, nausea, vomiting, and diarrhea, which are similar to
previous reports (Reljanovic et al., 1999a; Ziegler et al.,
2006). However, three patients in the ALA group
experienced dermatologic symptoms, but the incidence
was equal to that of the placebo group. Only one patient
withdrew because of dermatologic adverse effects, but he
recovered without sequalae after ALA discontinuation.
Although the maximum tolerated dose of ALA in human
participants has not been well defined, a recent study has
suggested that 1800 mg/day of oral ALA may be optimal
(Wollin and Jones, 2003). Thus, the dosages used in this
study were similar to those previously found to be tol-
erated in human participants.
Our research team previously reported an effect of ALA
on atypical antipsychotic-induced weight gain in a pre-
liminary study (Kim et al., 2008). Recently, as a ‘reverse
translational proof-of-mechanism study,’ our research
team carried out an animal study to verify the antiobesity
effects of ALA. The results of that study provided an
important mechanistic clue that the subchronically sus-
tained antiobesity effect of ALA is mediated by sup-
pressing hypothalamic AMPK. Therefore, we could carry
out both clinical and animal studies to validate the anti-
obesity mechanism of ALA (Kim et al., 2014).
Despite the visceral fat reduction in the ALA group, the
glucose and lipid profiles were not significantly different
between the two groups at the end of this study. Previous
studies reported that ALA improved metabolic dis-
turbances (Song et al., 2005; Kim et al., 2008; Koh et al.,
 8 International Clinical Psychopharmacology 2016, Vol 00 No 00
2011; Seo et al., 2012). Because of the small sample size, it
may be difficult to identify changes in metabolic values.
Previous studies have shown that weight reduction by
ALA is dose and time dependent; thus, ALA might have
led to improvements in metabolic disturbances as well as
weight loss if the study had continued for a longer period
with higher doses. In addition, the relatively better
metabolic status of participants may be considered. Kim
et al. (2008) showed that ALA might decrease the level of
fasting glucose level and insulin in their study. In the
study, most participants who improved weight and glu-
cose metabolism disturbances had been diagnosed with
diabetes at the initial points (fasting glucose 126 mg/dl),
whereas the others without improvement had been
diagnosed with diabetes. Therefore, it may be suggested
that ALA would be more effective in such diabetic
patients or those with diabetic-prone status resulting
from taking atypical antipsychotics (Kim et al., 2008). In
addition, insulin resistance is important in the patho-
physiology of dyslipidemia (Cohn et al., 2001), However,
our present study excluded diabetes patients. Diabetes
medications have been reported to be associated with
body weight and appetite (Wu et al., 2008; Mitri and
Hamdy, 2009). They can be confounding factors, there-
fore we excluded all participants with diabetes in order to
negate such factors. This might be the reason for the
limited effect on metabolic disturbances when excluding
participants with diabetes.
Many drugs have been used to manage weight gain
because of atypical antipsychotics (Maayan et al., 2010).
Despite the effects of the drugs, there were limitations in
their use, such as unclear mechanisms, unknown inter-
actions with atypical antipsychotics, and worsening of
psychotic symptoms (Taflinski and Chojnacka, 2000;
Werneke et al., 2002; Kim et al., 2008). Unlike other drugs
used to modify weight gain because of antipsychotics, the
weight control mechanism of ALA is not associated with
the actions of antipsychotics. ALA acts on AMPK, which
is a key factor in energy metabolism (Kim et al., 2004;
Kahn et al., 2005). It controls appetite by suppressing
hypothalamic AMPK and increases energy consumption
by activating peripheral AMPK (Kim et al., 2004). As
stated above, suppressing hypothalamic AMPK opposes
the weight gain mechanism induced by atypical anti-
psychotics. Therefore, ALA has the advantage of a rela-
tively clear underlying mechanism and no interaction
with the mechanism of the actions of antipsychotics on
the symptoms of schizophrenia (Kim et al., 2008). ALA
has a synergistic effect on weight control and is more
beneficial than other drugs, such as metformin, which
increases energy expenditure solely by activating per-
ipheral AMPK (Kola et al., 2006).
In addition, ALA has already been used to treat various
conditions, for example, diabetes, cardiovascular disease,
and metabolic syndrome. As a result, its safety, expected
adverse effects, and management have been investigated
Copyright r 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
by several groups (Packer et al., 1995; Reljanovic et al.,
1999b; Kamenova, 2006; Holmquist et al., 2007;
Pershadsingh, 2007). It is also used widely as a dietary
supplement and can be taken without a prescription;
thus, it is more accessible than antidiabetic drugs and
anticonvulsants, which have also been used to modify
weight gain associated with atypical antipsychotics. In
this study, only one patient discontinued the ALA regi-
men because of adverse effects, and he recovered soon
thereafter without sequalae. This safety result is con-
sistent with previous research findings (Yadav et al., 2005;
Ziegler et al., 2006; Koh et al., 2011). However, there are
insufficient studies on extreme dosages, chronic use
periods, and related adverse effects. In our study, we
administered a moderate dose (<1800 mg/day) for
12 weeks; thus, patients on high doses of ALA for longer
time periods should be carefully observed.
Limitation
This study has some limitations. First, the length of the
study was relatively short, and thus we could not assess
the long-term effects of ALA medications. An animal
study on the subchronic sustained antiobesity effect of
ALA has been carried out by our research team (Kim
et al., 2014), but the evidence is insufficient for general-
ization to humans. Second, the participants in this study
were all Korean. Because of the differences in gene and
lifestyle among ethnic groups, the generalization of these
results is difficult. Third, the sample size of this study
was relatively small; hence, some parameters might fail to
reach statistically significant results.
Conclusion
ALA exerted a positive effect in reducing body weight
and visceral fat areas compared with placebo after
12 weeks. These findings suggest that ALA could be an
effective and safe agent to prevent weight gain associated
with atypical antipsychotic use. Moreover, it may be
beneficial to improve metabolic disturbances beyond
reduction of body weight. Once larger short-term and
long-term studies of efficacy and safety are completed,
ALA may be developed into a commonly administered
useful agent.
Acknowledgements
This research was supported by the Otsuka schizo-
phrenia young investigator research fund (2011) by the
Korean Society for Schizophrenia Research.
Conflicts of interest
There are no conflicts of interest.
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