Original Contribution

A Preliminary Investigation of !-Lipoic Acid Treatment

of Antipsychotic Drug–Induced Weight Gain in Patients
With Schizophrenia
Eosu Kim, MD, Dong-Wha Park, MD, Song-Hee Choi, MA, Jae-Jin Kim, MD, PhD,
and Hyun-Sang Cho, MD

(J Clin Psychopharmacol 2008;28:138–146)

Abstract: Weight gain and other metabolic disturbances have now
become discouraging, major side effects of atypical antipsychotic
drugs (AAPDs). The novel strategies required to counteract these
serious consequences, however, should avoid modulating the
activities of the neurotransmitter receptors involved because those
receptors are the therapeutic targets of AAPDs. Adenosine mono-
phosphate–activated protein kinase is an enzyme that plays a pivotal
role in energy homeostasis. We hypothesized that !-lipoic acid
(ALA), which is known to modulate adenosine monophosphate–
activated protein kinase activity in the hypothalamus and peripheral
tissues, would ameliorate AAPD-induced weight gain.
We describe the case series of a 12-week ALA trial in schizo-
phrenia patients treated with AAPDs. Two of 7 enrolled subjects
were dropped from the study because of noncompliance and demand
for new medication to treat depressive symptoms, respectively.
The mean (SD) weight loss was 3.16 (3.20) kg (P = 0.043, last
observation carried forward; median, 3.03 kg; range, 0–8.85 kg).
On average, body mass index showed a significant reduction
(P = 0.028) over the 12 weeks. During the same period, a statistically
significant reduction was also observed in total cholesterol levels
(P = 0.042), and there was a weak trend toward the reduction in insulin
resistance (homeostasis model assessment of insulin resistance)
(P = 0.080). Three subjects reported increased energy subjectively.
The total scores on the Brief Psychiatric Rating Scale and the
Montgomery-Asberg Depression Rating Scale did not vary signifi-
cantly during the study.
These preliminary data suggest the possibility that ALA can
ameliorate the adverse metabolic effects induced by AAPDs. To
confirm the benefits of ALA, more extended study is warranted.
Department of Psychiatry and Institute of Behavioral Science in Medicine,
College of Medicine, Yonsei University, Seoul, Republic of Korea; and
Severance Mental Health Hospital, Gyeonggi-do, Republic of Korea.
Received June 26, 2007; accepted after revision December 20, 2007.
This study was supported by a grant from the Institute of Behavioral Science
in Medicine, College of Medicine, Yonsei University, Seoul, Republic of
Korea. !-lipoic acid was generously provided by ILDONG Pharmaceut-
ical Co., Ltd., Seoul, Republic of Korea.
Address correspondence and reprint requests to Hyun-Sang Cho, MD,
Department of Psychiatry and Institute of Behavioral Science in
Medicine, Severance Mental Health Hospital, 696-6 Tanbeol-dong,
Gwangju-si, Gyeonggi-do 464-100, Republic of Korea. E-mail:
chs0225@yumc.yonsei.ac.kr.
Copyright * 2008 by Lippincott Williams & Wilkins
ISSN: 0271-0749/08/2802-0138
DOI: 10.1097/JCP.0b013e31816777f7
O besity and other related metabolic disturbances have been
regarded as disappointing, major side effects of some
atypical antipsychotic drugs (AAPDs) over the last decade.
These side effects, related to increased morbidity and mortality,
are known to be serious enough to even offset the beneficial
effects of the agents.1 To devise a novel strategy to counteract
these untoward consequences, it would be necessary to under-
stand the precise mechanisms underlying the orexigenic or
diabetogenic actions of AAPDs. The issues regarding those
processes, however, have been seldom discussed beyond the
knowledge about the neurotransmitter receptors involved.2
Because any pharmacological interventions modulating the
activities of such receptors would be discredited by the notion
that the actions on those receptors are the therapeutic factors
of AAPDs, a search for an alternative agent that acts through
a mechanism other than by affecting those receptors is to
be undertaken.
We have thus focused on the pharmacological modu-
lators of an appetite-stimulating enzyme, adenosine mono-
phosphate–activated protein kinase (AMPK), which is known
to play a pivotal role in regulating food intake and whole-
body energy balance.3 Several lines of evidence support the
relationship between AMPK and the metabolic syndrome.3,4
A number of endogenous anorexigenic and orexigenic signals
are found to modulate hypothalamic and/or peripheral AMPK
to exert their physiological effects.4,5 However, the metabolic
actions of those energy-regulating signals seems to be very
complex and different among different tissues. For instance,
an adipocyte-secreted energy-regulating hormone, leptin, is
known to reduce appetite, yet enhance energy expenditure
by suppressing hypothalamic AMPK and, interestingly,
by activating peripheral AMPK, respectively.5 Acylation-
stimulating protein (ASP), another adipocytokine, is known
to stimulate glucose uptake as leptin6; however, blocking
ASP’s action increases AMPK activity in muscle tissues,7 and
inhibition of ASP is deemed as an antiobesity strategy
because ASP increases adiposity by enhancing triglyceride
(TG) synthesis, unlike leptin.6 Adiponectin, another adipo-
cytokine, has been shown, similar to leptin, to increase fatty
acid oxidation and glucose uptake in skeletal muscle and
liver.3 Adiponectin, like leptin, activates peripheral AMPK.3
However, the central effect of adiponectin is directly opposed

138 Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008

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Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008
to that of leptin; that is, adiponectin activates hypothalamic
AMPK, thus stimulates food intake.8
These different metabolic actions of adipocytokines
between the hypothalamus and peripheral tissues are mark-
edly implicative; to optimize the potency of a selective
hypothalamic AMPK inhibitor as an antiobesity agent, it
should also be a peripheral AMPK activator. !-Lipoic acid
(ALA)9 satisfies this criteria as leptin, whereas not all-known
peripheral AMPK activators,4 such as metformin, satisfy this
criteria. In this regard, ALA might be one of the most suitable
candidate agents for the treatment of AAPD-induced weight
gain among the known modulators of AMPK.4
ALA is a naturally occurring, essential cofactor of
mitochondrial respiratory enzymes.10 It has been used as a
safe and potent antioxidant for treatment of diabetic neuro-
pathy.10,11 This potent free radical scavenger has been
implicated in the treatment or prevention of the following
conditions associated with oxidative stress: heavy metal or
other toxin poisoning; metabolic disturbances, such as dia-
betes, hypertension, and nonalcoholic steatohepatitis; cerebral
ischemic or reperfusion injury; and chronic neurodegenerative
diseases, including multiple sclerosis, Parkinson’s disease, and
Alzheimer’s disease.10–16 This versatile agent has been recently
found to have an antiobesity effect in rodents.9 ALA exerts
such effects by suppressing hypothalamic AMPK (appetite
reduction effect) and by activating peripheral AMPK (energy
consumption–enhancing effect) as much the same way as
leptin does.9 The antiobesity effect of ALA, however, is known
to be independent of leptin signaling, which suggests that ALA
could overcome leptin resistance.9 Furthermore, ALA has been
reported to prevent diabetes mellitus,17 improve cardiovascular
function, and ameliorate atherogenic dyslipidemia.18
Taking all these into consideration, we selected ALA as
a novel agent for the treatment of AAPD-induced obesity. Our
hypothesis is that ALA would reduce body weight that has
been increased during the treatment with AAPDs in patients
with schizophrenia.
This case series presents the possible usefulness of
ALA not only for weight reduction but also for improvement
of glucose or lipid metabolism in the patients.
METHODS
Subjects
Outpatients with schizophrenia who had gained sig-
nificant weight since taking AAPDs were recruited for a
12-week open-label trial of ALA by advertising with posters
in the hospital. Inclusion criteria were: (1) age between 18
and 40 years; (2) schizophrenia diagnosed by 2 psychiatrists
(E.K. and H.S.C.) according to the Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition – Text Revision;
(3) history of a weight gain of more than 10% of the baseline
after the administration of AAPD and a current body mass
index (BMI) higher than 25 kg/m2; and (4) a willingness to
reduce weight although not currently participating in any
weight reduction program. Subjects who had a history of
medical illnesses (with the exception of current high serum
glucose), a family history of obesity, or weight change of
more than 2 kg within 2 months before entry were excluded.
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!-Lipoic Acid and Obesity
As a rule, doses of medications including AAPDs were
required to be fixed throughout the study period. Subjects
who needed their prescription or doses changed during the
study were regarded as dropouts.
Seven subjects (5 were females) were enrolled and asked
not to participate in any other program to reduce weight
throughout the total study period. Six subjects completed at
least 4 weeks of treatment and were included in the analysis.
Five of 6 subjects completed the total 12-week study. Two
female patients were excluded owing to noncompliance
(omission of medication for >2 weeks during the first month)
and a demand for new medication to treat depressive symptoms,
respectively. At the point of entry, 3 (C.C., E.E., and F.F.) of
7 subjects reported that they were gaining weight by roughly
1 kg/mo, whereas the rest reported that they were neither
gaining nor losing weight. More information about the subjects
is described in Table 1 and in the Appendix. This study was
approved by the institutional review board of Severance
Mental Health Hospital and followed the Declaration of
Helsinki.19 Given a full explanation of the study, all subjects
and their caregivers signed a written informed consent form.
Procedure
During the 12-week study period, patients were given
orally of 1200 mg/d of ALA in divided doses. Follow up visits
occurred at 4, 8, and 12 weeks. Compliance with the course of
medication was confirmed by requesting that subjects show
the physician how many pills were left on every visit and by
their caregivers’ report.
Body weight, waist-to-hip circumference ratio (WHR),
Brief Psychiatric Rating Scale (BPRS)20, and Montgomery-
Asberg Depression Rating Scale (MADRS)21 were measured
on every visit. The MADRS was included to examine the
possibility of any antidepressant effect of ALA.22 Fasting
glucose and insulin, HbA1c, total cholesterol, low- (LDL) and
high-density lipoprotein (HDL) cholesterols, TG, free fatty
acid (FFA), and prolactin levels were measured at the initial
visit and the end point. Body weight, WHR, and all laboratory
values listed previously were measured after patients, who had
fasted from midnight onward, voided at 9 AM. To investigate
the effect of ALA on insulin resistance, we used the homeo-
stasis model assessment of insulin resistance (HOMA-IR) as
an index known to correlate with insulin resistance measured
by the euglycemic clamp technique.23
Height was measured to the nearest 0.5 cm. Weight was
measured by a computer-linked scale, nBody NB-EX (CAS
Corp, Seoul, Korea), which measured weight in 50-g units.
Waist circumference was measured midway between the
lateral lowest rib and the iliac crest. Hip circumference was
measured on the horizontal line crossing the bilateral greater
trochanters. Waist-to-hip circumference ratios were obtained
by dividing waist circumference by hip circumference.
All subjects were given a written card listing the side
effects of ALA, so they could report, at each visit, any of the
items experienced.
Statistical Analysis
To compare values with the baseline, Wilcoxon signed
ranks test was performed. Analyses for changes in weight or
139
Kim and Associates Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008

14.1 (5.7)
BMI were performed with the last observation carried
MADRS

8–24
forward, including a subject who had dropped out after 4
10

10

24
19

10

14

14
8
weeks of treatment. Considering the small sample size, we
reconfirmed the level of statistical significance by adminis-
tering the last rank carried forward method,24 a nonparamet-

42.0 (9.6)
ric analog of the last observation carried forward.
BPRS

30–56
37

42

56
48

30

32

49

42
Statistical significance was defined at a level of ! =
0.05. Although the original hypotheses for the major outcome
measures, such as weight, HOMA-IR, lipids level, and so
forth, were unidirectional, P < 0.10 in those variables was
After AAPD, kg
Weight Gain

regarded as a statistical trend toward change. Statistical

21.5–31.8
26.2 (3.9)
28.8

25.4

21.9
29.4

24.8

31.8

21.5

25.4
Package for Social Sciences v12.0 (SPSS Inc., Chicago, Ill)
was used for the statistical analyses.

RESULTS
Duration of Current
Medication, mo

Anthropometric Measures
38.9 (37.9)

The mean (SD) weight loss at the 12-week end point

4–96
89

96

20
27

29

27
7

was 3.16 (3.20) kg (z = j2.02, P = 0.043; median, 3.03 kg;

range, 0–8.85 kg) (Fig. 1). One subject lost 3.20 kg in 4
weeks, although this subject dropped out before the next
visit. Three of 5 subjects who completed the study lost 2.85,
3.80, and 8.85 kg, respectively, whereas the 2 subjects
showed little change (j0.25 and 0 kg, respectively) over
Current Medication

Divalproex 500 mg

Divalproex 100 mg
Clozapine 500 mg

Clozapine 275 mg

Clozapine 300 mg

Clozapine 200 mg

Clozapine 100 mg

the 12-week period. The BMI, on average, showed a sig-

Risperidone 2 mg

Risperidone 6 mg

Risperidone 3 mg
Fluoxetine 40 mg

Fluoxetine 80 mg

Lithium 750 mg

nificant reduction from baseline in 12 weeks (28.71 [2.45]

—
—
—

kg/m2; median, 28.59 kg/m2; range, 25.66-32.35 kg/m2;

Duration of
Illness, mo

87.7 (49.9)

29–168
168

127

114
56
72

48

72
29
BMI, kg/m2

27.04–33.42
29.94 (2.02)
TABLE 1. Baseline Characteristics of Study Subjects (n = 7)

33.42

30.54

28.31
29.49

30.72

30.03

27.04

30.03
74.50–92.40
83.63 (7.29)
Weight, kg

88.80

90.35

80.85
92.40

74.75

83.75

74.50

83.75
30.9 (5.0)
Age, yrs

26–39
39

29

28
26

28

37

29

29
Sex

—
—
—
M
M
F

F
Subject A.A.

Subject G.G.
Subject C.C.
Subject D.D.
Subject B.B.

Subject E.E.

Subject F.F.

FIGURE 1. Mean (SEM) weight change from baseline to 12

Mean (SD)

weeks during treatment with ALA. Significant reduction from

Median
Range

baseline is observed at week 12 (n = 6, *P < 0.05, last

observation carried forward).

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Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008 !-Lipoic Acid and Obesity

TABLE 2. Profiles of Glucose Metabolism at Baseline and 12 Weeks During the !-lipoic Acid Trial (n = 5)
Glucose, mmol/L* Insulin, 2g/L* HOMA-IR HbA1c, %

3.89–6.11 0.08–1.04 <2.0–2.5 4.0–6.0

Reference Range. Baseline 12 Wk Baseline 12 Wk Baseline 12 Wk Baseline 12 Wk

Subject A.A. 7.67 6.89 0.62 0.57 5.04 4.16 6.1 5.7
Subject B.B. 5.39 5.61 0.75 0.79 4.28 4.73 5.5 5.4
Subject C.C. 6.50 6.22 0.65 0.46 4.47 3.04 6.0 6.1
Subject D.D. 7.56 6.67 0.51 0.44 4.13 3.14 5.8 5.5
Subject G.G. 7.11 6.00 0.44 0.35 3.35 2.26 6.4 5.6
Mean (SD) 6.84 (0.93) 6.28 (0.51) 0.59 (0.12) 0.52 (0.17) 4.25 (0.61) 3.47 (0.98) 5.96 (0.34) 5.66 (0.27)
Median 7.11 6.22 0.62 0.46 4.28 3.14 6.0 5.6
Range 5.39–7.67 5.61–6.89 0.44–0.75 0.35–0.79 3.35–5.04 2.26–4.73 5.5–6.4 5.4–6.1
Analysisz z = j1.75, P = 0.080 z = j1.75, P = 0.080 z = j1.75, P = 0.080 z = j1.63, P = 0.104
*Units were converted as [Glucose] (mmol/L) = [Glucose] (mg/dL)  [(mmol/L)/(180 mg/10 dL)], [Insulin] (2g/L) = [Insulin] (2IU/mL)  [(0.0000417 2g/0.001 L)/(2IU/mL)].
y
Reference range of the laboratory where the tests were conducted.
z
Two-tailed Wilcoxon signed rank test.

z = j2.20, P = 0.028). Mean (SD) WHR did not decrease
significantly from baseline to endpoint (0.94 [0.04] to 0.91
[0.07]; z = j1.15, P = 0.25).
Two patients (D.D. and G.G.) with longer-term follow-
up have shown remarkable weight reductions (16.4 and
12.5 kg, respectively) for 9 or 6 months as described in detail
in the Appendix.
Laboratory Measures
Changes of variables in the glucose metabolism are
described in Table 2. Fasting glucose, fasting insulin, and
insulin resistance index (HOMA-IR) were decreased in all
except 1 subject for the 12-week period of the ALA trial. The
mean changes of those variables, however, did not reach a
significant level but showed a weak trend toward reduction
(P = 0.080 for all). HbA1c values were reduced in 4 of 5
subjects, although the mean reduction of HbA1c was not
statistically significant (P = 0.104).
Changes of serum lipid levels are listed in Table 3.
Total cholesterol concentration has shown a statistically
significant reduction for 12 weeks (P = 0.042), whereas
LDL- and HDL-cholesterol levels have shown a trend toward
reduction (P < 0.07). The mean TG and FFA levels did not
change significantly for 12 weeks (Table 3). The mean (SD)
prolactin level did not change significantly during the study
(59.4 [64.50] to 53.7 [56.76] 2g/L; z = j0.40, P = 0.343).

TABLE 3. Profiles of Lipid Metabolism at Baseline and 12 Weeks During the !-lipoic Acid Trial (n = 5)
Total Cholesterol, LDL Cholesterol, HDL Cholesterol,
mmol/L* mmol/L* mmol/L* TG, mmol/L* FFA, 2mol/L*

3.89–6.47 <3.62 1.09–61.91 <2.26 176–6586

Reference range. Baseline 12 Wk Baseline 12 Wk Baseline 12 Wk Baseline 12 Wk Baseline 12 Wk

Subject A.A. 6.70 6.34 3.80 3.41 0.88 0.75 4.57 4.04 760 835
Subject B.B. 6.98 6.67 3.93 3.65 1.32 0.93 3.58 4.18 777 1489
Subject C.C. 5.66 5.30 3.15 2.77 0.83 0.78 2.54 3.32 1089 1142
Subject D.D. 4.71 4.16 2.59 2.35 0.70 0.70 1.06 1.20 1269 435
Subject G.G. 5.17 4.40 2.59 2.59 0.96 0.75 3.73 1.73 972 1036
Mean (SD) 5.84 (0.97) 5.37 (1.12) 3.21 (0.64) 2.95 (0.55) 0.94 (0.23) 0.78 (0.09) 3.10 (1.35) 2.89 (1.36) 973.4 (215.0) 987.4 (389.3)
Median 5.66 5.30 3.15 2.77 0.88 0.75 3.58 3.32 972 1036
Range 4.71–6.98 4.16–6.67 2.59–3.93 2.35–3.65 0.70–1.32 0.70–0.93 1.06–4.57 1.20–4.18 760–1269 435–1489
Analysisz z = j 2.03, P = 0.042 z = j 1.84, P = 0.066 z = j 1.83, P = 0.068 z = j 0.14, P = 0.893 z = j 0.67, P = 0.500
*Units were converted as [Cholesterol] (mmol/L) = [Cholesterol] (mg/dL)  [(0.002586 mmol/0.1 L)/(mg/dL)], [TG] (mmol/L) = [TG] (mg/dL)  [(0.001129 mmol/0.1 L)/
(mg/dL)], [FFA] (2mol/L) = [FFA] (2Eq/L)  [(2mol/L)/(2Eq/L)].
yReference range of the laboratory where the tests were conducted.
z
Two-tailed Wilcoxon signed rank test.

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Kim and Associates Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008
Psychiatric Measures
The mean (SD) BPRS scores did not vary significantly
during the study (the initial values are found in Table 1; at 12
weeks, 44.0 [4.6]; median, 45; range, 37–48; P = 0.273). No
significant change of MADRS was seen (at 12 weeks, 15.0
[7.5]; median, 13; range, 8–26; P = 0.577), although 3
patients (A.A., B.B., and D.D.) reported voluntarily that they
had felt more energized than before, even after weight loss in
2 of them (A.A. and D.D.).
Adverse Effects and Safety Issues
Mild to moderate reduction of appetite was the most
obvious side effect in all 4 subjects who experienced reduction
in weight, although this effect was regarded as beneficial. One
subject (G.G.) reported 1 or 2 episodes of easily tolerable
nausea, dizziness, and diarrhea, although she reported that she
had experienced those symptoms at times before the study.
One subject (F.F.) who has dropped from the study showed a
relapse of depressive symptoms as described further in the
Appendix.
DISCUSSION
This preliminary case series offers very limited data,
yet suggests that ALA may reduce body weight and have
some benefits in relation to other abnormal metabolic
profiles, such as insulin resistance and dyslipidemia, in the
patients treated with AAPDs.
In the present study, the observed weight loss seemed to be
related to the reduction of appetite, because those who have
shown weight reduction all reported decreased appetite. It should
be noted, however, that the antiobesity effect of ALA is not
solely mediated by a decrease in food intake through inhibition
of hypothalamic AMPK, because more weight reduction was
observed in ALA-administered rats than in pair-fed rats.9 This
difference was found to be caused by the increase of energy
expenditure in peripheral tissues through the activation of
peripheral AMPK by ALA.9,25 These findings indicate that
ALA might have synergistic effects on other adverse metabolic
consequences of AAPDs as well as on weight gain.
Indeed, ALA also seemed to improve glucose metabo-
lism of some patients in the present study. The levels of fasting
glucose, which had been over the diagnostic value, 7.0 mmol/L
(126 mg/dL) in 3 subjects, were all decreased below the value
in 12 weeks. Additionally, ALA also decreased the level of
insulin in 4 of 5 subjects. These findings might suggest the
possibility that ALA improves insulin resistance in the patients,
although the mean change of HOMA-IR has shown only a
trend toward reduction (Table 2). Interestingly, 3 of 4 subjects
who lost significant weight should have been diagnosed with
diabetes mellitus at the initial point according to the definition
of a fasting glucose of more than 7.0 mmol/L, whereas the
other 2 with no weight reduction should not have been diag-
nosed with diabetes. This might imply that ALA would be
more effective in such diabetic or diabetic-prone status re-
sulting from taking AAPDs.
Although the general association between obesity and
insulin resistance seems evident, it has not been clearly deter-
mined whether the insulin resistance is independently caused by
the action of AAPDs, or whether it is secondary to the increase in
142
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adiposity resulting from the use of AAPDs.26 Glucose dysregu-
lation in some patients taking AAPDs, however, seemed to be
independent of weight or adiposity differences.26,27 Given that
certain AAPDs were found to induce hyperglycemia by
inhibiting glucose transporters,28 which are known to be
activated by AMPK,29,30 it can be speculated that insulin
resistance and obesity may be induced independently by the
similar mechanisms of action of AAPDs, that is, the change
of AMPK activity in peripheral tissues and in the hypothal-
amus, respectively. Thus, ALA might work synergistically on
both insulin resistance and obesity by modulating peripheral
and hypothalamic AMPK activity previously disturbed by
AAPDs.
Additionally, insulin resistance is also regarded as a key
factor in the pathophysiology of dyslipidemia, which consists of
elevated FFA, TG, and LDL cholesterol levels, and lowered levels
of HDL cholesterol.31 Thus, the amelioration of lipid profiles
observed in previous studies with ALA14,18,32 could be
associated with the improvement of insulin resistance through
AMPK modulation. Our results also show that ALA decreases
total serum cholesterol level, whereas mean TG and FFA levels
seem not to be affected. Previous findings as to the changes of
TG and FFA levels by ALA administration have been
conflicting in animal studies.18,32 The levels of serum TG and
FFA would be determined by the balance between the rate of
lipolysis in adipocyte-releasing FFA and free glycerol into
circulation, as well as the rate of the oxidation of FFA in skeletal
muscle, as both of them are stimulated by ALA.25,32 Without
the "-oxidation surpassing the FFA and glycerol increase, FFA
and glycerol once resolved from TG would be resynthesized
into TG by reesterification in the liver.32 Therefore, the serum
FFA and TG levels in our subjects might have been in a
dynamic equilibrium between the increased release of FFA
and glycerol into circulation and the enhanced use at a given
dose of ALA; higher doses might be needed to break the
equilibrium.
Another interesting clinical observation was that several
subjects reported feeling an increase in energy. This might be a
result of the hypothesized antidepressant effect of ALA22 or
the improved efficiency in energy utilization through activat-
ing AMPK in the skeletal muscles.25 The latter is supported
indirectly by the observation that mice with decreased AMPK
activity show greater fatigue during exercise.33
Although several currently available antiobesity drugs
have been suggested to be effective in the treatment of AAPD-
induced obesity,2 these drugs may have potential drawbacks for
patients taking AAPDs. Sibutramine, for example, may increase
the risk of serotonin syndrome when used together with other
psychotropic drugs.2 Such neurotransmitter- modulating anti-
obesity agents may have unpredictable, psychotomimetic
adverse consequences.34 One novel and promising drug,
although also acting on a central nervous system (CNS)–
receptor system, is rimonabant, a cannabinoid-1-receptor
antagonist.35 Because it has been found that cannabinoid
stimulates appetite by activating the hypothalamic AMPK,4
the cannabinoid antagonist would likely reduce the appetite and,
thus, overall weight by suppressing the hypothalamic AMPK as
does ALA. However, it is also evident that rimonabant has CNS
side effects, such as anxiety and depression.35 Orlistat, although
* 2008 Lippincott Williams & Wilkins
Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008
seemingly safer, is not specific to AAPD-induced Bhyper-
appetite[, unlike ALA. Moreover, the unique gastrointestinal
discomforts2 would also matter to the patients taking psycho-
tropic drugs, which may affect serotonergic or dopaminergic
systems in the gastrointestinal tract.
!-Lipoic acid would have biochemically distinct advan-
tages over other agents as previously mentioned for several
reasons. One of them might be a fact that ALA does act
specifically on AMPK, a major energy-regulating enzyme.3,9
Because body weight is considered to be the result of the
homeostatic function of energy metabolism, obesity is
regarded as a balance problem where the body’s set point is
abnormally shifted. Hypothalamic AMPK is known to be the
key fuel gauge that sets the point of energy balance.30 In
addition, because the hypothalamic AMPK, as a target enzyme
of ALA’s action, is thought to be placed at a relatively later or,
presumably, final step in the central energy control path-
way,5,30 ALA would not disturb the original pharmacological
action of AAPDs at the neurotransmitter receptors.
Another aspect detailing the specificity of ALA is that
AMPK is shared by both ALA and AAPDs as a common target
in the central control over metabolism. To explain, leptin, an
endogenous modulator of the Bbalancing enzyme[ AMPK, is
regarded as a peripheral feedback signal to the central nervous
system in response to increased adiposity. Recently, however,
leptin has been found to play a role as a signal of negative
energy balance and low energy reserves rather than of
excessive energy reserves.6 Thus, the metabolic response to
increased leptin levels in obese persons, as in AAPD-induced
obesity, is regarded as already physiologically maximal.6 This
condition could be referred to as leptin resistance. Mean-
while, leptin’s effect was found to be blocked by constitu-
tively activating hypothalamic AMPK.5 Taken together, it can
be supposed that the leptin resistance results in these patients,
at least in part, from the altered activity of hypothalamic
AMPK by way of AAPDs’ action. Indeed, during preparation
of the manuscript, Kim et al36 have reported that some
AAPD-induced weight gain is mediated by the activation of
hypothalamic AMPK. Hence, besides its action on peripheral
AMPK, ALA, a newly known suppressant of hypothalamic
AMPK,9 may be regarded as one of the most suitable agents
to counteract specifically the orexigenic effect of AAPDs,
that is, the hypothalamic AMPK activators.36
Finally, ALA is considered a fairly safe antioxidant
agent.10 A toxicological study, designed to assess the safety
of ALA, reported that ALA has a markedly broad safety
margin.37 Clinicians, therefore, would be able to modify its
dose up to the anorectic level with less concern for serious
adverse reactions. Although human data on the safety of
prolonged use with high doses is limited, scores of clinical
trials with ALA in which doses ranged from 600 to 2400 mg/d
from a few weeks to 24 months have also supported the safety
of the agent in human subjects.11,16,37,38 However, it should be
noted that the side effects reported in those human studies,
such as nausea, vomiting, dizziness, headache, and weakness,
although being comparable with those of the placebo
group,11,38 should be always monitored carefully in patients
taking psychotropics, because the underlying mechanisms of
such side effects have not been elucidated.
* 2008 Lippincott Williams & Wilkins
Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
!-Lipoic Acid and Obesity
Despite these optimistic views on ALA, this case series
has obvious limitations, which demand a great deal of caution
before interpretation. Above all, the number of enrolled
subjects is too small to have statistically appropriate validity,
although the statistical analyses have been presented for
clarity. In addition, the overall effects, when averaged with
large variances, do not make the analyses unequivocal. A
study with a larger sample size is warranted to clearly
answer the questions we have tried to address. Thus, this
preliminary report describing the respective cases should be
interpreted for descriptive purposes toward stimulating
further investigation.
The fixed dose and duration of ALA administration is
also an issue in that the total requirements of dose and duration
for effective weight reduction may vary among individuals or
AAPD dosages. !-Lipoic acid has been shown to reduce the
weight of rodents in a dose- and time-dependent manner.9
The common features of those who lost weight in this study
were appetite reduction and higher initial glucose level; the
former is suggestive of the requirement of ALA dosage up to
an anorectic level.
Another limitation is that subjects were taking several
kinds of other psychotropics, including divalproex, lithium,
and fluoxetine. In a strict sense, the implication of these
results should not be restricted to AAPDs, although they may
be more representative of realistic clinical situations. Because
the doses of all medications, however, had been held constant
for at least 2 months before and during the study, the effect of
such regimens might be minimal.
Nevertheless, the possible interactions between ALA and
those psychotropics deserve consideration. Several psycho-
tropic drugs, including clozapine and valproic acid, are known
to be metabolized by certain phase II detoxification enzymes
such as uridine 5¶-diphosphate–glucuronosyltransferase as well
as phase I cytochrome P450 isoenzymes.39 !-Lipoic acid is
found to mediate up-regulation of several kinds of phase II
enzymes in cultured astroglial cells.40 Thus, the concentration
of certain psychotropics might be decreased at least within
brain tissues through the action of ALA, although this
detoxifying effect is originally regarded as one of the neuro-
protective actions of ALA.40 Taken together, the possibility
cannot be excluded that the relapse of depressive symptoms in
subject F.F. may have to do with such activity of ALA, despite
the theoretical antidepressant effect of ALA.22 However, it still
needs to be elucidated whether ALA induces the same kind of
phase II enzymes that are known to metabolize psychotropics,
and whether such effects of ALA are indeed manifested in
clinical settings.
In addition to the putative drug interactions, underlying
mechanisms of ALA’s action in the CNS are also worth
consideration, because pharmacotherapeutic actions of
AAPDs are exerted primarily in brain regions other than
the hypothalamus. To begin with, the beneficial actions of
ALA to the CNS is generally regarded to involve enhancing
brain mitochondrial biogenesis, which is also thought to be
mediated by AMPK.15 However, several antipsychotics have
been found to cause the inhibition of the mitochondrial
complex I in several brain regions of mice.41 This phenom-
enon was also observed in human postmortem brain tissue42
143
Kim and Associates Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008
and in peripheral blood mononuclear cells.43 Pretreatment
with a combination of ALA and other thiol antioxidants
abolished the inhibition of mitochondrial complex I caused
by haloperidol.41
More specifically, cognitive-enhancing or neuroprotec-
tive actions of ALA have been reported to involve the following:
compensation of the N-methyl-D-aspartate receptor deficit in
the frontal cortex of aged mice without alteration of mus-
carinic, benzodiazepine, and !2-adrenergic receptor deficits44;
activation of Akt/phosphatidylinositol 3-kinase signaling in
cortical neurons,45 which is also related to the neuroprotective
effect of lithium46; Na+K+ATPase activation and reduction
of lipofuscin accumulation in several brain regions of aged
rats47; reduction of cerebral iron,48 of which the oxidant effect
may also be involved in tardive dyskinesia49; facilitation of
presynaptic glutamate exocytosis in the cortex50; and stabiliza-
tion of blood-brain barrier integrity and the decrease of
inflammation in the CNS in the animal model for multiple
sclerosis.51 However, most of these findings are suggested
only with regard toward the beneficial effects of ALA. Thus,
the clinical manifestation of central effects during chronic use
of ALA should be monitored carefully hereafter.
!-Lipoic acid, as a small fatty acid itself, may share
common mechanisms of action on the CNS with the
essential fatty acids such as the eicosapentaenoic and
docosahexaenoic acids, namely the omega-3 fatty acids, which
have also shown positive effects on cardiovascular function
and certain types of psychopathology.52,53 Both ALA and
those essential fatty acids are known to modulate phospha-
tidylinositol 3-kinase/Akt signaling.29,54,55 The concomitant
use of ALA with the essential fatty acids has shown
beneficial effects on the CNS in animal models with
diabetes.56 In addition, ALA was found to increase the
proportions of such essential fatty acids in several areas of the
porcine brain.57
Finally, although all the subjects reported considerable
psychological distress for their gained weight, which ranged
from 21.5 to 31.8 kg, only some of them had any apparent
physical problem (ie, diabetes mellitus or dyslipidemia)
associated with obesity. Given the notion that pharmacother-
apy for obesity should be regarded as the last resort to
manage obesity-related morbidity and mortality,2 the avail-
ability of an antiobesity agent for subjects in the trial may be
limited. However, antiobesity pharmacotherapy with ALA, a
hypothalamic AMPK inhibitor, may have some priority in
patients with pharmacologically treated schizophrenia, in that
they have a known perpetuating factor, that is, taking AAPDs
and hypothalamic AMPK activators.36 Moreover, licensed
antiobesity drugs, such as sibutramine or rimonabant, may
be psychotropically unfavorable,2,34,35 and the lifestyle
modification seems to be less likely to be successful in those
patients.
In conclusion, ALA might be a promising candidate
with particular advantages and specificity for the treatment or
prevention of the adverse metabolic effects of AAPDs in pa-
tients with schizophrenia. An extended, placebo-controlled
study with a larger sample to confirm the long-term benefits
and safety of ALA in AAPD treatment should be conducted
in the future.
144
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AUTHOR DISCLOSURE INFORMATION
The authors have no conflict of interest.
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APPENDIX
Subject A.A. was a 39-year-old housewife with 2
children. She reported increased appetite and weight gain as
her chief complaints since she had been treated with 500 mg/d
of clozapine and 2 mg/d of risperidone. Her husband
complained of her unrestrained eating behavior, especially
overeating at night. He also complained of her sedentary
lifestyle and lack of initiative in taking care of their children
and household chores.
After commencing the ALA treatment, she had a little
weight loss during the first 4 weeks, and she reported a mild
reduction in appetite and some increase of volition for daily
living, saying that she put things off less often than before and
she was able to work more easily. Her husband agreed and was
delighted with such changes in his wife. After the termination
of the 12-week trial of ALA with a total reduction of 2.85 kg,
she complained of the recovery of her appetite and the
reintroduction of night-time eating. She also regained some
of the weight (1.55 kg) after 4 weeks.
Subject B.B. was a 29-year-old woman treated with 275
mg/d of clozapine and 40 mg/d of fluoxetine. She reported
that she had gained more than 25 kg after taking anti-
psychotic medication and had tried to reduce her weight with
a number of methods including pharmacotherapy several
years ago, but none of the methods were successful.
The patient reported that she had felt slightly increased
energy levels after taking ALA, but did not notice any other
changes, including toward appetite. Indeed, the patient did not
show weight change or any of the known side effects of ALA.
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Kim and Associates Journal of Clinical Psychopharmacology
Volume 28, Number 2, April 2008
Subject C.C. was a 28-year-old man, attending the com-
munity mental health center in part because of pressure from his
mother. He was treated with risperidone (6 mg/d). At enroll-
ment, he said, in his restricted affect, that he did not have any
expectation for the new drug to have positive effects, because
every attempt he or his physician had made to reduce his weight
had not been fruitful. He told the observer that he was gaining
weight at the rate of approximately 1 kg/mo at enrollment.
Subject C.C. reported that he had not felt any change at
all after commencement of the ALA medication and showed
no weight change. However, at the 8th week of visit, his
mother, quoting the comments of a social worker in the
mental health center, reported that he had seemed to talk
somewhat more than before in group therapy. Although the
patient responded to his mother’s report with smile, which
had been seldom shown, the patient said that he did not think
his increased outgoingness was due to the ALA medication.
Subject D.D., aged 26 years, working in another hospital
as an orderly, was treated with clozapine (300 mg/d) and with
fluoxetine (80 mg/d) for obsessive symptoms induced by
clozapine treatment. He said that he had gained approx-
imately 30 kg after undergoing antipsychotic medication and
had tried several times before to reduce the amount of meals
he ate to control his weight but had failed to do so.
He reported an increase in energy despite a moderate loss
of appetite and weight (approximately 4 kg) in the first 4
weeks of the ALA trial. In 12 weeks, he had lost a considerable
amount of weight (8.85 kg) and still reported an increase in
energy level in the workplace. He reported that he had been
able to eat far less than before due to his loss of appetite. He
has been followed up as a private patient beyond the 12-week
study, and he is taking ALA to validate the long-term effects of
ALA treatment. He has shown a continuous reduction in
weight, as much as 16.4 kg in 9 months from the experiment
end point, and reports that he is still losing his weight.
Subject E.E. was a 28-year-old woman treated with
clozapine (200 mg/d) and divalproex (500 mg/d). She was
146
Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
gaining weight by 1 or 2 kg/mo before the enrollment. She
was dropped out of the study because of noncompliance with
the medication; at 2 weeks past the appointment, she arrived
at the clinic demanding a continuous prescription for ALA.
Her reasoning was that she thought that ALA had halted the
increase in her weight.
Subject F.F., aged 37 years, was a housewife, and she
had been treated with clozapine (100 mg/d) and divalproex
(1000 mg/d). She reported that she had been gaining
approximately 1 kg/mo before the study.
At the 4th week of visit, she was delighted with her weight
loss of 3.20 kg, but in contrast with other subjects, she reported
a mild loss of interest and asked whether it is a side effect of
ALA. When she visited the outpatient clinic just before the 8-
week point, she reported more aggravated depressive symp-
toms, including anxiety and loss of volition to her physician,
who made a judgment that she would need an antidepressant
medication. Considering her history of a seasonal pattern and
the clinical features of her depression, her physician supposed
that she was undergoing a seasonal relapse of depressive
symptoms. Because of safety concerns and the addition of
medication, she was dropped from the study.
Subject G.G. was a 29-year-old woman treated with
risperidone (3 mg/d) and lithium (750 mg/d). She reported
that she had failed to reduce her food intake several times
before because of her increased appetite.
After the first 4 weeks of the ALA trial, she seemed to
lose little weight. She has, however, shown gradual weight
reduction on subsequent visits by a total of 3.8 kg for 12
weeks. She reported that she gained a sense of self-competence
in controlling her diet thanks to a reduction of appetite.
She has taken ALA for additional 2 months after the study
and lost additional weight. Interestingly, even after cessation of
the ALA medication, she said that she has not regained her
appetite, and so she continues to eat an appropriate amount of
food. She lost 12.5 kg in the 6 months after the end point of the
study and is in generally good condition.
* 2008 Lippincott Williams & Wilkins