Nutrition 28 (2012) 892895

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Nutrition
journal homepage: www.nutritionjrnl.com

Applied nutritional investigation

Evaluation of oral zinc sulfate effect on obsessive-compulsive disorder:

A randomized placebo-controlled clinical trial
Mehdi Sayyah M.D. a, *, Alireza Olapour M.D. a, Yashar shahhosseini Saeedabad M.D. b,
Rezvan Yazdan Parast M.D. b, Alireza Malayeri Ph.D. a
a
b

Jundishapur University of Medical Sciences, Ahwaz, Iran

Imam Khomeini General Hospital, Ahwaz, Iran

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 16 June 2010
Accepted 26 November 2011

Objective: Obsessivecompulsive disorder is a common neuropsychiatric condition. Although

various pharmaceutical agents are available for the treatment of obsessivecompulsive disorder,
psychiatrists often nd that many patients cannot tolerate the side effects of these medications, the
patients do not respond properly to the treatment, or the medications lose their effectiveness after
a period of treatment. The augmentation with safe supplementation of medication, such as with
trace elements, may be a solution to some of these problems.
Methods: This study was a prospective, double-blinded, 8-wk trial. Twelve patients were given
uoxetine (20 mg/d) plus zinc (440 mg/d) and 11 patients were given uoxetine plus placebo for
8 wk.
Results: Both groups showed a decrease in the mean YaleBrown ObsessiveCompulsive Scale
score. Based on t tests, in weeks 2 and 8, patients treated with uoxetine plus zinc had signicantly
lower scores than those treated with uoxetine plus placebo.
Conclusion: The results show that zinc, as adjuvant agent for obsessivecompulsive disorder,
produces improved outcomes.
2012 Elsevier Inc. All rights reserved.

Keywords:
Obsessivecompulsive disorder
Zinc
Clinical trial

Introduction
Zinc is a transition metal that is required for processes as
diverse as gene expression, enzymatic catalysis, hormonal
storage, tissue repair, DNA replication, and transcription and
protein synthesis [1,2]. In addition, this trace element acts as
a cellular signaling molecule, being present in many regions of
the mammalian central nervous system, particularly in the
cerebral cortex, pineal gland, and hippocampus [3,4]. Less than
5% of the total zinc in the brain is stored in the synaptic
vesicles in zinc-containing neuron terminals. This vesicular zinc
concentration in the hippocampal mossy bers ranges from
300 to 350 mM [5]. Zinc may play a considerable role in the
relation between the pineal gland and leptin levels [6]. Vesicular
zinc may play a role in the synaptic neurotransmission in the
mammalian brain and serves as an endogenous neuromodulator
[7]. Zinc is an important modulator of inhibitory and excitatory
synaptic transmissions [8]. It has been shown to modulate
the action of multiple receptors and channels, increasing
* Corresponding author. Tel.: 98-611-222-2114; fax: 98-611-222-5763.
E-mail address: sayah_bargard@Hotmail.com (M. Sayyah).
0899-9007/$ - see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.nut.2011.11.027

a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid and

adenosine triphosphatesensitive potassium channel activity
and inhibiting N-methyl-D-aspartate (NMDA), g-aminobutyric
acid (GABA) A, and voltage-dependent channel responses [911].
Moreover, zinc has been reported to inhibit glycogen synthase
kinase-3b [12], a serine/threonine protein kinase that has been
proposed as a target for the treatment of mood disorders [13,14].
Zinc may also be considered one of the preventive agents against
oxidative stress in the brain [15]. Alterations in brain zinc
homeostasis have been associated with behavioral disturbances,
such as anorexia, dysphoria, impaired learning, and cognitive
function, and with some neurologic disorders (e.g., epilepsy and
Alzheimers disease) [2]. There is much evidence about zinc and
brain function. Baltaci et al. [16] showed a correlation between
zinc deciency and pineal function in rats and suggested there
may be a direct interaction between melatonin and zinc [16].
Obsessivecompulsive disorder (OCD) is a heterogeneous
disorder of unknown etiology, characterized by the presence of
upsetting and persistent worries and images or impulses that are
experienced as intrusive and senseless (obsessions) and/or
excessive repetitive behaviors (compulsions) performed in
response to these obsessions or according to rigid rules [17].

M. Sayyah et al. / Nutrition 28 (2012) 892895

In recent years, an increasing body of evidence has pointed

also to the involvement of the glutamatergic system in OCD [18].
Specically, increased glutamate levels have been found in the
cerebrospinal uid of drug-naive patients with OCD [19]; the
symptom severity has been found to correlate with the level of
several glutamatergic metabolites (measured using magnetic
resonance spectroscopy) in various brain regions implicated in
OCD, including the caudate nucleus, the orbitofrontal cortex, and
the cingulate cortex [20]; and riluzole, a glutamatergic antagonist,
has been found to improve the symptoms of adult and pediatric
patients with OCD who were non-responsive to serotonin reuptake inhibitors [21,22]. Several lines of evidence have specically
implicated the glutamatergic inotropic NMDA receptor in the
pathophysiology of OCD. Thus, Arnold et al. [23] found that certain
polymorphisms in the NMDA receptor gene were associated with
a susceptibility to OCD; D-cycloserine, a partial NMDA agonist, has
been used successfully to augment cognitive behavior therapy in
patients with OCD [24,25]; and memantine, a non-competitive
NMDA antagonist, has been shown to improve OC symptoms in
patients with treatment-resistant OCD when given as an
augmentation therapy to serotonin reuptake inhibitors [26].
Based on the effect of zinc on inhibitory and excitatory
synaptic transmissions such as GABA and NMDA and role of
these neurotransmitters on OCD etiology, we decided to evaluation efcacy of zinc on OCD in a double-blinded clinical trial.
Materials and methods

893

Statistical analysis
Data were collected and analyzed using intention-to-treat analyses. Repeated
measures analysis of variance was used to assess the effects of treatment (two
study groups), time (weeks of visit), and the interaction of treatment and time.
The signicance of the difference in the mean scores at each visit was assessed by
unpaired Students t test. The frequency of treatment-induced adverse effects in
the groups was analyzed by Fishers exact test. All statistical tests were two-sided
and were considered statistically signicant at P < 0.05.

Results
Demographic characteristics
Twenty-three patients enrolled in the study; 12 were
assigned to the zinc group and 11 to the placebo group. The
characteristics of the two study groups are present in Table 1. The
two groups were well matched and there were no statistically
signicant differences between the groups regarding demographic factors.
Attrition
Twenty-three patients completed the 8-wk trial, and 1
patient discontinued the trial. The treatment attrition did not
differ between the two groups. One patient in the placebo group
withdrew from the study because this patient moved away from
the city (Fig. 1).

Trial design
The study was a prospective, double-blinded, 8-wk trial. Two parallel groups
of outpatients with OCD in the Imam Khomeini General Hospital (Ahwaz, Iran)
participated in the study from September 2009 through March of 2010.

Participants
Eligible participants in the study were 32 patients with OCD (age range 22 to
49 y). All participants were outpatients who met the criteria for OCD according to
the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision. All patients had normal complete blood cell counts, hepatic and renal
panels, and negative toxicologic screens. A minimum score of at least 21 on the
YaleBrown ObsessiveCompulsive Scale (Y-BOCS) [27] was required for entry
into the study. The patients did not receive any medicine from 2 mo before
entering the trial or monoamine oxidase inhibitors for at least 8 wk before the
study. Patients were excluded from the study if they had a clinically signicant
organic and neurological disorder, current abuse or dependence on drugs within
the previous 6 mo, psychotic disorders, suicidal ideation, and abnormal liver or
renal function (based on functional parameters: serum urea nitrogen, aspartate
aminotransferase, alanine aminotransferase, and creatinine). Pregnant or
lactating women and those of reproductive age without adequate contraception
were also excluded. The trial was performed in accordance with the Declaration
of Helsinki and subsequent revisions [28] and approved by the ethics committee
at the Jundishapur University of Medical Sciences. Written informed consents
were obtained before entering into the study.

Intervention
Zinc and placebo were prepared in similar capsules by the research center of
the pharmacy college in the Jundishapur University of Medical Sciences. Patients
were randomly allocated to the study group or the control group. Twelve patients
were assigned to the study group and were given uoxetine 20 mg/d plus zinc
440 mg/d (220 mg two times daily). Eleven patients were assigned to the control
group and were given uoxetine 20 mg/d plus placebo for an 8-wk, doubleblinded, placebo-controlled study using a computer-generated list of random
numbers. Patients in the placebo group received two identical capsules (morning
and evening). If the patients had insomnia, they were given one tablet of oxazepam 5 mg per night. No other psychotropic medication was prescribed. One
patient dropped out of the trial (from the placebo group). Patients were assessed
by the Y-BOCS at baseline and after 2, 4, 6, and 8 wk after the start of the
treatment.

Effect on the Y-BOCS scores

As shown in Figure 1, the mean Y-BOCS scores gradually
deceased in the two groups during the trial. In the zinc group, the
decrease in the mean Y-BOCS score began in the second week of
the trial, whereas that in the placebo group began in the fourth
week. Analysis of variance showed no signicant effect of time
(F 21.2, P < 0.062). The effect of treatment was signicant
(F 2.18, P 0.015). The time-by-treatment interaction was not
signicant (F 1.8, P 0.061). Based on Students t test, in weeks
2 and 8, the patients treated with uoxetine plus zinc had
signicantly lower mean scores than those treated with uoxetine plus placebo (t 2.34, P 0.017, and t 2.11, P 0.047,
respectively; Table 2).
Clinical complications and side effects
About 10 side effects were observed during the trial. The
difference between the zinc and placebo in the frequency of side
effects was not signicant (Table 2).

Table 1
Demographic data of the participants
Characteristic

Sex
Female
Male
Marital status
Married
Single
Age (y), mean  SD

Fluoxetine placebo
group

Fluoxetine zinc
group

(n 11)

(n 12)

5
6

6
6

4
7
28  1.54

5
7
27  1.21

NS

NS

NS

894

M. Sayyah et al. / Nutrition 28 (2012) 892895

were unknown, so we suggest dening these factors in further

research.
Acknowledgments
The authors thank the staff of the outpatient psychiatry clinic
of Imam Khomeini General Hospital for their contribution in
conducting this study.
References

Fig. 1. Effect of zinc plus uoxetine on the Y-BOCS score. Each point represents the
mean  SD for 11 to 12 patients (* P < 0.05, Students t test). Y-BOCS, YaleBrown
ObsessiveCompulsive Scale.

Discussion
There is great deal of evidence that selective serotonin
reuptake inhibitors are effective in the treatment of OCD. The
two groups of patients showed signicant improvements in the
Y-BOCS during the 8 wk of treatment with uoxetine. The zinc
group showed a greater improvement over the 8-wk trial. The
results of this study provide statistically signicant support for
the increased antiobsessive and anticompulsive effects of
uoxetine by concurrent treatment with zinc.
The results of this study show that zinc, as adjuvant agent for
OCD, produces improved outcomes by decreasing obsession and
compulsion. The clinical characteristics of the patients, such as
sex, age, and marital status, did not differ between the two
groups. The therapy with zinc 440 mg/d was well tolerated, and
no clinically important side effects were observed. The therapeutic benet of the combined therapy can be attributed to zinc.
The results of this study showed that an augmentation of zinc
with uoxetine can initiate the therapeutic effects in a shorter
time and more efciently than uoxetine alone.
Due to the impact on the neurotransmitter GABA [8] in OCD,
further studies in this eld should be considered.
The ndings of this study should be considered with caution.
The experimental group was small. The short term of the study
(8 wk) was another disadvantage of the study, and it seems that
longer periods of treatment and study would result in more
reliable data. The use of outpatients, the difculty of entering the
trial and the ease of withdrawing from it, and administering the
lowest possible dosage of uoxetine (20 mg) were some limitations of the trial. The most important limitation of this study was
that the blood zinc concentration and its relevancy to the Y-BOCS
Table 2
Reported adverse effects
Side effect

Somnolence
Headache
Blurred vision
Constipation
Decreased appetite
Nausea
Tremor

Fluoxetine placebo
group

Fluoxetine zinc
group

(n 11)

(n 12)

1
1
1
1
0
1
0

1
0
1
0
1
0
1

NS
NS
NS
NS
NS
NS
NS

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