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sha.D.

Received 16 June 2010Accepted 26 November 2011

Keywords:Obsessivecompulsive disorderZincClinical trial

relation between the pineal gland and leptin levels [6]. Vesicularzinc may play a role in the synaptic neurotransmission in themammalian brain and serves as an endogenous neuromodulator[7]. Zinc is an important modulator of inhibitory and excitatorysynaptic transmissions [8]. It has been shown to modulatethe action of multiple receptors and channels, increasing

brain function. Baltaci et al. [16] showed a correlation betweenzinc deciency and pineal function in rats and suggested theremay be a direct interaction between melatonin and zinc [16].

Obsessivecompulsive disorder (OCD) is a heterogeneousdisorder of unknown etiology, characterized by the presence ofupsetting and persistent worries and images or impulses that areexperienced as intrusive and senseless (obsessions) and/orexcessive repetitive behaviors (compulsions) performed in

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Nutrition 28 (2012) 892895* Corresponding author. Tel.: 98-611-222-2114; fax: 98-611-222-5763.Introduction

Zinc is a transition metal that is required for processes asdiverse as gene expression, enzymatic catalysis, hormonalstorage, tissue repair, DNA replication, and transcription andprotein synthesis [1,2]. In addition, this trace element acts asa cellular signaling molecule, being present in many regions ofthe mammalian central nervous system, particularly in thecerebral cortex, pineal gland, and hippocampus [3,4]. Less than5% of the total zinc in the brain is stored in the synapticvesicles in zinc-containing neuron terminals. This vesicular zincconcentration in the hippocampal mossy bers ranges from300 to 350 mM [5]. Zinc may play a considerable role in the

a-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid andadenosine triphosphatesensitive potassium channel activityand inhibiting N-methyl-D-aspartate (NMDA), g-aminobutyricacid (GABA) A, and voltage-dependent channel responses [911].Moreover, zinc has been reported to inhibit glycogen synthasekinase-3b [12], a serine/threonine protein kinase that has beenproposed as a target for the treatment of mood disorders [13,14].Zinc may also be considered one of the preventive agents againstoxidative stress in the brain [15]. Alterations in brain zinchomeostasis have been associated with behavioral disturbances,such as anorexia, dysphoria, impaired learning, and cognitivefunction, and with some neurologic disorders (e.g., epilepsy andAlzheimers disease) [2]. There is much evidence about zinc andE-mail address: sayah_bargard@Hotmail.com (M.

0899-9007/$ - see front matter 2012 Elsevier Inc. Adoi:10.1016/j.nut.2011.11.027various pharmaceutical agents are available for the treatment of obsessivecompulsive disorder,psychiatrists often nd that many patients cannot tolerate the side effects of these medications, thepatients do not respond properly to the treatment, or the medications lose their effectiveness aftera period of treatment. The augmentation with safe supplementation of medication, such as withtrace elements, may be a solution to some of these problems.Methods: This study was a prospective, double-blinded, 8-wk trial. Twelve patients were givenuoxetine (20 mg/d) plus zinc (440 mg/d) and 11 patients were given uoxetine plus placebo for8 wk.Results: Both groups showed a decrease in the mean YaleBrown ObsessiveCompulsive Scalescore. Based on t tests, in weeks 2 and 8, patients treated with uoxetine plus zinc had signicantlylower 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.Article history: Objective: Obsessivecompulsive disorder is a common neuropsychiatric condition. Althougha r t i c l e i n f o a b s t r a c tApplied nutritional investigation

Evaluation of oral zinc sulfate effect onA randomized placebo-controlled clini

Mehdi Sayyah M.D. a,*, Alireza Olapour M.D. a, YaRezvan Yazdan Parast M.D. b, Alireza Malayeri Pha Jundishapur University of Medical Sciences, Ahwaz, Iranb Imam Khomeini General Hospital, Ahwaz, Iran

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journal homepage:Sayyah).

ll rights reserved.bsessive-compulsive disorder:l trial

r shahhosseini Saeedabad M.D. b,a

le at ScienceDirect

ion

w.nutr i t ionjrnl .comresponse to these obsessions or according to rigid rules [17].

patients with OCD who were non-responsive to serotonin reup-

Trial design

Eligible participants in the study were 32 patients with OCD (age range 22 to

Statistical analysis

Datawere collected and analyzed using intention-to-treat analyses. Repeatedmeasures analysis of variance was used to assess the effects of treatment (twostudy groups), time (weeks of visit), and the interaction of treatment and time.The signicance of the difference in themean scores at each visit was assessed byunpaired Students t test. The frequency of treatment-induced adverse effects inthe groups was analyzed by Fishers exact test. All statistical tests were two-sidedand were considered statistically signicant at P < 0.05.

Results

signicant differences between the groups regarding demo-

deceased in the two groups during the trial. In the zinc group, the

tine plus placebo (t 2.34, P 0.017, and t 2.11, P 0.047,

Table 1Demographic data of the participants

rition 28 (2012) 892895 89349 y). All participants were outpatients whomet the criteria for OCD according tothe Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, TextRevision. All patients had normal complete blood cell counts, hepatic and renalpanels, and negative toxicologic screens. A minimum score of at least 21 on theYaleBrown ObsessiveCompulsive Scale (Y-BOCS) [27] was required for entryinto the study. The patients did not receive any medicine from 2 mo beforeentering the trial or monoamine oxidase inhibitors for at least 8 wk before thestudy. Patients were excluded from the study if they had a clinically signicantorganic and neurological disorder, current abuse or dependence on drugs withinthe previous 6 mo, psychotic disorders, suicidal ideation, and abnormal liver orrenal function (based on functional parameters: serum urea nitrogen, aspartateaminotransferase, alanine aminotransferase, and creatinine). Pregnant orlactating women and those of reproductive age without adequate contraceptionwere also excluded. The trial was performed in accordance with the Declarationof Helsinki and subsequent revisions [28] and approved by the ethics committeeat the Jundishapur University of Medical Sciences. Written informed consentswere obtained before entering into the study.

Intervention

Zinc and placebo were prepared in similar capsules by the research center ofthe pharmacy college in the Jundishapur University of Medical Sciences. Patientswere randomly allocated to the study group or the control group. Twelve patientswere assigned to the study group and were given uoxetine 20 mg/d plus zinc440 mg/d (220 mg two times daily). Eleven patients were assigned to the controlgroup and were given uoxetine 20 mg/d plus placebo for an 8-wk, double-blinded, placebo-controlled study using a computer-generated list of randomnumbers. Patients in the placebo group received two identical capsules (morningand evening). If the patients had insomnia, they were given one tablet of oxaz-epam 5 mg per night. No other psychotropic medication was prescribed. OneThe study was a prospective, double-blinded, 8-wk trial. Two parallel groupsof outpatients with OCD in the Imam Khomeini General Hospital (Ahwaz, Iran)participated in the study from September 2009 through March of 2010.

Participantstake inhibitors [21,22]. Several lines of evidence have specicallyimplicated the glutamatergic inotropic NMDA receptor in thepathophysiologyofOCD. Thus,Arnoldet al. [23] found that certainpolymorphisms in the NMDA receptor genewere associatedwitha susceptibility toOCD;D-cycloserine, apartialNMDAagonist, hasbeen used successfully to augment cognitive behavior therapy inpatients with OCD [24,25]; and memantine, a non-competitiveNMDA antagonist, has been shown to improve OC symptoms inpatients with treatment-resistant OCD when given as anaugmentation therapy to serotonin reuptake inhibitors [26].

Based on the effect of zinc on inhibitory and excitatorysynaptic transmissions such as GABA and NMDA and role ofthese neurotransmitters on OCD etiology, we decided to evalu-ation efcacy of zinc on OCD in a double-blinded clinical trial.

Materials and methodsIn recent years, an increasing body of evidence has pointedalso to the involvement of the glutamatergic system in OCD [18].Specically, increased glutamate levels have been found in thecerebrospinal uid of drug-naive patients with OCD [19]; thesymptom severity has been found to correlate with the level ofseveral glutamatergic metabolites (measured using magneticresonance spectroscopy) in various brain regions implicated inOCD, including the caudate nucleus, the orbitofrontal cortex, andthe cingulate cortex [20]; and riluzole, a glutamatergic antagonist,has been found to improve the symptoms of adult and pediatric

M. Sayyah et al. / Nutpatient dropped out of the trial (from the placebo group). Patients were assessedby the Y-BOCS at baseline and after 2, 4, 6, and 8 wk after the start of thetreatment.Characteristic Fluoxetine placebogroup

Fluoxetine zincgroup

P

(n 11) (n 12)Sex NSFemale 5 6Male 6 6

Marital status NSMarried 4 5respectively; Table 2).

Clinical complications and side effects

About 10 side effects were observed during the trial. Thedifference between the zinc and placebo in the frequency of sideeffects was not signicant (Table 2).decrease in the mean Y-BOCS score began in the second week ofthe trial, whereas that in the placebo group began in the fourthweek. 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 notsignicant (F 1.8, P 0.061). Based on Students t test, inweeks2 and 8, the patients treated with uoxetine plus zinc hadsignicantly lower mean scores than those treated with uoxe-graphic factors.

Attrition

Twenty-three patients completed the 8-wk trial, and 1patient discontinued the trial. The treatment attrition did notdiffer between the two groups. One patient in the placebo groupwithdrew from the study because this patient moved away fromthe city (Fig. 1).

Effect on the Y-BOCS scores

As shown in Figure 1, the mean Y-BOCS scores graduallyDemographic characteristics

Twenty-three patients enrolled in the study; 12 wereassigned to the zinc group and 11 to the placebo group. Thecharacteristics of the two study groups are present in Table 1. Thetwo groups were well matched and there were no statisticallySingle 7 7Age (y), mean SD 28 1.54 27 1.21 NS

M. Sayyah et al. / Nutritio894Discussion

There is great deal of evidence that selective serotoninreuptake inhibitors are effective in the treatment of OCD. Thetwo groups of patients showed signicant improvements in theY-BOCS during the 8 wk of treatment with uoxetine. The zincgroup showed a greater improvement over the 8-wk trial. Theresults of this study provide statistically signicant support forthe increased antiobsessive and anticompulsive effects ofuoxetine by concurrent treatment with zinc.

The results of this study show that zinc, as adjuvant agent forOCD, produces improved outcomes by decreasing obsession andcompulsion. The clinical characteristics of the patients, such assex, age, and marital status, did not differ between the twogroups. The therapy with zinc 440 mg/d was well tolerated, andno clinically important side effects were observed. The thera-peutic benet of the combined therapy can be attributed to zinc.The results of this study showed that an augmentation of zincwith uoxetine can initiate the therapeutic effects in a shortertime 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.

Fig. 1. Effect of zinc plus uoxetine on the Y-BOCS score. Each point represents themean SD for 11 to 12 patients (* P < 0.05, Students t test). Y-BOCS, YaleBrownObsessiveCompulsive Scale.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 thatlonger periods of treatment and study would result in morereliable data. The use of outpatients, the difculty of entering thetrial and the ease of withdrawing from it, and administering thelowest possible dosage of uoxetine (20 mg) were some limita-tions of the trial. The most important limitation of this study wasthat the blood zinc concentration and its relevancy to the Y-BOCS

compulsive disorder: relationship between metabolite concentrations and

17:7617.[23] Arnold PD, Rosenberg DR, Mundo E, Tharmalingam S, Kennedy JL,

Table 2Reported adverse effects

Side effect Fluoxetine placebogroup

Fluoxetine zincgroup

P

(n 11) (n 12)Somnolence 1 1 NSHeadache 1 0 NSBlurred vision 1 1 NSConstipation 1 0 NSDecreased appetite 0 1 NSNausea 1 0 NSTremor 0 1 NSRichter MA. Association of a glutamate (NMDA) subunit receptor gene(GRIN2B) with obsessivecompulsive disorder: a preliminary study.Psychopharmacology (Berl) 2004;174:5308.symptom severity. J Neural Transm 2008;115:105162.[21] Coric V, Taskiran S, Pittenger C, Wasylink S, Mathalon DH, Valentine G, et al.

Riluzole augmentation in treatment-resistant obsessivecompulsivedisorder: an open-label trial. Biol Psychiatry 2005;58:4248.

[22] Grant P, Lougee L, Hirschtritt M, Swedo SE. An open-label trial of rilu-zole, a glutamate antagonist, in children with treatment-resistantobsessivecompulsive disorder. J Child Adolesc Psychopharmacol 2007;were unknown, so we suggest dening these factors in furtherresearch.

Acknowledgments

The authors thank the staff of the outpatient psychiatry clinicof Imam Khomeini General Hospital for their contribution inconducting this study.

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M. Sayyah et al. / Nutrition 28 (2012) 892895 895

Evaluation of oral zinc sulfate effect on obsessive-compulsive disorder: A randomized placebo-controlled clinical trialIntroductionMaterials and methodsTrial designParticipantsInterventionStatistical analysis

ResultsDemographic characteristicsAttritionEffect on the Y-BOCS scoresClinical complications and side effects

DiscussionAcknowledgmentsReferences