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Neuroscience and Biobehavioral Reviews 37 (2013) 911– 929

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

j ourna l ho me pa ge: www.elsev ier .com/ locate /neubiorev

eview

otential roles of zinc in the pathophysiology and treatmentf major depressive disorder

alter Swardfagera,b, Nathan Herrmanna,c,d,e, Roger S. McIntyrec,d,e,f, Graham Mazereeuwa,c,yle Goldbergera, Danielle S. Chae,f, Yael Schwartza, Krista L. Lanctôta,b,c,d,∗

Neuropharmacology Research Group, Sunnybrook Research Institute, Toronto, ON, CanadaToronto Rehabilitation Institute, Toronto, ON, CanadaDepartment of Psychiatry, University of Toronto, Toronto, ON, CanadaDepartment of Pharmacology & Toxicology, University of Toronto, Toronto, ON, CanadaInstitute of Medical Science, University of Toronto, Toronto, ON, CanadaMood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada

a r t i c l e i n f o

rticle history:eceived 14 November 2012eceived in revised form 19 March 2013ccepted 27 March 2013

eywords:incepressionajor depressive disordereuroprogressionntidepressants

a b s t r a c t

Incomplete response to monoaminergic antidepressants in major depressive disorder (MDD), and thephenomenon of neuroprogression, suggests a need for additional pathophysiological markers and phar-macological targets. Neuronal zinc is concentrated exclusively within glutamatergic neurons, acting as anallosteric modulator of the N-methyl d-aspartate and other receptors that regulate excitatory neurotrans-mission and neuroplasticity. Zinc-containing neurons form extensive associational circuitry throughoutthe cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. Inanimal models of depression, zinc is reduced in these circuits, zinc treatment has antidepressant-likeeffects and dietary zinc insufficiency induces depressive behaviors. Clinically, serum zinc is lower inMDD, which may constitute a state-marker of illness and a risk factor for treatment-resistance. Marginalzinc deficiency in MDD may relate to multiple putative mechanisms underlying core symptomatology

lutamateMDA

nflammationeuroplasticityntioxidantorced swim test

and neuroprogression (e.g. immune dysfunction, monoamine metabolism, stress response dysregula-tion, oxidative/nitrosative stress, neurotrophic deficits, transcriptional/epigenetic regulation of neuralnetworks). Initial randomized trials suggest a benefit of zinc supplementation. In summary, molecularand animal behavioral data support the clinical significance of zinc in the setting of MDD.

© 2013 Elsevier Ltd. All rights reserved.

PR39

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9122. Localization of zinc in the central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9123. Molecular actions of zinc in the mammalian central nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 912

3.1. NMDA receptor modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9133.2. Neuroplasticity and neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9133.3. GPR39, a zinc sensing receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914

4. Effects of zinc in animal behavioral models of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9154.1. Experimental zinc depletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
4.2. Forced swim test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4.3. Passive-avoidance acquisition and open-field hyperactivity in olfa4.4. Chronic stress models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue,ax: +1 416 480 6022.

E-mail address: [email protected] (K.L. Lanctôt).

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912 W. Swardfager et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 911– 929

5. Neurochemical effects of chronic zinc administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9175.1. Synaptic zinc concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9175.2. Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9175.3. Neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9195.4. Neurogenesis and synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9195.5. Transcriptional regulation and epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920

6. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9206.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9206.2. Marginal zinc deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9206.3. Immune activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9226.4. Clinical evidence for antidepressant activity of zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Major depressive disorder (MDD) is a recurrent and often debil-tating condition that contributes prominently to the cumulativelobal burden of disease. Notwithstanding evidence of monoamin-rgic dysfunction in MDD (Meyer et al., 2006), only half of thosereated with monoaminergic antidepressant medications achieveemission (Casacalenda et al., 2002). Moreover, despite treatment,DD is associated with ongoing social and occupational dysfunc-

ion, reduced somatic health status and poorer overall quality of lifeue to the persistence of depressive symptoms between episodesThase, 2003). Incomplete antidepressant response, as well as thehenomenon of “neuroprogression” in nonresponders has stim-lated the search for new pathophysiological markers that mayirect additional or adjunctive therapeutic targets (Moylan et al.,012). Chronic MDD can be conceptualized as a neuroprogressiveisease, where each episode impacts brain structure and func-ion, increasing susceptibility to future episodes. This has drawnttention to a number of physiological/biochemical/immunologicalathways that can lead to neurodegenerative changes, as indi-ated, for example, by reduced hippocampal volume and a declinen neurocognitive performance in those with MDD (Campbellnd Macqueen, 2004; Millan et al., 2012). Accordingly, observedhysiological correlates of MDD collectively implicate a deficit

n neuroplasticity as a key pathophysiological element (Eyre andaune, 2012; Pittenger and Duman, 2008). With this in mind,he present review summarizes the neurophysiology, animalehavioral evidence, epidemiology and emerging clinical interven-ional data concerning the possible involvement of perturbed zincomeostasis in MDD. As an important cofactor for many enzymesincluding those that regulate apoptosis, monoaminergic functionnd epigenetic control of gene expression), a potent neuroen-ocrine regulator, an essential immune constituent, an allostericodulator of neurotransmitter receptors, and a powerful antioxi-

ant, zinc may be pertinent to the presentation and progression ofDD.

. Localization of zinc in the central nervous system

The uptake of zinc into the mammalian central nervous systemCNS) was first described in 1943 by Sheline et al. in mice and dogsSandstead et al., 2000). A few decades later, using absorption spec-roscopy, it was determined that the highest zinc concentrationsre present in the hippocampus and cortical gray matter (Hu andriede, 1968). In 1967, Haug et al. determined that hippocampal
inc was localized to the mossy fibers (Haug, 1967), cataloging theinc-containing neurons of the temporal lobe and the rest of theorebrain including the amygdala (Haug, 1974). Zinc is retained inhese neurons with a half-life on the order of days to weeks (Takeda
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923

et al., 1995). While the majority of zinc in the brain is protein bound,free zinc, or that which can be detected histochemically, is local-ized exclusively to presynaptic vesicles at concentrations estimatedaround 300–350 �M (Frederickson et al., 1983) with comparativelylittle in the cytosol (Takeda, 2011). Vesicular zinc is concentratedby zinc-selective intracellular transporters, notably ZnT-3, whichis richly expressed in areas of the brain where zinc is sequestered,stored and released by neurons (Palmiter et al., 1996).

Zinc is localized in nodal structures that subserve myriad cog-nitive and affective processes (e.g. memory, affect regulation,psychomotor function, hedonic tone, attention and executive func-tion), providing the basis for hypothesizing that perturbations inzinc homeostasis may be integral to both core symptoms of MDDand the associated cognitive dysfunction (Millan et al., 2012; Sensiet al., 2009). In general, zinc-containing afferents originate in thecerebral cortex and amygdala, and zinc-containing efferents fromthese regions project to targets in the cerebral cortex, amygdalaand striatum, or to limbic loci including the hypothalamus, whichregulates endocrine functions via the pituitary gland (Christensenand Geneser, 1995; Howell et al., 1991; Long et al., 1995; Perez-Clausell et al., 1989; Sorensen et al., 1995). The zinc-containingneurons form associational fibers, comprising circuits that relaysignals between brain regions within the same lobe or hemisphere.A particularly zinc-rich pathway is located within the hippocam-pus, which consists of contiguous dentate granule neurons, CA3pyramidal neurons, CA1 pyramidal neurons and prosubicular neu-rons, and it terminates in non-zinc-containing subicular pyramidalcells (Fig. 1). The subiculum thus receives signals from the hip-pocampus, and the subsequent activity of the subicular pyramidalcells routes information to the other regions (Gigg et al., 2000).The hippocampus is critical to higher cognitive functioning suchas memory and learning, and hippocampal volume reduction pro-portional to episode number, severity and duration, is observed inMDD (Campbell and Macqueen, 2004).

3. Molecular actions of zinc in the mammalian centralnervous system

The concentration of zinc in human cerebrospinal (CSF) isapproximately 0.15 �M (Takeda and Tamano, 2009). Glutathione,albumin and metallothioneins exhibit nanomolar zinc affinities(Wensink et al., 1988) and metallothioneins (MT-I, MT-II and MT-III) in particular are known to sequester zinc as part of a tightlyregulated homeostatic mechanism. Of these proteins, MT-III isbrain specific and localized to glutamatergic neurons (Aschner
et al., 1997).
Physiological concentrations of zinc can protect against oxida-tive stress and apoptosis (Meerarani et al., 2000). Specific inhibitorsof apoptosis have recently been shown to have antidepressant

W. Swardfager et al. / Neuroscience and Biob

Fig. 1. Zinc projections in the hippocampus. A particularly zinc-rich associationalpathway consisting of dentate granule cell mossy fibers, CA3 pyramidal neurons,CA1 pyramidal neurons and prosubicular neurons interconnects hippocampal sub-fields. The pathway terminates in non-zinc-containing subicular pyramidal cells.The subgranular zone of the dentate gyrus is a source of neural progenitor cells,which migrate to distal hippocampal subfields, mature, and arborize to form newsynaptic connections, processes implicated in antidepressant activity. Sprouting ofhb

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ippocampal mossy fibers is involved in learning, and synaptic plasticity is affectedy zinc modulation of kainite, NMDA and other receptors in this pathway.

ffects in animal models (Malkesman et al., 2012), corroborat-ng evidence that pathophysiological processes associated with

DD and effective treatments may converge on inhibition ofro-apoptotic pathways (Dygalo et al., 2012; Kosten et al., 2008;ubera et al., 2011). However, under conditions of ischemia, acid-sis, seizure, or mechanical injury, dysregulated zinc release fromrotein-bound pools can exacerbate excitotoxicity and predisposeeurodegeneration by activating calcium influx through voltage-ated channels and activating apoptotic machinery (Aizenmant al., 2000; Hyrc et al., 1997; Jiang et al., 2001; Sensi et al., 2009;orensen et al., 1998). Accordingly, dysregulated release of zinc canause degeneration of CA1 and CA3 hippocampal neurons (Lee et al.,000).

Zinc appears to have a biphasic effect on oxidative stress andhis may partially involve perturbation of nitric oxide homeostasis.igh concentrations of zinc are associated with increased expres-

ion of neuronal nitric oxide synthase (nNOS) and NADPH oxidaseeading to increased nitric oxide and superoxide formation, whichombine to induce oxidative and nitrosative stress through the pro-uction of the enduring nitrosative stress mediator peroxynitriteNoh and Koh, 2000). Excessively low extracellular concentrationsf zinc are also associated with increased oxidative and nitrosativetress, also via nNOS and NADPH oxidase (Aimo et al., 2010). How-ver, intermediate concentrations are neuroprotective (Aimo et al.,010). Thus, any perturbation of zinc homeostasis may increasexidative/nitrosative stress, highlighting the critical importancef maintaining zinc homeostasis in the function and structuralntegrity of the brain. Changes in systemic labile zinc concentra-ions may therefore increase susceptibility to pathophysiologicalhanges both within the central nervous system (CNS) and else-here in the body (Chai et al., 1999).

Within in the CNS, histochemical studies have determinedhat the zinc-containing neurons are exclusively glutamatergic
Frederickson and Danscher, 1990). Glutamatergic neurons releaseinc in response to depolarizing currents (Howell et al., 1984) in
calcium-dependent manner (Frederickson and Danscher, 1990)onsistent with vesicular release/exocytosis. At rest, extracellular

ehavioral Reviews 37 (2013) 911– 929 913

concentrations of zinc around the glutamatergic neuron have beenestimated on the order of 0.02 �M (Frederickson et al., 2006). Elec-trophysiological evidence and fluorescent staining have confirmedthat zinc is co-released in discrete increments with glutamatefrom presynaptic nerve terminals (Qian and Noebels, 2005; Vogtet al., 2000), increasing concentrations of zinc in the glutamatergicsynapse to between 10 and 100 �M (Frederickson et al., 2006; Vogtet al., 2000).

3.1. NMDA receptor modulation

Zinc regulates a number of ligand and voltage gated ion channelsessential for experience-dependent plasticity of synaptic circuits(Aras et al., 2009; Harrison and Gibbons, 1994). Of these, the excit-atory NMDA receptor complex, which responds to glutamate byincreasing its permeability to calcium, is a compelling moleculartarget of zinc. The NMDA receptors are heterotetrameric complexescomprised of combinations of NR1 and NR2 subunits. Each subunitcontains an extracellular N-terminal domain that houses bindingsites for extracellular small molecules that modulate channel gat-ing (Mony et al., 2009). Zinc can bind these allosteric sites of the twomost commonly expressed NR2 NMDA receptor subunits, NR2Aand NR2B, with the effect of partially inhibiting ion channel con-ductance (Mony et al., 2009; Rachline et al., 2005). The NR2A andNR2B subunits differ greatly in their affinities for zinc; NR2A has arelatively high affinity, on the order of 15 nanomolar (Mony et al.,2009) while NR2B has an affinity several orders of magnitude lower,in the micromolar range (Mony et al., 2009; Rachline et al., 2005).Consistent with modulation at the NR2B low affinity site, zinc caninhibit NMDA-induced currents with an apparent Kd of approxi-mately 8.6 �M (Reichling and MacDermott, 1991). Zinc tonicallyoccupies the high-affinity binding site whereas lower affinity zincbinding is associated only with action potential-driven zinc releaseat the hippocampal mossy fiber synapses (Vogt et al., 2000). Thusboth the background tone of conductance at NMDA receptors andacute phasic responses to glutamate can be modulated by zinc atNR2A and NR2B NMDA receptors such that concentrations of up to300 nM selectively affect NR2A containing receptors (Izumi et al.,2006; Mony et al., 2009).

3.2. Neuroplasticity and neurogenesis

The hippocampus participates in various forms of learningand memory, and in regulating the salience of affective informa-tion (Fanselow, 2000; Riedel et al., 1999). The hippocampus andparahippocampal gyrus are activated when perceiving negativelyvalenced stimuli or negative affective states (Blood et al., 1999).Immunohistochemical and in situ hybridization experiments showthat the hippocampus extensively expresses NR2A and NR2B con-taining NMDA receptors (Ishii et al., 1993; Monyer et al., 1994;Wenzel et al., 1995) on which memory and affective responses arelikely to depend (Daw et al., 1999).

In the adult brain, the subgranular zone of the hippocampaldentate gyrus supports neurogenesis (Kaplan and Hinds, 1977), aprocess critical for working and contextual memory (Kempermannet al., 2004). New neurons migrate from the subgranular zone tothe granular layer of the dentate gyrus, traverse set paths to distallocations in other hippocampal subfields and undergo arboriza-tion and synaptogenesis, thereby integrating into the circuitry ofthe hippocampus (Lledo et al., 2006). A decrease in the number ofproliferating cells in the dentate gyrus is associated with impairedlearning and memory, as observed in animal models of depression
(Jaako-Movits and Zharkovsky, 2005).
The proliferation of hippocampal neural progenitor cells inthe dentate gyrus can be stimulated by NMDA receptor activa-tion (Chun et al., 2006; Joo et al., 2007). Zinc has been shown to

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ncrease in the rat hippocampus during acquisition of informa-ion (Gigineishvili Ts et al., 2007) and zinc is released in muchigher concentrations in the dentate gyrus than in the CA3 orA1 regions (Komatsu et al., 2005). Tonic zinc concentrationsctive at NR2A containing NMDA receptor complexes are requiredor the induction of long-term potentiation (LTP), a neurogenesisependent sensitization process whereby repetitive strong stim-lation results in greater post-synaptic responses over a periodf days to weeks (Izquierdo et al., 2008). Zinc deprivation in ratsroduces deficits in hippocampal activation following repeated

ow-frequency stimulation of the dentate gyrus which can beeversed by zinc supplementation (Hesse, 1979). Similarly, zinchelation completely abrogates LTP in the dentate gyrus andmpairs object recognition (Izumi et al., 2006; Takeda et al., 2012).

Persistent weak stimulation in the hippocampus results in long-erm depression (LTD), a process functionally opposed to LTPhereby the signal between neurons is diminished following a

epeated weak stimulus, which may fine-tune noisy synapses.hronic stress models of depression increase LTD (Holderbach et al.,007). At 1–10 �M concentrations, zinc inhibits LTD without affect-

ng LTP via blockade of NR2B containing NMDA receptors (Izumit al., 2006), Thus, the pattern of NMDA modulation by zinc maye beneficial in reversing the pattern of deficits associated withepression.

Interestingly, Src-family kinases have been shown to mod-late NR2A and NR2B containing NMDA receptors by tyrosinehosphorylation and this process could represent a mechanismf “metaplasticity”, a modulatory effect of the current state ofignaling on the degree of synaptic plasticity that can be evoked byubsequent stimulation (MacDonald et al., 2007). Browning et al.,howed that zinc deficiency impairs NMDA receptor evoked Ca2+

urrents in guinea pig synaptosomes by decreasing NMDA recep-or number (Browning and O‘Dell, 1995). Conversely, 0.3–1.0 mMinc increases Src-mediated tyrosine phosphorylation of the NR2And NR2B subunits in hippocampal slices and cell cultures, increas-ng both the magnitude of post-synaptic excitatory potentialsver time, and the expression of NR2A and NR2B subunits (Kimt al., 2002). Impaired neuroplasticity has been implicated in MDDEyre and Baune, 2012; Pittenger and Duman, 2008), and synapticomponents that decrease responsiveness to certain stimuli (e.g.eward) or prime responsiveness to others (e.g. guilt, sadness, fear,egative emotional valence) may be relevant. In addition, NR2Bubunits may be more plentiful in extrasynaptic NMDA recep-ors, where they can contribute to Ca2+ influx in the absencef an action potential (e.g. when extracellular glutamate con-entrations are pathologically increased) predisposing cells toxcitotoxicity and impairing neuroplasticity in response to nor-al stimulus-dependent synaptic glutamate release (Thomas et al.,

006). Glutamate receptors on astrocytes modulate the expres-ion of glutamate transporters responsible for the re-uptake oflutamate, regulating extracellular glutamate concentrations androtecting neurons and oligodendrocytes from excessive stimula-ion. Zinc is also likely to play a role in modulating this process.

Modulation by zinc has been described for numerous otherxcitatory and inhibitory ion channels and metabotropic recep-ors involved in synaptic plasticity and mood regulation (Harrisonnd Gibbons, 1994). For instance, �-aminobutyric acid (GABA)eceptors are modulated by zinc (Legendre and Westbrook, 1991),hich can either functionally oppose or reinforce NMDA receptor

ctivation in specific regions, ensuring specificity in the synap-ic modifications that are made in times of conditioned learningKodirov et al., 2006; Sensi et al., 2009). For example, cortical
eurons projecting to the lateral amygdala release zinc, whichuppresses feed-forward inhibition by GABA interneurons, enhanc-ng long-term potentiation in fear conditioning pathways (Kodirovt al., 2006).
ehavioral Reviews 37 (2013) 911– 929

The ionotropic glutamate receptors comprise the most promi-nent excitatory system in the mammalian brain and thefamily also includes the alpha-amino-3-hydroxy-5-methyl-4-isoxaxolepropionic acid (AMPA) and kainate receptors, both ofwhich are modulated by zinc at physiological concentrations(Mayer et al., 1989; Mott et al., 2008). Kainate and AMPA recep-tors are also important in synaptic plasticity and zinc can inhibitpost-synaptic kainate receptors at mossy fiber synapses (Mott et al.,2008) and modulate AMPA currents biphasically (Bresink et al.,1996), playing crucial roles in learning and memory since potenti-ation of AMPA currents can increase LTP (Rassendren et al., 1990;Sirtori et al., 1998). Like the NMDA receptor, the AMPA receptor hasbeen implicated in the antidepressant-like effects of zinc; in themouse, an AMPA antagonist blocked the antidepressant-like effectof zinc whereas a positive modulator of the AMPA receptor demon-strated a synergistic benefit in the forced swim test (Szewczyk et al.,2010).

Allosteric modulatory effects of zinc on the presynaptic sero-tonin 5HT1A autoreceptors have also been described, suggestinga role of zinc in modulating serotonergic neurotransmission(Barrondo and Salles, 2009). In the forced swim test, theantidepressant-like effects of zinc could be attenuated by pre-treatment with, p-chlorophenylalanine (an inhibitor of serotoninsynthesis), ritanserin (a 5HT-2A/C antagonist) or WAY 1006335 (a5HT1A antagonist) (Szewczyk et al., 2009) suggesting involvementof the serotonergic system in the antidepressant-like effects ofzinc. Interactions between 5HT1A receptors and the brain derivedneurotrophic factor (BDNF) system in the hippocampus have beenimplicated in depression and in treatment resistance (Anttila et al.,2007; Wu et al., 2012). The interaction between BDNF and its cog-nate TrkB receptor enhances neurogenesis, neuronal viability andarborization, implicating BDNF in the remodeling of the synapticarchitecture that leads to long-term changes in neurotransmis-sion, connectivity and function throughout the hippocampus andneocortex (Altar, 1999; Kozisek et al., 2008). Thus BDNF playsimportant roles downstream of excitatory neurotransmission inlearning and memory, and in the modulation of these processesby emotional valence (Bekinschtein et al., 2007). Although AMPAand NMDA receptor stimulation can release BDNF, excessive NDMAreceptor stimulation can also halt BDNF translation, impairingplasticity (Sutton et al., 2007). Neurogenesis can be impaired byinflammation (Das and Basu, 2008; Goshen et al., 2008), aging(Kuhn et al., 1996) and stress (Joca et al., 2007; Karten et al.,2005), and it can be promoted by physical exercise (van Praaget al., 1999) and antidepressants, which increase BDNF expression(Farmer et al., 2004; Saarelainen et al., 2003). BDNF can have antide-pressant effects (Shirayama et al., 2002) in animal models, and theefficacy of the serotonergic antidepressants seems depend on theirability to increase BDNF signaling (Adachi et al., 2008; Koponenet al., 2005; Saarelainen et al., 2003). These data are consistent witha deficit in neuroplasticity proposed as a pathognomonic feature ofMDD, which may be affected by zinc modulation of the receptorsthat regulate BDNF transcription and translation.

3.3. GPR39, a zinc sensing receptor

In 2001, Hershfinkel et al. demonstrated the existence ofa receptor that initiates intracellular calcium release via thephospholipase C pathway in response to micromolar zinc concen-trations (Hershfinkel et al., 2001). This receptor has been identifiedas the orphan member of the ghrelin receptor family, GPR39,due to its response to physiologically relevant concentrations of
zinc (Holst et al., 2007). GPR39 is expressed in the hippocampus,most abundantly in the CA3 region, and it initiates metabotrophicsignaling following synaptic zinc release (Besser et al., 2009). Themolecular targets upstream of GPR39 signaling remain to be fully

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lucidated, but interestingly, stimulation of GPR39 can upregulatehe anti-apoptotic protein clusterin (Cohen et al., 2012). Clusterins notable because it is expressed in astrocytes throughout thedult brain, and in neurons of the hippocampus, substantia nigradopaminergic), locus ceruleus (noradrenergic), pontine nuclei and

idbrain tegmentum (Pasinetti et al., 1994). Genetic variants in thelusterin gene, CLU, are associated with altered coupling betweenippocampal and prefrontal activation during memory processingErk et al., 2011). Thus, GPR39 may play a role in initiating clusterinelease that maintains functional frontal-subcortical connectivity,mpairments in which are often reported in mood disorders.

In mice, a 6-week zinc-deficient diet initiated depression-likeehavior in the forced swim test and reduced expression of GPR39

n the frontal cortex by 53% (Mlyniec et al., 2013). In that study,DNF expression was also reduced (by 49%). Although intriguing,

urther work will be required to determine how these observationsight be causally related. Another study found that knocking downPR39 produced anxiolytic and anorectic effects in rats, whicharrants further investigation (Ishitobi et al., 2012).

. Effects of zinc in animal behavioral models of depression

.1. Experimental zinc depletion

Studies have reported increases in depression and anxiety likeehaviors, anhedonic symptoms and increased aggression in ani-als fed zinc deficient diets for several weeks (Table 1). For

xample, in the light-dark box paradigm rats fed a zinc deficientiet for three weeks exhibited reductions in the number of entries

nto the light compartment and the total amount of time spent thereTassabehji et al., 2008). In the elevated plus maze, rats spent lessime in the open arms of the maze following two weeks of zinceprivation (Takeda et al., 2007). These anxiogenic effects could beeversed by fluoxetine administration (Tassabehji et al., 2008) andndices of behavioral despair associated with zinc depletion in mul-iple paradigms could be restored by reinstating a zinc sufficientiet (Watanabe et al., 2010).

In mice, the anxiogenic effects of chronic zinc deficiencyere related to exaggerated stress-evoked immediate-early gene

xpression in the amygdala and chronic desipramine or Hypericumerforatum treatment could partially prevent the development of
nxious behaviors (Whittle et al., 2009). In addition, increasedABA and glutamate concentrations in the whole brain, and
ncreased amygdala glutamate concentrations, were observed inonjunction with increased aggression (Takeda et al., 2008). Zinc

able 1ffects of zinc deprivation in animal studies.

Model Animal Duration Finding

Forced swimming test Rat 4 weeks ↑ immoRat 2 weeks ↑ immoRat 2 weeks ↑ immoMouse 7.5 weeks ↑ immo

deficieRat 3 weeks (Zinc d

affecteMouse 2 weeks ↓ immo

4 weeks ↑ immo10 weeks ↑ immo

Tail suspension test Mouse 2 weeks ↓ immo4 weeks ↑ immo10 weeks ↑ immo3 weeks ↔ imm

↑ immoMouse 7.5 weeks ↑ immo

deficie

Saccharin Preference Rat 3 weeks ↓ sacch


deprivation produces elevated serum glucocorticoid concentra-tions, both basally and following exposure to stressors (Mlyniecet al., 2012; Takeda et al., 2008; Watanabe et al., 2010), whichoccurs contemporaneously with increased anxiety-like and depres-sive behavior (Mlyniec et al., 2012; Takeda et al., 2007) but prior todecreased hippocampal zinc concentrations (reviewed (Takeda andTamano, 2009)). In fact, other neurobiological changes that occurwith chronic zinc deprivation, including increased intracellularCa2+ concentrations in the hippocampus, can be mimicked by corti-costerone exposure (Tamano et al., 2009). Moreover, the observeddecrease in hippocampal glutamate, GABA, and glutamine can benormalized by adrenalectomy (Tamano et al., 2009). Observationsof increased glucose metabolism in the hippocampus, amygdalaand thalamus, and decreased serum glucose, would also be consis-tent with zinc deficiency exacerbating cortisol secretion (Tamanoet al., 2009). The animal data suggesting the involvement of HPAaxis hyperactivity in the effects of zinc deprivation is consistentwith human data, which demonstrated inhibition of cortisol secre-tion by acute zinc administration in humans (Brandao-Neto et al.,1990). Even in animals on a zinc sufficient diet, acute zinc adminis-tration shows some anxiolytic-like effects with chronic schedulesproducing more robust effects (Joshi et al., 2012; Partyka et al.,2011; Tassabehji et al., 2008).

4.2. Forced swim test

Numerous replicated studies now support directantidepressant-like effects of zinc in animal models (Table 2).The first indication that zinc may be active in these models camefrom the laboratory of Gabriel Nowak, who showed that acuteadministration of zinc reduced behavioral despair as measured byimmobility time in Porsolt’s forced swimming test (FST). In mice,the effect of zinc sulfate was comparable to that of imipramine(Kroczka et al., 2000). Similar effects of zinc have been observedin the tail suspension test (TST) based on the same principle(Rosa et al., 2003). Since both tests rely on the measurement ofdecreased immobility time to detect antidepressant activity itis important to note that zinc was found to decrease locomotoractivity in the open field test in mice and not to change loco-motor activity in rats at doses active in these tests, suggestinga true non-stimulant antidepressant-like effect (Kroczka et al.,
2000).
In several subsequent studies, subchronic or chronic dosing hasproven more effective than acute schedules, decreasing immobil-ity time in the FST at lower doses (Franco et al., 2008). A lack of

s Study

bility time Takeda et al. (2012)bility time Watanabe et al. (2010)bility time Tamano et al. (2009)bility time (desipramine normalized

ncy-induced immobility)Whittle et al. (2009)

eficiency induced depression was notd by fluoxetine)

Tassabehji et al. (2008)

bility time Mlyniec et al. (2012)bility timebility time

bility time Mlyniec and Nowak (2012)bility timebility timeobility timebility timebility time (Desipramine normalized

ncy-induced immobility)Whittle et al. (2009)

arin preference Tassabehji et al. (2008)


Table 2Effects of zinc in animal behavioral models.

Model Animal Schedule Findings Study

Chronic unpredictable/mildstress

Rat Chronic Zinc restored footshock-induced fighting behavior Cieslik et al. (2007)Zinc and imipramine had more than additive effects

Rat Subchronic Zinc restored sucrose preference and increasedhippocampal BDNF expression

Sowa-Kucma et al.

Olfactory bulbectomy Rat Chronic Zinc improved passive avoidance acquisition Nowak et al. (2003c)Zinc ↓ hyperactivity in open field test

Rat Acute Zinc improved passive avoidance acquisitionZinc ↓ hyperactivity in open field test

Forced swimming test Rat Acute Zinc ↓ immobility time Szewczyk et al. (2010)Mouse Acute Zinc ↓ immobility time

Synergism with NDMA antagonists and an AMPA positivemodulator

Mouse Subchronic Zinc ↓ immobility time Joshi et al. (2012)Zinc ↑ swimming time (comparable to imipramine)

Mouse Acute Zinc ↓ immobility time Szewczyk et al. (2009)Zinc ↑ swimming time (synergistically with fluoxetine andcitalopram)

Mouse Acute Zinc ↓ immobility time Poleszak et al. (2008)Rat Chronic Zinc ↓ immobility time Franco et al. (2008)

Subchronic Zinc ↓ immobility timeAcute Zinc ↔ immobility time

Rat Chronic Zinc ↓ immobility time Nowak et al. (2003c)Subchronic Zinc ↓ immobility timeAcute Zinc ↓ immobility time

Mouse Acute Zinc ↓ immobility time Rosa et al. (2003)Mouse Acute Zinc ↓ immobility time Kroczka et al. (2000)

(Zinc ↓ psychomotor activity in open field test)Mouse Subchronic Zinc ↓ immobility time Kroczka

et al.(2001)

(Zinc ↓ psychomotor activity in open field test)Rat Subchronic Zinc ↓ immobility time (more than additive with

imipramine)(Zinc ↔ locomotor effect in the open field test)

Mouse Acute Zinc ↓ immobility time (additive with citalopram orimipramine)

Szewczyk et al. (2002)

Rat Acute Zinc attenuated malathion-induced immobility Brocardo et al. (2007)Rat Acute Zinc ↓ immobility time Lobato et al. (2008)

Tail suspension test Mouse Acute Zinc ↓ immobility time Rosa et al. (2003)Mouse Acute Zinc ↓ immobility time Cunha et al. (2008)

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ignificant effects on immobility times in acute and sub-chronicchedules may be confounded by reduced locomotor activityFranco et al., 2008; Rosa et al., 2003), which subsides with chronicosing (e.g. after 30 days) (Franco et al., 2008). These studies suggest

favorable psycho-activity profile with chronic dosing.

.3. Passive-avoidance acquisition and open-field hyperactivityn olfactory bulbectomy

Olfactory bulbectomized (OBX) rats exhibit behavioral charac-eristics that parallel human depression. One of the most prominenteatures of the OBX model is hyperactivity (Webster et al., 2000). Inhe open field test, OBX rats show increases in indices of locomo-or activity such as walking time and the number of rearings andeepings, which can be attenuated by monoaminergic antidepres-ants (Kelly et al., 1997). Nowak et al. showed that walking timend the number of rearings and peepings returned to the level ofontrols after both acute and chronic zinc administration (Nowakt al., 2003c). In contrast, in control animals, the same doses of zincad no effect on these parameters, suggesting that the effect of zincas not due to general locomotor retardation.

In the passive avoidance paradigm, the animal acquires a fear-
otivated propensity to refrain from certain behaviors, a process
hat engages the hippocampus through NMDA receptor stim-lation (Baarendse et al., 2008) and depends on neurogenesisJaako-Movits and Zharkovsky, 2005). Nowak’s OBX rats required

y time (synergistic with fluoxetine,ramine, desipramine, and buproprion)

significantly more trials to acquire the avoidance behavior but bothchronic and acute treatment with zinc improved acquisition to thelevel of sham-operated animals even though no effect of zinc onacquisition was observed in sham-operated animals (Nowak et al.,2003c). NMDA antagonists can improve behavioral deficits in OBXand other behavioral models, including learned helplessness andchronic stress (Meloni et al., 1993; Papp and Moryl, 1994; Redmondet al., 1997).

In mice pretreated with zinc, additive effects were observedwith monoaminergic antidepressants but not with NMDA antag-onists (Rosa et al., 2003) although Szewczyk et al. found additiveeffects of zinc and NMDA antagonists in the forced swim test(Szewczyk et al., 2010). While most current antidepressant ther-apies are monoaminergic, a hyperglutamatergic hypothesis fordepression has also been proposed (Machado-Vieira et al., 2009)because NMDA antagonists mimicked the behavioral effects ofantidepressants in several animal models (reviewed (Skolnicket al., 2009). Radioligand studies show decreased NMDA receptorglutamate-site binding in the cortex of MDD patients (Nudmamud-Thanoi and Reynolds, 2004) and increased binding in thehippocampus (Beneyto et al., 2007) in agreement with the glu-tamergic dysfunction observed in animal models (Webster et al.,
2000). In another post-mortem study, the potency of zinc to inhibitNMDA receptors in the hippocampus was reduced in suicide vic-tims compared to controls who died of natural causes (Nowak et al.,2003b).

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There remain few centrally penetrating orally active NMDAntagonists free of dissociative side-effects at doses thatould produce antidepressant effects. Minocycline can producentidepressant-like behavioral effects (Molina-Hernandez et al.,008), normalize glutamate reuptake (Nie et al., 2010) and reducerain kynurenine production during systemic inflammatory chal-

enge (O‘Connor et al., 2009b) (reviewed (Soczynska et al., 2012).he most clinically promising agent, ketamine, infused at a lowoses (0.5 mg/kg), can rapidly induce a reduction in depressiveymptoms that persists for 3–7 days (Berman et al., 2000). Theapacity of NMDA receptors to promote learning and memory,n part through BDNF transcription (Gallo and Iadecola, 2011;urauchi et al., 2011), may seem to contradict the antidepressantenefits of blocking NMDA receptors; however, this apparent con-radiction is resolved by the understanding that signaling throughMDA receptors during an action potential can produce adaptivelasticity, but NMDA activation in the absence of an action potentialan prevent BDNF translation (Sutton et al., 2007). Therefore, block-ng inappropriate NMDA signaling (i.e., that which occurs at rest)

ay produce antidepressant effects by restoring BDNF translationAutry et al., 2011). The direct effects of ketamine on learning and

emory would not be expected to exceed their systemic clearance;owever, a temporary increase in BDNF translation and subse-uent TrkB-mediated neurotrophic effects might account for therolonged antidepressant effect of ketamine observed clinically.

.4. Chronic stress models

The chronic stress paradigm results in motor activity deficits,educed food and water consumption and decreased respon-iveness to rewarding stimuli reminiscent of anhedonic MDDymptoms as well as indications of behavioral despair (Ossowskat al., 1999, 2002; Willner et al., 1992). Tricyclic antidepressants,onoamine oxidase inhibitors and selective serotonin reuptake

nhibitors can attenuate these behavioral changes when admin-stered on a chronic schedule (Ossowska et al., 1999, 2002;owa-Kucma et al., 2011; Zebrowska-Lupina et al., 1991). Whenieslik et al. exposed rats to stressful stimuli over 16 days, theghting behavior induced by a footshock stimulus on day 17as reduced by 75% (Cieslik et al., 2007). Administration of zincydroaspartate (30 mg/kg/day) prior to application of the stressorrevented the acquisition of deficits in fighting behavior whereas5 mg/kg/day was insufficient, as was a single 30 mg/kg dosedministered on day 17 prior to the footshock test (Cieslik et al.,007). Administration of 15 mg/kg/day zinc hydroaspartate as andjunct to sub-effective doses of imipramine was able to com-letely restore the fighting behavior, demonstrating a similardditive property as seen in other models. Chronic zinc treatmentan also reverse the decrease in glucose consumption observedollowing chronic stress (Nowak et al., 2005; Sowa-Kucma et al.,008).

The chronic mild stress model is particularly compelling becausehe acquisition of depression-like behaviors parallels the kindlingffect of stressors in the development of human depression. Inats, chronic stress has been shown to result in long-term neu-oendocrine changes that affect the hippocampus, resulting inacilitation of LTD (Holderbach et al., 2007). These changes haveeen related to various putative interacting pathophysiological ele-ents, including chronic stimulation of the HPA axis resulting in

xcessive stimulation and downregulation of hippocampal glu-ocorticoid receptors (Bratt et al., 2001), increased inflammatoryctivity (Goshen et al., 2008), glutamatergic hyperactivity exac-
rbating hippocampal excitability (Papp and Moryl, 1993, 1994),euroinflammation and oxidative stress (Eren et al., 2007), and
ower hippocampal BDNF expression (Joca et al., 2007; Kartent al., 2005) compromising neurogenesis/neuroplasticity (Eyre and


Baune, 2012; Pittenger and Duman, 2008), reducing neuronal via-bility/resilience (Mineur et al., 2007) and predisposing apopotosis(Lucassen et al., 2006). An extensive body of literature is grow-ing concerning the roles of zinc in each of these interconnectedmechanisms (Fig. 2).

5. Neurochemical effects of chronic zinc administration

5.1. Synaptic zinc concentrations

In animals, reduced concentrations of extracellular zinc havebeen observed in the hippocampus after 4 weeks of zinc deprivation(Takeda et al., 2012), which may have considerable consequencesfor neuroprogression of MDD. Chronic administration of zinc (butnot acute dosing) can increase synaptic zinc concentrations in sev-eral brain regions including the CA1, CA3 and dentate gyrus mossyfibers of the hippocampus (Sowa-Kucma et al., 2011; Szewczyket al., 2006). These data might indicate an increase in zinc at existingnerve terminals, or sprouting of new terminals. Electroconvulsiveshock therapy (ECT), one of the most effective antidepressant ther-apies, is known to induce mossy fiber sprouting (Gombos et al.,1999; Lamont et al., 2001) and to increase hippocampal zinc byalmost 30% (Nowak and Schlegel-Zawadzka, 1999). It is notablehowever, that monoaminergic antidepressants do not consistentlyinduce mossy fiber sprouting (Lamont et al., 2001) and treatmentwith imipramine or citalopram increases hippocampal zinc levelsin the rat brain very little or not at all (Nowak and Schlegel-Zawadzka, 1999; Sowa-Kucma et al., 2011). It is possible that thisdifference may be related to the superior efficacy of ECT, even incases refractory to pharmacotherapy. Likewise the additive effectof zinc co-administration with antidepressants may be related toincreases in brain zinc levels (Cieslik et al., 2007; Nowak et al.,2003a; Szewczyk et al., 2002). Interestingly, zinc, citalopram, and toa lesser extent imipramine, increased presynaptic and extracellularzinc concentrations in the rat prefronal cortex (Sowa-Kucma et al.,2011). Though further work will be required to place these findingsin their appropriate context, zinc, ECT and antidepressant pharma-cotherapy may share some effects on synaptic zinc concentrationsand neuroplasticity.

In a genomic screen of changes in rats acquiring learnedhelplessness, only two transcripts were altered in both the hip-pocampus and frontal cortex, one of which was the ZnT-4 zinctransporter (Nakatani et al., 2004). Like ZnT-3, this transporter islocalized to the terminal boutons (Wang et al., 2005). Interestingly,this transcript was upregulated in the hippocampus and downregu-lated in the frontal cortex by learned helplessness (Nakatani et al.,2004). ZnT-4 expression returned to control levels in the frontalcortex following treatment with imipramine and it returned tocontrol levels in the hippocampus following treatment with flu-oxetine (Nakatani et al., 2004). Deficiencies in the machinery ofcellular zinc homeostasis could thus account for the redistributionof zinc in the brain of depressed patients and the normalizationof zinc distribution following treatment with zinc and/or antide-pressants might facilitate resilience/recovery. In addition to theconsequences of impaired vesicular zinc concentrations, the cyto-toxicity of high cytosolic and intracellular zinc concentrationssuggests that perturbed zinc homeostasis could predispose braincells to apoptosis and neurodegenerative changes (Aizenman et al.,2000; Hyrc et al., 1997; Jiang et al., 2001; Sensi et al., 2009; Sorensenet al., 1998).

5.2. Oxidative stress

Increased markers of lipid peroxidation and a compensatoryelevation in levels of antioxidant enzymes in MDD suggest the


Fig. 2. Relationships between zinc and putative pathophysiological elements of MDD. Tryptophan (Trp) can be used to synthesize serotonin (5-HT) and melatonin (MT) or,due to pro-inflammatory cytokine activation of indoleamine 2,3-dioxygenase (IDO), it can be used to synthesize kynurenine (Kyn) and its metabolites quinolinic acid (Quin)and kynurenic acid (Kyna). These species modulate signaling through the presynaptic �7 nicotinic acetylcholine receptors (�7NAchR), controlling glutamate (Glu) release inthe hippocampus, striatum and frontal cortex. Signaling through glutamatergic neurons can increase dopamine (DA) concentrations and activate dopamine receptors (DR),contributing to attention, activation of reward pathways and psychomotor function. Normal cognitive and affective processes therefore depend on appropriate concentrationsof Kyna in these regions. Activation of the NR2A containing N-methyl-d-aspartate type glutamate receptors (NMDARs) can lead to brain derived neurotrophic factor (BDNF)release and neurogenesis/synaptogenesis facilitating long-term potentiation (LTP), learning, memory and neuroprotection. However, activation of extrasynaptic NR2B NMDAreceptors or over-excitation of synaptic NR2A NMDA receptors by excess extracellular glutamate can suppress BDNF translation, and induce excitotoxic calcium currentsleading to apoptosis and neuroprogression. Subsequent neurodegeneration is modulated by neuronal constituents such as the anti-apoptotic B cell lymphoma-2 (Bcl-2) andthe pro-degenerative glycogen synthase kinase-3� (GSK-3�). Processes depicted in green are adaptive/protective, whereas processes in red are pathological. Interactionswith zinc are noted. Zinc is an agonist at GPR39 and an allosteric modulator of cortical, hippocampal and striatal receptors/ion channels (e.g. �7NAchR, NMDAR, 2-amino-3-[3-hydroxy-5-methyl-isoxazol-4-yl]propanoic acid receptors [AMPAR], kainite receptors, �-aminobutyric acid receptors [GABAR] and 5HT1A receptors) involved in normalcognitive functions (e.g. memory, cognitive flexibility, psychomotor functions, etc.), increasing BNDF and facilitating LTP. Quin is a potent generator of reactive oxygen species(ROS) and some neuroprotective properties of zinc may stem from antioxidant activity. Stress and activation of the inflammatory response system may contribute to perturbedzinc homeostasis in MDD, resulting in disruption of hypothalamic-pituitary-adrenal (HPA) axis regulation, impaired cellular growth pathways, increased susceptibility toa lin-liM

iaetsoamordceczft

poptosis, reduced availability of growth and survival factors such as BDNF and insuDD.

nvolvement of oxidative stress (Maes et al., 2010). Successfulntidepressant treatment is associated with a return of these mark-rs to normal levels (Bilici et al., 2001), a neurochemical effecthey share with zinc. Zinc administration can attenuate the depres-ant effects of malathion in the FST (Brocardo et al., 2007), anrganophosphate insecticide known to cause depressive behaviornd oxidative stress in the rodent brain (Trevisan et al., 2008). Inalathion-treated rats, Brocado et al. characterized a pattern of

xidative damage, including an increase in lipid peroxidation and aeduction in glutathione peroxidase activity in the cerebral cortex, aecrease in glutathione reductase activity in the hippocampus, andhanges in chromatin structure in dentate gyrus cells (Brocardot al., 2007). Co-administration of zinc attenuated these neuro-
hemical changes suggesting that the antidepressant-like effect ofinc may be related to protection against oxidative damage in theorebrain. In healthy animals, Franco et al. detected reduced glu-athione reductase and glutathione S-transferase activities in the
ke growth factor-1 (IGF-1) and some immunological abnormalities associated with

hippocampus and cerebral cortex following acute zinc administra-tion (Franco et al., 2008) but these changes did not persist withchronic dosing, nor did any changes in oxidized glutathione levels.However, rats chronically treated with zinc showed higher totalglutathione content both in the hippocampus and in the cortex, sug-gesting increased antioxidant buffering capacity over time (Francoet al., 2008).

Interactions between zinc and oxidative stress have also beenobserved in rats chronically treated with lithium. Administrationof zinc for 4 months in lithium-treated rats attenuated lithium-induced reductions in catalase and glutathione S-transferaseactivities in the cerebral cortex (Bhalla et al., 2007) similar to theeffects of chronic treatment with the low-affinity NMDA antagonist
memantine in the rat forebrain (Pieta Dias et al., 2007). In addition,zinc is a known modulator of metal-responsive transcription factor1, which is involved in the regulation of metallothionein expressionand glutathione biosynthesis (Andrews, 2001).

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.3. Neuroprotection

Magnetic resonance imaging has demonstrated atrophy ofhe hippocampus in patients with MDD, which was related tohe duration of illness (Bhalla et al., 2007), suggesting neuro-rogressive damage to the hippocampal network. High levelsf endogenous glutamate or glutamate agonists can cause exci-otoxicity, or overstimulation of NMDA receptors, producing aramatic influx of Ca2+ that results in neuronal damage and apo-tosis (Kemp and McKernan, 2002). Non-competitive inhibitorsf the NMDA receptor such as zinc can inhibit arachidonic acidurnover and potentially attenuate downstream neuroinflamma-ion (Viu et al., 1998). A prominent mechanism proposed to causeepressive symptoms is activation of indoleamine 2,3-dioxygenaseIDO) by pro-inflamamtory cytokines (e.g. IFN-�, TNF-� and IL-�) or tryptophan 2,3-dioxygenase, notably in the liver. Thesenzymes synthesize kynurenine from tryptophan, reducing tryp-ophan availability for serotonin and melatonin synthesis andncreasing kynurenine metabolites implicated in the symptoms ofepression. In animals treated with inflammatory stimuli, inhib-

ting IDO can markedly attenuate sickness behaviors (O‘Connort al., 2009a, 2009b). Similarly, in humans administered IFN-�, themergence of depressive symptoms was associated with elevatedynurenine in plasma (Bonaccorso et al., 2002). The increase inynurenine was associated with increased CSF concentrations ofynurenine and the kynurenine metabolite quinolinic acid (Raisont al., 2010). Within the brain, quinolinic acid is synthesized fromynurenine by kynurenine monooxygenase (KMO), primarily inicrolgia (Schwarcz and Pellicciari, 2002). Quinolinic acid is a

otent oxidative neurotoxin, which also contributes to excitotox-city by triggering glutamate release via presynaptic �7 nicotiniceceptors, inhibiting astrocyte glutamate reuptake, and possiblyy directly stimulating NDMA receptors (Schwarcz and Pellicciari,002). Zinc at nanomolar or low micromolar concentrations canct as an endogenous noncompetitive antagonist at excitatorylutamate receptors, attenuating excitotoxicity induced by gluta-ate or NMDA (Choi and Koh, 1998). Excitotoxicity is observed in

nimal models of premature senescence where ZnT-3 levels areeduced in the hippocampal mossy fiber pathways in conjunctionith excessive presynaptic glutamate release and histochemicalarkers of neuronal injury (Saito et al., 2000). Zinc deficient ani-al models (ZnT-3-null mice) show increased susceptibility to

ainate-induced seizures (Cole et al., 2000). These results paral-el a placebo-controlled clinical study in schizophrenic patients

herein the excitability of cortical neurons could be modulatedy zinc administration, resulting in a shift toward a more normalEG pattern (Goldstein and Pfeiffer, 1978).

Quinolinic acid toxicity is endogenously attenuated by activa-ion of kynurenine aminotransferase II (KAT II) in astrocytes, whichroduces the neuroprotective kynurenine metabolite, kynureniccid (Zmarowski et al., 2009). Endogenous kynurenic acid regulatesholinergic, glutamatergic and dopaminergic tone via allostericodulation of �7 nicotinic receptors and thus protects against

euronal, glial and oligodendral toxicity (Poeggeler et al., 2007;hevandavakkam et al., 2010). However, dysregulated inhibi-ion of �7 nicotinic acetylcholine receptors by kynurenic acidan also contribute to impaired cognitive flexibility (Alexandert al., 2012) and memory function (Pocivavsek et al., 2011) byontrolling cortical and hippocampal glutamate concentrationsZmarowski et al., 2009). Similarly, NMDA receptor excitotoxic-ty has been implicated in striatal neurodegeneration (Poeggelert al., 2007; Thevandavakkam et al., 2010) and kynurenic acid influ-
nces striatal dopamine concentrations (Amori et al., 2009), whichould produce symptoms of anhedonia, psychomotor slowing andpathy. Consistent with this suggestion, inflammatory cytokineslter basal ganglia activity, presynaptic striatal dopamine function

and hedonic tone (Capuron et al., 2012). Cognitive features aris-ing from neurochemical and/or neurodegenerative changes areincreasingly appreciated as common neuroprogressive compo-nents of MDD and many interactions along these neural circuitsare modulated by zinc (Fig. 2). Zinc can regulate �7 nicotinic acetyl-choline receptors biphasically (Garcia-Colunga et al., 2004), whichmay normalize presynaptic NMDA release, reducing excitotoxicityand/or attenuating cognitive dysfunction. In addition, physiolog-ical zinc concentrations can inhibit GSK-3� (Ilouz et al., 2002), adownstream facilitator of apoptosis that impairs synaptic plastic-ity implicated in affective disorders that is targeted by lithium (Jopeand Roh, 2006).

Like zinc, the uncompetitive, low affinity open-channelantagonist memantine can inhibit NMDA receptor-mediatedcurrents without inhibiting LTP until much higher concentrations(Frankiewicz et al., 1996). Thus, both zinc and memantine mayinhibit excitotoxic stimuli while facilitating LTP and involved innormal synaptic transmission and plasticity (Wilcock et al., 2008).These neuroprotective properties may be of long-term cognitivebenefit in MDD and in a variety of clinical scenarios associated withdepressive symptoms where excitotoxicity and neurodegenera-tion have been implicated, including traumatic brain injury (Copeet al., 2012), stroke (Gold et al., 2011) and coronary artery disease(Swardfager et al., 2009).

5.4. Neurogenesis and synaptic plasticity

Preliminary rat studies have shown that the administration ofzinc on a chronic schedule can increase the transcription of BDNFin cortical and hippocampal regions (Nowak et al., 2004, 2005;Sowa-Kucma et al., 2008), although like antidepressants (Koziseket al., 2008) acute administration is insufficient. Regulation of neu-rogenesis may also involve neuronal nitric oxide synthase (nNOS)upstream of NMDA activation (Contestabile, 2000; Nowak et al.,2003c; Rosa et al., 2003). Loss of nNOS contributes to deficits inlearning and memory resulting from chronic stress (Palumbo et al.,2007); however, both nNOS inhibitors and NO donors can haveantidepressant-like activity in the FST (da Silva et al., 2000) demon-strating that any acute perturbation of the NO system can havebehavioral effects. Dynamic interactions between NO and BDNFhave been described, suggesting that their balance may be criticalin regulating neurogenesis and synaptic plasticity. For instance, NOfavors the collapsing of growth cones during dendrite outgrowthwhile BDNF has an opposing stimulatory effect (Moreno-Lopez andGonzalez-Forero, 2006). Likewise, while BDNF can be neuropro-tective and stimulate neurogenesis, NO can stimulate apoptosisof neural progenitor cells (Kalinichenko and Matveeva, 2008).Rosa et al. demonstrated the interaction of the NO pathway withthe effects of zinc in the FST, finding that treatment with a NOdonor or l-arginine (the substrate for NO synthase) abrogated theantidepressant-like effects of zinc (Rosa et al., 2003).

Insulin-like growth factor-1 (IGF-1) has complex effects onstructural plasticity in the hippocampus, including increased neu-ral stem cell proliferation in the dentate gyrus and an increase indendritic spine density of CA1 pyramidal neurons (Glasper et al.,2010). IGF-1 can also protect against oxidative stress by activat-ing anti-apoptotic signaling (Floratou et al., 2012; Wang et al.,2010) and reduce brain cytokine expression (Park et al., 2011a).Behavioral studies suggest that these effects are relevant to mood,showing that IGF-1 deficiency can induce depressive-like behaviorin mice (Mitschelen et al., 2011) whereas administration of IGF-1can reduce depression-like behavior in mice treated with inflam-
matory stimuli (Park et al., 2011b). Evidence suggests that zincis involved in the regulation of IGF-1 activity by increasing IGF-1receptor sensitivity and by decreasing IGF-1 inactivation by insulin-binding proteins (McCusker and Novakofski, 2004). In humans,

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onventional antidepressants can increase IGF-1 in CSF, suggest-ng a possible commonality or basis for synergy between zinc andntidepressants (Schilling et al., 2011).

Zinc is required for cellular growth and proliferation at sev-ral levels, including response to multiple growth factors (O‘Dellnd Browning, 2011). At the second messenger level, the extra-ellular signal-related kinases 1 and 2 (ERK1/2) are involved innitiating a variety of neuronal and glial cell functions (Tarditot al., 2006). Deficits in ERK1/2 activity have been implicated in theathophysiology of MDD since ERK1/2 mRNA and protein levels areeduced in the hippocampus and frontal cortex of depressed sui-ide victims compared to non-psychiatric controls matched for agend post-mortem interval (Dwivedi et al., 2001). ERK1/2 activationccurs in the rat cerebral cortex after chronic zinc administra-ion (Franco et al., 2008), an effect common to antidepressantsFumagalli et al., 2005). The selective serotonin reuptake inhibitorsertraline and fluoxetine stimulate ERK1/2 activation in cell cul-ures (Levkovitz et al., 2007). Activation of the ERK1/2 pathwayy tricyclic antidepressants has been shown to stimulate neuralrogenitor cell differentiation into serotonergic neurons, stimu-

ate the release of neurotrophic factors from glial cells, and protecteurons against inflammation-mediated apoptosis (Hisaoka et al.,001). The ERK1/2 pathway is activated by nerve growth factors

ncluding BDNF and it stimulates the anti-apoptotic protein Bcl-2Patapoutian and Reichardt, 2001). Thus the activation of ERK1/2y zinc is consistent with neuroplastic and neuroprotective rolesGallo and Iadecola, 2011; Huang et al., 2007; Kurauchi et al., 2011).

.5. Transcriptional regulation and epigenetics

Zinc dependent transcriptional and epigenetic regulation ofene expression has been implicated in mood disorders. For exam-le, variation in the ZNF804A gene, which encodes a zinc fingerrotein that modulates a network of other schizophrenia associ-ted genes, has been implicated as a risk factor for schizophreniaGirgenti et al., 2012; O‘Donovan et al., 2008; Williams et al., 2011).he ZNF804A risk variant is associated with altered functional con-ectivity of the dorsolateral prefrontal cortex across hemispheresnd with the hippocampus and amygdala, which may define aroad endophenotype (Esslinger et al., 2009). A second zinc-fingerrotein, ZNF326, was recently implicated in treatment response tontidepressants, with concordant data from animals and humansLiou et al., 2012).

Epigenetic mechanisms stably alter gene expression, contribut-ng to the structural and functional brain changes associated with

DD (reviewed Sun et al., 2012). Such mechanisms may providexplanations for how early life stressors can inhibit neurogenesisnd alter behavior in adulthood (Karten et al., 2005). Roles of zincnger containing proteins in key epigenetic modifications, includ-

ng DNA methylation and histone acetylation, may regulate stressesilience/vulnerability (Jakobsson et al., 2008). The chronic unpre-ictable stress model can alter histone acetylation in the CA3 regionnd dentate gyrus (Ferland and Schrader, 2011), and histone acety-ation inhibitors can have antidepressant properties (Yamawakit al., 2012). Interfering with zinc finger protein function in theouse forebrain altered histone acetylation, dysregulated hip-

ocampal gene expression, increased anxiety-like behaviors andmpaired spatial learning and memory (Jakobsson et al., 2008). DNA

ethylation maintains genome stability and silences expression ofpecific genes, which may represent a key interface for genetic-nvironmental interactions. For example, environmental stressas been associated with decreased methylation of the serotonin
ransporter promoter, potentially increasing transporter expres-ion, reducing synaptic serotonin concentrations and increasinghe risk of MDD (Alasaari et al., 2012). Zinc finger proteins areesponsible for recognizing methylation sites and the necessary

regulatory DNA sequences, which may be sensitive to perturbationsin intracellular zinc concentrations (Buck-Koehntop et al., 2012).Age-related increases in inflammation correlated with methylationof the zinc transporter promoter and with reduced intracellular zincconcentrations in immune cells, which could be reversed with zincsupplementation (Wong et al., 2012).

6. Clinical studies

6.1. Epidemiology

Numerous studies have reported lower serum zinc concentra-tions in major depressed patients as compared to healthy controls(Table 3). This effect has also been observed in other popu-lations, including post-partum depression (Brownlie and Legge,1990; Wojcik et al., 2006) and depressive symptoms in late-life(Marcellini et al., 2006). In depressed subjects, serum zinc has beencorrelated with depression severity as assessed by the HamiltonDepression Rating Scale, in some but not all studies (Maes et al.,1994b, 1997d; Siwek et al., 2010; Wojcik et al., 2006). In some stud-ies, serum zinc normalized to control levels when patients weretreated to remission with antidepressants (McLoughlin and Hodge,1990b; Narang et al., 1991; Siwek et al., 2010; Stanley and Wakwe,2002) though this effect is not always observed (Maes et al., 1997d),possibly because not all of the patients recovered to the samedegree, but their serum zinc levels were compared as a group (Maeset al., 1997d). Furthermore, mean serum zinc concentrations maybe even lower in treatment-resistant patients (Maes et al., 1997d).Based on this evidence, it is suggested that lower serum zinc may bea state marker of depression. Because serum zinc can be controlledby diet and/or supplementation, this abnormality may be effec-tively reversed, which might have effects on both somatic healthstatus of depressed patients, and on mood symptoms as suggestedby emerging clinical trial data (see below). Periods of decreased zincbioavailability may contribute to long-term progression of deficitsassociated with MDD via the mechanisms discussed (e.g. neu-rotrophic/neuroplastic deficits, increased oxidative stress, immunefunction, stress hormone dysregulation, etc.).

Some caution is advised in interpreting the clinical data, sinceassessment of zinc status using serum samples does not necessar-ily indicate zinc availability in the cerebrospinal fluid (CSF), in braintissue, or at the synapse. However, in healthy subjects, a close corre-lation between serum and CSF levels is observed (Palm et al., 1983),consistent with rat studies showing a bidirectional zinc flux acrossthe blood-brain barrier (Pullen et al., 1991). CSF zinc concentrationshave not been compared between depressed and control patientsbut a post-mortem study did not find differences in hippocampalzinc between suicide victims and controls (Nowak et al., 2003b).On the other hand, a 50% reduction in brain zinc was observed inschizophrenic patients compared to controls post-mortem, withdeficits of the greatest magnitude occurring in the hippocampus(Kimura and Kamura, 1965). In neurodegenerative illnesses andfebrile convulsions, reductions in CSF zinc tend to be greater thanreductions seen in serum (Gunduz et al., 1996; Jimenez-Jimenezet al., 1998; Molina et al., 1998) suggesting that small serum fluc-tuations may indicate larger changes in CSF concentrations, but thesensitivity and specificity of the serum assays to deficiencies in CNSconcentrations is low. The search for superior biomarkers of zincdeficiency is ongoing (Ryu et al., 2011).

6.2. Marginal zinc deficiency

The reasons for lower serum zinc concentrations in MDD remainincompletely understood. In outpatient samples, the observedmarginal zinc deficiency could be related to extrinsic factors

W. Swardfager et al. / Neuroscience and Biobehavioral Reviews 37 (2013) 911– 929 921

Table 3Human serum/plasma findings.

Population Findings Study

Psychiatric inpatients ↑ copper/zinc ratio in depressed Van Kempen et al. (1985)Mood disorder outpatients ↑ proportion of zinc deficient patients were depressed Little et al. (1989)Psychiatric inpatients ↓ plasma zinc in affective disorder (Feigner’s criteria) patients vs. age and

sex-matched controls; plasma zinc increased from admission to dischargeMcLoughlin and Hodge (1990a)

Psychiatry outpatient ↓ zinc in depressed patients than in patients who had recovered from depression;copper levels significantly ↑ in depressed vs. control or recovered patients

Narang et al. (1991)

Psychiatric inpatients ↓ in major depressed participants, minor depressed participants showed values;significant negative correlations between serum zinc and severity of depressionand plasma neopterin concentrations

Maes et al. (1994a)

Male psychiatric inpatients Serum HDL correlated with serum zinc; participants with MDD had ↓ serum HDLand ↓ HDL/cholesterol ratios

Maes et al. (1997c)

Psychiatric inpatients Inverse correlation between serum zinc and omega 3 polyunsaturated fatty acids Maes et al. (1999)Major depressed patients Lower zinc correlated with higher IL-6 in serum Maes et al. (1997a)Major depressed patients and controls Lower serum zinc correlated with serum dipeptidyl peptidase IV activity (marker

of T cell activation and cytokine production)Maes et al. (1997b)

Treatment resistant depression ↓ in treatment resistant depression than in controls; zinc negatively correlatedwith the CD4+/CD8+ T cell ratio; zinc positively correlated with total serumprotein, serum albumin, and serum transferrin

Major depressed patients Lower serum zinc associated with lower serum tryptophan Maes et al. (1997e)Depressed vs. volunteers ↓ serum zinc in MDD vs. control Nowak et al. (1999)Geriatric inpatients ↑ proportion with respiratory infections, cardiac failure and depression (screened

with GDS) in zinc deficient patientsPepersack et al. (2001)

Depressed inpatients and outpatients ↓ zinc in depressed; ↑ cadmium and ↑ lead in depressed patients Stanley and Wakwe (2002)Psychiatric major depressed outpatients ↓ serum zinc lower in depressed patients (measured by BDI) Mousavi et al. (2006)Depressed inpatients ↓ zinc in female depressed vs. male depressed; positive correlation between serum

zinc and psychomotor retardation score of HAM-D in depressionYang et al. (2005)

Female outpatients ↔ in depressed and non-depressed; ↑ copper in women with history of PPDcompared to non-depressed without history of PPD

Crayton and Walsh (2007)

Major depressed patients ↓ zinc in hair of depressed patients vs. non-depressed but ↔ in whole blood Momcilovic et al. (2008)Clinically identified depressed volunteers ↓ serum zinc in depressed; significant correlation between serum zinc and

albumin in depressedSalimi et al. (2008)

Female volunteers Mean depression scores and depression prevalence decreased after folic acidsupplement (combined with iron, zinc, vitamin B12); no association betweendepression and serum folate, zinc, ferritin

Nguyen et al. (2009)

Aged care residents Lower serum zinc associated with higher depressive symptoms (measured by GDS) Grieger et al. (2009)Female students Linear inverse correlation between BDI scores and serum zinc; dietary zinc intake

correlated with serum concentrations in depressed females but not innon-depressed females

Amani et al. (2010)

Major depressed inpatients ↔ zinc concentrations, ↑ total and free copper and ↓ transferrin in depressed vs.control

Salustri et al. (2010)

Major depressed inpatients and outpatients ↓ serum zinc in depressed vs. control Siwek et al. (2010)ntrols

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Depressed inpatients ↔ serum zinc in depressed vs. coacid concentrations differed in p

uch as intake from dietary sources (e.g. meat, fish, legumes)esulting from appetitive and behavioral changes associated withepression. Lower zinc intake has been associated with increasedepressive symptoms (Yary and Aazami, 2012). Differences ininc concentrations were detected in inpatient samples, includ-ng those where controls were also hospitalized and fed similariets. By the same token however, the normalization of zinc lev-ls on “effective treatment” in these studies might also haveesulted from dietary improvement related to institutionaliza-ion or recovery. In outpatients with MDD, alcohol consumptionould reduce the absorption of dietary zinc by increasing urinaryinc excretion (Russell, 1980). Thus, chronic alcoholic consump-ion is associated with lower serum zinc and lower brain zinconcentrations (Kasarskis et al., 1985; Menzano and Carlen,994).

Marginal zinc deficiency can be induced by other substances,nd this effect may be exacerbated in persons with psychiatricorbidity (Arnold and DiSilvestro, 2005). For example, in two

ouble-blind studies of children challenged with tartrazine, thoseith attention deficit disorder showed decreased serum and sali-

ary zinc concentrations and increased urinary excretion, but this
ffect was not observed in children without attention deficit dis-rder (Adibhatla and Hatcher, 2008). In both studies, hyperactivitynd behavioral changes accompanied zinc wasting, but only in sus-eptible children. Susceptibility may depend on intrinsic/genetic
; correlations between zinc and serum fattys vs. controls

Irmisch et al. (2010)

factors and inherent inter-subject variations in zinc metabolism,which have also been demonstrated in adults. For instance, whenchallenged with mental stress, persons with Type A personalityexcrete more zinc and catecholamines in their urine than personswith Type B personalities (Henrotte et al., 1985). Zinc is a cofactorin the synthesis of coenzymes that mediate the production andturnover of biogenic amine neurotransmitters, which may be rele-vant to the treatment and pathogenesis of MDD (Aizenman et al.,2010; Sandstead et al., 2000).

Monozygotic twin studies demonstrate variation in serum zincand susceptibility to low dietary intake based on genetics (Darluet al., 1985; Henrotte and Levy-Leboyer, 1985), suggesting thatzinc homeostasis might be useful in defining an endophenotype.The Slc39A gene family encodes the ZIPs that mediate intracellu-lar trafficking, the Slc30A family encodes the ZnTs that mediateuptake, and numerous other genes encode zinc binding proteinsthat regulate intracellular concentrations (e.g. the MTs) (Devirgiliiset al., 2007). Genetic variability in these zinc related genes mightbe examined in relation to the differences in immune function andcell cycle gene expression that can be induced by experimentalzinc deficiency in humans (Ryu et al., 2011). Zinc related genetic
polymorphisms, particularly when interacting with low dietaryintake, have been associated with cardiometabolic risk factors(Kanoni et al., 2011; Liu et al., 2007), while the intermediate phe-notype (i.e. serum zinc concentrations) has been associated with

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ardiovascular morbidity/mortality (Pilz et al., 2009), which isighly comorbid with MDD.

Gender differences have also been suggested, for example in onetudy, dietary zinc intake and depressive symptoms were corre-ated only in women (Maserejian et al., 2012), which was confirmedecently in a large female cohort (Jacka et al., 2012). In youngomen, serum measures and dietary intake estimates of zinc were

orrelated in depressed subjects (Amani et al., 2010) suggestinghat those with MDD may be susceptible to the consequences ofietary insufficiency. In pregnant women, zinc intake was foundo moderate the relationship between stress and depression (Royt al., 2010). In healthy populations, serum zinc concentrationsave been reported to be marginally lower in women than in men,lthough there were no gender differences in the prevalence of zinceficiency (Ghasemi et al., 2012; Schuhmacher et al., 1994), andhese results have been inconsistent (Schuhmacher et al., 1994),ossibly due to dissimilar patterns of diet and alcohol consump-ion between men and women or across cultures (Arnaud et al.,010; Ghasemi et al., 2012; Schuhmacher et al., 1994).

Another factor may be a dependence on age; the incidence ofinc deficiency as a function of age increased in men (Ghasemit al., 2012), but not in women, and serum zinc concentrationsere negatively associated with age only in males (Arnaud et al.,

010), suggesting potential relevance to depressive symptomsmergent in men in later-life. Moreover, zinc supplementationan increase circulating testosterone concentrations, correctingeficits in serum testosterone observed in marginally zinc defi-ient men (Prasad et al., 1996). Testosterone has been implicateds a key checkpoint in adult neurogenesis and low testosteronean impair stress resilience and induce depressive symptoms (Kimt al., 2008). Testosterone has also been associated with lymphocyteinc concentrations, suggesting interactions between hormonalnd immune dysfunction mediated by zinc status (Prasad et al.,996).

.3. Immune activity

Inflammatory activity can contribute to lower serum zinc con-entrations and conversely, lower serum zinc can exacerbatemmunological dysfunction. In animal models, increased periph-ral and central inflammatory activity can be induced by chronicild stress (You et al., 2011) and olfactory bulbectomy (Kelly et al.,

997). Maes et al., described a strong negative correlation betweenerum zinc and IL-6 (Maes et al., 1997d) in MDD patients, draw-ng attention to the physiology of the acute phase response, during

hich decreased serum zinc levels result from zinc sequestrationy metallothionein, which is upregulated in the liver, thymus, andone marrow by pro-inflammatory cytokines such as IL-6, TNF-

and IL-1� (Cousins and Leinart, 1988; Kim et al., 2004) and bypregulation of the zinc transporter, Zip14, by IL-6 in the liverLiuzzi et al., 2005). Inflammation might also upregulate metal-othionein in the CNS (Manso et al., 2011). These findings suggest aignificant redistribution of zinc during an inflammatory response.ommunication between the brain and the liver during the stressesponse is partially mediated by HPA axis activation. Cortisol is thend-product of HPA activation, and corticosteroids are known toncrease serum zinc acutely, resulting in increased elimination andltimately, zinc depletion (Fodor et al., 1975; Yunice et al., 1981).ccordingly, patients experiencing an acute phase response showerturbed zinc homeostasis and lower serum zinc concentrationsCraig et al., 1990; Maes et al., 1994b; Oliva et al., 1987).

Extensive evidence suggests that MDD is associated with an
nflammatory response, both in peripheral blood (Dowlati et al.,010; Howren et al., 2009; Liu et al., 2011) and in the CNS (Lindqvistt al., 2009; Shelton et al., 2011). As discussed, studies of hepatitis Catients treated with interferon-� suggest that pro-inflammatory

cytokines can play a causative role in susceptible patients (Raisonet al., 2009). The proposition that lower serum zinc may be aresult of increased elimination during an extended cellular immuneresponse is supported by the correlation between lower serumzinc and elevated concentrations of neopterin (Maes et al., 1994b)and multiple additional immune markers (Table 3). Zinc playsimportant roles in cell-mediated immunity, including immune celldevelopment and maturation (Prasad, 2009) and low zinc con-sumption can depress immune function (Ryu et al., 2011). Zincdeficiency is associated with impaired function of T cells, B cells,and macrophages, as well as impaired cytokine secretion (Prasad,2009). Poor dietary zinc is associated with an increased susceptibil-ity to infection and disease (Prasad, 2009), which can be reversed byzinc supplementation (Prasad, 2009), implicating zinc as a crucialimmune constituent.

An unbalanced or ineffective cellular immune response relatedto zinc depletion could impair pathogen clearance and prolonginflammatory activity in MDD. Lower serum zinc has been asso-ciated with a lower ratio of helper T cells to cytotoxic T cellsin MDD (Maes et al., 1997d) and even subtle zinc deficiency hasbeen associated with lower IFN-�, a prominent cytokine of thepathogen-fighting type 1 helper T cells (Th1) (Beck et al., 1997;Prasad et al., 1997). Among the many other functions, IFN-� inhibitsthe development of IL-17 secreting CD4+ T cells (Th17) (Korn et al.,2009), suggesting a possible basis for overactive but ineffectivecellular immunity in MDD, and a the possibility of an autoim-mune tendency (Chen et al., 2011). Zinc deficiency may augmentthe number of IL-17 secreting T cells (Th17) by enhancing activa-tion of STAT3, a transcription factor needed for Th17 development(Kitabayashi et al., 2010). Accordingly, zinc aspartate suppressedproliferation of human T cells as well as production of IL-2, IL-10 andIL-17 after mitogen stimulation (Stoye et al., 2012). The possibil-ity that marginal zinc deficiency might compromise Th1 mediatedhost defenses while predisposing Th17 autoimmune processes inMDD warrants investigation. Zinc is also involved in the functionand regulation of B cells, which can be “helped” by Th17 cells toproduce autoantibodies. An overabundance of B cells producingautoantibodies has been described in MDD (Robertson et al., 2005)consistent with other reports of increased autoantibody production(Laske et al., 2008; Maes et al., 2010). In older subjects, lower serumzinc is associated with increased IgG2 concentrations (Pepersacket al., 2001). Extended inflammatory activity and/or autoimmu-nity might damage healthy cells and initiate or prolong regulatorymechanisms, such as kynurenine production by IDO. Regardlessof the mechanisms, zinc deficiency exacerbates chronic low-gradesystemic inflammation, which can be corrected with supplemen-tation (Wong et al., 2012).

6.4. Clinical evidence for antidepressant activity of zinc

The recommended daily allowance (RDA) of zinc is 11 mg forpersons over 19 years of age. However, for reasons discussed above,certain individuals may have impaired absorption or increasedelimination of zinc and they may benefit from supplementation athigher doses. According to the National Academy of Sciences, theupper level of intake is suggested to be 40 mg for adults (12–23 mgfor children). Apart from the safety guidelines, there are limiteddata on which to base dosing of zinc for clinical trials in MDD.

The first clinical trial in the setting of MDD was staged by Nowaket al. to assess the antidepressant efficacy of zinc (25 mg elementalzinc administered as the hydroaspartate) as an adjunctive ther-apy in a small (n = 20) randomized double blind placebo controlled
trial (Nowak et al., 2003a). When compared to placebo plus anantidepressant, zinc plus an antidepressant produced a more robustdecrease in depressive symptoms, an additional 50% reduction inHDRS scores by 6 weeks, which was sustained over the full 12

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eeks of the trial. Although only 14 patients completed the trial,he preliminary data provided a strong impetus for additional con-rolled studies. Three subsequent intervention studies have beeneported (reviewed Lai et al., 2012). Siwek et al. used 25 mg of zincas the hydroaspartate) as an adjunct to imipramine, finding thatinc attenuated depressive symptoms both in previously treatmentesistant and non-treatment resistant patients (Siwek et al., 2009).pidemiological evidence supports the evidence of additive ben-fit with antidepressants since dietary zinc intake was associatedith fewer depressive symptoms in women using antidepressants

Maserejian et al., 2012).The synergistic effects of zinc and antidepressants in inter-

ention studies are consistent with the animal studies whereub-effective doses of an antidepressant and zinc in combinationere able to produce an antidepressant-like effect; for citalopram

nd fluoxetine the effect was additive (Szewczyk et al., 2002;zewczyk et al.) and for imipramine the effect was more-than-dditive (Cieslik et al., 2007; Szewczyk et al., 2002). The benefit ofinc supplementation would also be consistent with lower seruminc being a sensitive marker for resistance to treatment withntidepressants (Maes et al., 1997d; Siwek et al., 2010). Chronicntidepressant treatment can also increase the inhibitory effect ofinc at NMDA receptors in the mouse cerebral cortex (Szewczykt al., 2001) and antidepressant treatment can increase hippocam-al zinc concentrations in the rat (Nowak and Schlegel-Zawadzka,999). In both mice and humans, genetic variation in the zinc fingerrotein, ZNF326, implicated in neuronal differentiation, predictedesponse to fluoxetine (Liou et al., 2012), warranting additionallinical investigation.

. Conclusions

Clinical evidence suggests marginal zinc deficiency in MDD, andhat this may be secondary to immune activation/perturbed zincomeostasis in susceptible individuals. However, the relationshipetween serum zinc and CNS concentrations has yet to be qualified.n animal models, zinc deficiency for 2–3 weeks produces signifi-ant reductions in serum zinc, a heightened stress-response andncreased intracellular calcium concentrations in the hippocampus

ith reduced extracellular zinc concentrations in the hippocampusbservable at 4 weeks. Zinc supplementation can produce anxio-ytic and antidepressant like effects in animals, and increase theynaptic zinc pool with chronic administration. As an allostericodulator of NMDA, GABA, metabotropic glutamate, serotonin

eceptors and other ion channels, zinc can inhibit pathological LTDnd excitotoxicity without affecting LTP, which suggests a favor-ble neuropharmacological profile. The presynaptic release of zincrom axon terminals of glutamatergic neurons is prominent in theippocampus where zinc exerts complex pleiotropic effects oneuronal plasticity, neurogenesis and neuronal viability affecting

earning, memory and affect regulation. The neuroprotective prop-rties of zinc at physiological concentrations may be attributableo blockade of excitotoxic Ca2+ influx and upregulation of cellu-ar antioxidant systems. Chronic zinc administration can increaseDNF expression, a hallmark of antidepressant activity required fornhanced neuroplasticity and neuroprotection.

The antidepressant-like activity of zinc in animal modelsppears to be additive with the effects of monoaminergic antide-ressants. The mechanism(s) responsible for potentiation arenknown, but they may involve synergistic (additive serotoner-ic, cholinergic or neurotrophic) or complimentary (glutamatergic,ntioxidant) properties. Alternatively, zinc may be required for
he effects of traditional antidepressants, since treatment-resistantatients have lower serum zinc levels and antidepressants affectinc homeostasis, normalizing regional zinc distribution in therain. To date, findings from animal models have extended into

the clinic in only 4 trials, showing greater apparent effects whenadministered as an adjunctive treatment to monoaminergic antide-pressants. The outcomes of these studies suggest the need for largerrandomized controlled trials, including longer-term follow-ups toestablish safety, effects on somatic health status, neuroprogression(e.g. structural brain changes, neurocognitive outcomes), quality oflife, and effectiveness in the prevention of future episodes.

Acknowledgments

The Authors would like to thank the Reviewers for theirhelpful review of this manuscript. Dr. Swardfager would like toacknowledge post-doctoral support from the Toronto Rehabilita-tion Institute and Heart and Stroke Foundation Center for StrokeRecovery. The Toronto Rehabilitation Institute receives fundingunder the Provincial Rehabilitation Research Program from theMinistry of Health and Long-Term Care in Ontario, Canada; how-ever, the views expressed in this paper do not necessarily reflectthose of the Ministry.

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potential of major depressive disorder · w. swardfager et al. / neuroscience and biobehavioral...

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