ReviewThe efficacy of zinc supplementation in depression: Systematic review of randomised controlled trials
Introduction
Depression is a mental disorder that is associated with decreased productivity, poor psychosocial outcomes, and decreased quality of life and wellbeing. In 2007, mental disorders were identified as the leading cause of healthy years of life lost due to disability in Australia, and it is estimated that 20% of Australians suffered from at least one mental disorder in that year.
Although there are many effective treatments for depression, pharmacotherapy is usually costly and has potential side effects (Gartlehner et al., 2007), and psychotherapy requires time and commitment (World Health Organisation (WHO), 2001). Therefore, there is a need to investigate alternative treatments or prevention strategies. Recent research has focused on the role of zinc in various mental health disorders including depression (Szewczyk et al., 2011). Zinc is a micronutrient that is essential for optimal function of the human body, especially the brain and neural structures, where it is found at the highest concentration in the hippocampus and amygdala regions of the brain (Takeda and Tamano, 2009).
Studies have suggested that the hippocampus plays a part in the onset of major depression. Magnetic Resonance Imaging (MRI) studies of the brain of depressed patients have shown a significant reduction in hippocampus volume (Sahay and Hen, 2007), which is proposed to be a result of decreased hippocampal neurogenesis (Czeh et al., 2002, Heine et al., 2004, Pham et al., 2003). Moreover, many studies utilising animal models of depression have demonstrated suppression in hippocampal neurogenesis (Ho and Wang, 2010, Mineur et al., 2007, Vollmayr et al., 2007). Recent laboratory studies have found an association between zinc deficiency and a reduction in hippocampal neurogenesis. Suh et al. (2009) found that rats fed a zinc deficient diet had a decrease in the number of progenitor cells and immature neurons within the Dentate Gyrus (DG) of the hippocampus. Other studies have found that zinc increases brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus or cortex (Nowak et al., 2004, Shimizu et al., 2003, Sowa-Kucma et al., 2008), an effect also observed with antidepressant treatment. A number of studies found low levels of BDNF in the brain of depressed patients and treatment with antidepressants was found to return the level of BDNF to normal (Castren et al., 2007, Schmidt and Duman, 2007). Hence zinc may possess antidepressant-like properties that are mediated through BDNF-induced mechanisms.
A number of animal studies have found an association between zinc deficiency and development of depressive illness as rats fed a zinc deficient diet were observed to express depressive-like behaviour such as behavioural despair, anxiety, and anorexia (Ho and Wang, 2010, Tassabehji et al., 2008, Whittle et al., 2009). This association has led investigators to examine zinc as possible intervention for reducing depressive symptoms in rodents. Animal studies have demonstrated antidepressant-like effects of zinc in various rodent tests and models of depression. Administration of zinc in rats reduced immobility time in the forced swim test (FST) and tail suspension test (TST) indicating decreased behavioural despair (Cunha et al., 2008, Kroczka et al., 2001). Zinc was also found to demonstrate antidepressant activity in the olfactory bulbectomy (OB), chronic mild stress (CMS) and chronic unpredictable stress (CUS) animal models of depression (Nowak et al., 2004, Sowa-Kucma et al., 2008).
In humans, several cross-sectional studies have found an association of low zinc status (defined as serum zinc level < 10 or 11 μmol/L) with high depression scores (defined by a Geriatric Depression Scale score of > 5 or 6) amongst the elderly (Grieger et al., 2009, Marcellini et al., 2006, Pepersack et al., 2001). Another study involving perinatal women on the 3rd and 30th day post-delivery found a gradual increase in serum zinc throughout that period and this was negatively correlated with postnatal depressive symptoms, as evident by scoring < 9 on the Edinburgh Postnatal Depression Rating Scale (EPDRS) (Wojcik et al., 2006). Another study found that depressed patients (defined by DSM-III criteria) had a lower serum zinc concentration and urinary zinc excretion level compared to a population reference value (Little et al., 1989).
The association between serum zinc level and depression has also been reported in case–control studies. Lower serum zinc levels were reported amongst patients diagnosed with depression compared to those of non-depressed healthy volunteers (Irmisch et al., 2010, Maes, 1994, McLoughlin and Hodge, 1990, Mousavi et al., 2006, Narang et al., 1991, Salimi et al., 2008). Most studies used the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association, 1994), or the Composite of International Diagnostic Interview (classified as ICD-10) (World Health Organisation (WHO), 1994) to diagnose depression. Another study suggested that moderate to severe depressive symptoms (defined by a Beck Depression Inventory, BDI score of > 19) in young female students were associated with a decreased consumption of food sources rich in zinc, compared to controls (Amani et al., 2010).
Although a considerable amount of research has explored the association of low serum zinc and depressive symptoms, few human studies have investigated the cause and effect relationship of zinc deficiency and depressive symptoms. As such, we are unable to determine if low zinc status precedes the development of depression. A longitudinal study could address this gap in our understanding, but to our knowledge no such study has been performed or published. Moreover, our interest extends to examining the use of zinc supplementation as treatment for depressive symptoms. Randomised controlled trials unlike other epidemiological studies provide high quality evidence to assess the efficacy of zinc supplementation as an intervention for depressive symptoms. In addition, many narrative reviews which include animal studies and non-randomised controlled trials (RCTs) have been published but there has been no systematic review of randomised controlled trials that have examined the effect of zinc supplementation on depressive symptoms. Therefore, the aim of this research was to systematically review all published randomised controlled trials (RCTs) examining the efficacy of zinc supplementation for reducing or preventing depressive symptoms.
Section snippets
Search strategy
Six databases were searched from all years of record until March 2011. The databases consisted of PubMed, Medline, Embase, PsycInfo, the Cochrane Database of Systematic Review, and the Cochrane Controlled Trial Register. Combinations of the following key terms were used: “zinc”, “depression”, “depressive symptom”, “depressive disorder”, “major depressive disorder”, “dysthymia”, and “mood disorder”. The reference lists of relevant review papers were also examined to include additional studies
Results
A total of 2103 articles were retrieved from database searches. The titles and abstracts of 1138 articles were screened, and 41 full-text articles were assessed for inclusion. Six articles met eligibility criteria for inclusion in this review. Duplicate publications were combined to form one set of data — Siwek et al., 2009, Siwek et al., 2010, Nguyen et al., 2008, Nguyen et al., 2009. In total, four RCTs were included (Nguyen et al., 2008, Nguyen et al., 2009, Nowak et al., 2003, Sawada and
Discussion
There are a limited number of randomised controlled trials examining the effect of zinc supplementation as an intervention for depressive symptoms. Most trials have a small sample size, and not all studies used placebo for comparison. The intervention, target populations, and outcome measures differed substantially between trials, and results could only be pooled for two studies.
Role of funding source
This study was conducted as part of a student project; no funding were sought.
Conflict of interest
All authors declare that they have no conflicts of interest.
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