Depression and the Efficacy of Zinc Supplementation In adults, does zinc supplementation prevent and lower the severity

of depressive symptoms? Ruth Capistrano November 20, 2012

Introduction Depression is no longer an obscure, ambiguous disease in the general publics eye. On the contrary, depression has proven to be a growing problem among American adultsso much so that 1 in 10 suffer from depression, according to the Center for Disease Control and Prevention (CDC). Granted, the CDC included all forms of depression (its milder variants as well as the most serious case of major, or clinical, depression) when collecting the data, but that doesnt undermine the gravity of depressions current nationwide prevalence and its debilitating ramifications. The National Institute of Mental Health (NIMH) describes depression as the leading cause of disability in the U.S. In any given year, 6.7% of the American adult population experiences depression, implying that the number of those who qualify as having been successfully treated match the number of those who become newly diagnosed with depression. The fact that the prevalence rate is not decreasing highlights the inefficacy of conventional antidepressant medication, and should attract professionals outside of the field of psychology perhaps the more effective treatment of depression lies within these circles instead. Clinical Depression and Depressive Symptoms For the purpose of this literature review, the term depression will always refer to clinical, or major, depression unless stated otherwise. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) outlines the diagnostic criteria that practicing psychiatrists and clinical psychologists use to determine whether or not a patient has depression. The criterion is detailed and extensive but in general, a person must exhibit at least five symptoms concurrently within the minimum of a 2-week period and as a consequence, experiences extreme distress and dysfunction. One of these five symptoms must be either a depressed mood or an uncharacteristic

disinterest in activities that were once considered pleasurable. Milder forms of depression simply have a fewer number of depressive symptoms, and thus a lesser extent of distress and dysfunction. Obviously, the more often a person experiences depressive symptoms, the higher the likelihood that he or she will develop mild forms of depression and eventually, clinical depression. Some depressive symptoms include fatigue, a difficulty concentrating, persistent thoughts of suicide or death, as well as significant changes in weight and sleeping pattern. Weight and sleep cycle changes can occur on both sides of the spectrumsignificant weight gain and significant weight loss are considered equally alarming and qualify as depressive symptoms. Similarly, insomnia and hypersomnia are deemed depressive symptoms, with no given preference for one or the other. Extreme dysfunction, as mentioned earlier, is an important requisite to the diagnosis of depression. It is characterized as a person being unable to carry out normal, everyday activities; their disorder stands in the way of their survival and functioning. For example, a person with the depressive symptoms of hypersomnia and a depressed mood fails to go to work or buy groceries, since he or she is either sleeping or feeling too deflated to get out of bed. Conventional Antidepressant Medication Present conventional antidepressant treatment does not produce uniform results throughout a population. Interpersonal differences of patients exist, and are the reason why 2040% of those exposed to treatment fail to respond to that treatment.4 Such patients are termed treatment-resistant. These differences are accounted for by geneticsa patients potential responsiveness is most likely the same level of responsiveness demonstrated by the patients

first-degree family member. So for example, if a patients immediate family member was more responsive to antidepressant treatment, then the patient would be more responsive as well. There are also adverse side effects posed by the currently-established antidepressant medication. Zinc in Research Literature History It has been demonstrated in research findings that zincs behaviors align with many of other more well-established antidepressants.5 Electroconvulsive shocks and antidepressant medication, for instance, inhibit the phosphorylation process of an enzyme named glycogen synthase kinase-3 (GSK-3). Likewise, zinc inhibits GSK-3 as well. Both zinc and conventional antidepressant treatments increase neurotrophic factor levels (specifically that of brain-derived neurotrophic factor) from depression-inducing low numbers to normal values within the patients blood and brain. Zinc behaves like a serotonin reuptake inhibitor by allowing serotonin to remain in the synaptic cleft, giving the neurotransmitter more opportunities for it to bind to the postsynaptic receptor.6 Being as to how high levels of serotonin are inversely associated with the onset of a depressive episode, zincs influence on serotonin adds to its antidepressant-like properties. In addition to being a serotonin reuptake inhibitor, zinc acts as a glutamate signaling inhibitor as well. This is important because the signaling of glutamate across neurons (also called glutamatergic neurotransmission) is associated with depression. Studies have shown a positive correlation between glutamatergic neurotransmission and depression. The risk for this mental disorder becomes alarming especially in the instance of zinc deficiency where already low amounts of synaptic zinc levels are coupled with an increased sensitivity and excitability of the glutamatergic neurons.

Research showcases more than zincs biological behavior; human cross-sectional studies have shown repeatedly, among various populations, the strong correlation between the amounts of zinc an individual has and depression. Adult depressed patients have relatively low serum zinc level, compared to adults who do not meet the DSM-IV diagnostic criteria of depression. The inverse association between dietary zinc intake and depression is seen in samples with elderly subjects, exclusively female subjects, and subjects suffering from chronic illness.7, 8 Animal studies also support the correlation of zinc levels and depression by reporting that the mice with insufficient zinc levels (by way of a zinc-deficient diet) carried out depression-like behaviors.9 These behaviors were particularly seen in stress induced tests like the tail suspension test and force swim test. Studies like these have led researchers to believe that zinc deficiency is influential in the onset of depression. Although a strong correlation is compelling evidence, it alone is not enough to determine whether or not a certain treatment is effective. Intervention studies, also known as randomizedcontrolled trials (RCTs), in which an intervention or treatment is tested and compared to a placebo, must be conducted. Intervention Studies and Method In the entire research literature history, there are only three RCTs conducted in which the efficacy of zinc supplementation as a potential treatment for alleviating depression symptoms was examined. All three of the RCTs were double-blind and measured efficacy in the same basic approachby way of depression symptom scores. Depression symptom scores are quantitative values associated with the severity of the depression symptoms. They are designated through the evaluation of a clinical psychologist. The particular score range varies

and depends on the outcome measure used in the intervention study, but with regards to all three of the RCTs, the higher the individual or composite depression symptom scores, the more severe the depression symptoms were. In the RCTs, the subjects depressive symptom scores were measured before the intervention, in which a placebo or zinc supplementation was given, as well as after the intervention period. The researchers compared baseline scores, or pre-intervention scores, with that of post-intervention scores. If there was a significant reduction, then the intervention could be considered a potential, viable treatment. Of course, it must be continually tested to draw a sound and unbiased conclusion based on a thorough investigation of zinc supplementation. To fulfill the significant component of the significant reduction distinction, statistical analyses were conducted. If the test statistic fell below the p-value, only then were the results considered significant. The three RCTs followed this general process but they all differed with regards to the sample size, outcome measures, and even the intervention (amount of zinc the subjects received, as well as the duration). In the study conducted by Siwek, Dudek, Paul, Sowa-Kucma, Zieba, Popik, Pilc, and Nowak at Poland in 2009, there were 60 clinically depressed subjects.10 Thirty subjects received a conventional antidepressant, Imipramine, in conjunction with 7.5 mg of zinc every day for 12 weeks. The other 30 subjects were a part of the control group and received a placebo with Imipramine for the same amount of time. The particular outcome measures used to assign depressive symptoms a quantitative value were the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI).

The study conducted by Sawada and Yokoi at Japan in 2010 was designed slightly differently.10 The depression symptom scores were still measured and a reduction in such scores was still sought after, but this time, the sample was composed of healthy, non-clinically depressed subjects, casting zinc supplementation in a preventative role instead. The study was composed of a smaller sample30 female subjects, all of which received a multivitamin every day for 10 weeks. Only half, however, received the intervention treatment of 7 mg of zinc while the other half received a placebo. The outcome measure of this study was the Depression Dejection Score of the Profile of Mood State (POMS-D). The study conducted by Nguyen, Grajeda, Melgar, Marcinkevage, Flores and Martorell at Guatemala in 2008 also examined whether or not zinc supplementation was effective in preventing depressive symptoms from ever occurring.10 The sample consisted of 369 healthy, non-clinically depressed female subjects who were divided into four separate groups as displayed in the table below. Group Number Sample size Intervention 1 88 6.8 mg Zn, 5000 g Folic Acid (FA), 120 mg Fe, 16.8 g B-12 Weekly for 12 weeks 2 97 Placebo, 2800 g FA, 120 mg Fe, 16.8 g B-12 Weekly for 12 weeks 3 84 3.4 mg Zn, 400 g FA, 60 mg Fe, 2.4 g B-12 Daily for 12 weeks 4 100 Placebo, 200 g FA, 60 mg Fe, 2.4 g B-12 Daily for 12 weeks

Duration

The outcome measure used in this study was the Center for Epidemiologic Studies Depression Scale (CES-D).

Results and Limitations The first two studies discussed above yielded significant reductions while the last study conducted by Nguyen et al. produced insignificant reductions in depressive symptom scores. The insignificant results may be due to the multi-mineral intervention treatment the subjects were given. Iron, being one of the distributed minerals, is known to inhibit the absorption of zinc. Its also possible that the other two minerals given (folic acid and vitamin B-12) and/or the combination of these minerals led to an unsuccessful absorption of zinc. Interestingly, the study that tested clinically depressed subjects reported even more significant reductions within a subgroup of patients that were known to be treatment-resistant. There were a couple of limitations posed by the RCTs. The third study was conducted in Guatemala; although the other studies featured subjects of non-American ethnicities as well, their sample sizes were not nearly as large. Looming cultural differences may have impacted the results in this case. Additionally, 37 subjects withdrew from the study; most complained of side effects associated with the intervention, others had to be hospitalized for reasons unrelated to the study, and still yet, a smaller number of subjects simply did not want to continue and complete the 12-week long intervention. Other limitations concerned with the sample composition is the fact that two of the three studies used only female subjects, so if any generalizations could be made from these studies, they can only be applied to the female population. Also, the sample sizes for the studies that were not conducted in Guatemala were rather small.

Conclusions The practical application of recommending zinc supplementation to clients of nutrition professionals and patients of psychiatrists and clinical psychologists cannot be made based off of these three studies alone, especially when one of the studies yielded insignificant results. Further investigations that can specifically hone in on the effects multi-mineral supplementation may have on zinc absorption, within the context of depression and depressive symptom scores, must be conducted. Additionally, replicated studies with larger sample sizes that include male subjects as well as American and other non-American ethnicities is advised to broaden the generalizability of these studies. For now, it is suggested to adhere to the current Recommended Dietary Allowance (RDA) values of zinc. The Office of Dietary Supplements from the National Institutes of Health (NIH) states that a male adult is advised to consume 11 mg/day; a female adult is advised to consume 8 mg/day. In adult pregnant women, it is recommended to consume 11 mg/day, and in adult lactating women, it is recommended to consume 12 mg/day. Dietary sources of zinc are generally red meat and poultry, beans and nuts, whole grains, and dairy items. Plant-based sources, however, may not be the ideal choice because it contains phytate, which prevents the absorption of zinc.11 Some precaution must be taken with regards to zinc levels and intake: an excess of zinc has been found to lead to anemia and lower copper levels. Some foods that are particularly high in zinc are pumpkin seeds, peanuts, wheat germ, liver, lamb, crab and oysters. The Upper Limit (UL) for zinc is 40 mg/day.

References 1. Center for Disease Control and Prevention. An Estimated 1 in 10 U.S. Adults Report Depression. Available at http://www.cdc.gov/features/dsdepression/. Accessed November 16, 2012. 2. National Institute of Mental Health. The Numbers Count: Mental Disorders in America. Available at http://www.nimh.nih.gov/health/publications/the-numbers-count-mentaldisorders-in-america/index.shtml. Accessed November 16, 2012. 3. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Diagnosis of Depression DSM-IV-TR Criteria for Major Depressive Episode and Major Depressive Disorder. Available at http://alerecares.com/pl/MultiSiteIncludes/PDF/pdfs/Depression%20Guideline%20Summ ary%2003-11.pdf. Accessed October 2, 2012. 4. Gower-Winter S and Levenson C. Zinc in the central nervous system: from molecules to behavior. Biofactors. 2012; 38(3): 186-193. 5. Szewczyk B, Kubera M, Nowak G. The role of zinc in neurodegenerative inflammatory pathways in depression. Prog Neuro-Psychoph. & Biol Psychiatry. 2011; 35(3):693701. 6. Levenson C. Zinc: the new antidepressant? Nutr Rev. 2006; 64(1): 39-42. 7. Pepersack T, Rotsaert P, Benoit F, Willems D, Fuss M, Bourdoux P, Duchateau J. Prevalence of zinc deficiency and its clinical relevance among hospitalized elderly. Arch Gerontol Geriat. 2001; 33(3): 243-253. 8. Wojcik J, Dudek D, Schlegel-Zawadzka, Grabowska M, Marcinek A, Florek E, Piekoszewski W, Nowak R, Opoka W, Nowak G. Antepartum/postpartum depressive

symptoms and serum zinc and magnesium levels. Pol J Pharmacol. 2006; 58(4): 571576. 9. Tassabehji N, Corniola R, Alshingiti A, Levenson C. Zinc deficiency induces depression-like symptoms in adult rats. Physiol Behav. 2008; 95(3): 365-369. 10. Lai J, Moxey A, Nowak G, Vashum K, Bailey K and McEvoy M. The efficacy of zinc supplementation in depression: Systematic review of randomized controlled trials. J Affect Disorders. 2012; 136(1): e31-e39. 11. National Institutes of Health. Dietary Supplement Fact Sheet: Zinc. Available at http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/. Accessed October 2, 2012.