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Background: Mounting evidence suggests a link between low zinc levels and depression. There is, however, little knowledge about zinc levels in older persons with other psychiatric diagnoses. Therefore, we explore the zinc status of elderly patients suffering from a wide range of psychiatric disorders. Methods: Clinical data and blood samples for zinc analyzes were collected from 100 psychogeriatric patients over 64 of age. Psychiatric and cognitive symptoms were assessed using the Montgomery and Aasberg Depression Rating Scale, the Cornell Scale for Depression in Dementia, the Mini-Mental State Examination, the Clockdrawing Test, clinical interviews and a review of medical records. In addition, a diagnostic interview was conducted using the Mini International Neuropsychiatric Interview instrument. The prevalence of zinc deficiency in patients with depression was compared with the prevalence in patients without depression, and the prevalence in a control group of 882 older persons sampled from a population study. Results: There was a significant difference in zinc deficiency prevalence between the control group (14.4%) and the patient group (41.0%) (χ(2) = 44.81, df = 1, p<0.001). In a logistic model with relevant predictors, zinc deficiency was positively associated with gender and with serum albumin level. The prevalence of zinc deficiency in the patient group was significantly higher in patients without depression (i.e. with other diagnoses) than in patients with depression as a main diagnosis or comorbid depression (χ(2) = 4.36, df = 1, p = 0.037). Conclusions: Zinc deficiency is quite common among psychogeriatric patients and appears to be even more prominent in patients suffering from other psychiatric disorders than depression. Limitations: This study does not provide a clear answer as to whether the observed differences represent a causal relationship between zinc deficiency and psychiatric symptoms. The blood sample collection time points varied in both the control group and the patient group. No data regarding zinc supplementation were collected.
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Zinc Deficiency Is Common in Several Psychiatric
Disorders
Ole Grønli
1,2
*, Jan Magnus Kvamme
1
, Oddgeir Friborg
2,3
, Rolf Wynn
1,2
1Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway, 2Division of Addictions and Specialized Psychiatric Services,
University Hospital of North Norway, Tromsø, Norway, 3Department of Psychology, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway
Abstract
Background:
Mounting evidence suggests a link between low zinc levels and depression. There is, however, little
knowledge about zinc levels in older persons with other psychiatric diagnoses. Therefore, we explore the zinc status of
elderly patients suffering from a wide range of psychiatric disorders.
Methods:
Clinical data and blood samples for zinc analyzes were collected from 100 psychogeriatric patients over 64 of age.
Psychiatric and cognitive symptoms were assessed using the Montgomery and Aasberg Depression Rating Scale, the Cornell
Scale for Depression in Dementia, the Mini-Mental State Examination, the Clockdrawing Test, clinical interviews and a review
of medical records. In addition, a diagnostic interview was conducted using the Mini International Neuropsychiatric
Interview instrument. The prevalence of zinc deficiency in patients with depression was compared with the prevalence in
patients without depression, and the prevalence in a control group of 882 older persons sampled from a population study.
Results:
There was a significant difference in zinc deficiency prevalence between the control group (14.4%) and the patient
group (41.0%) (x
2
= 44.81, df = 1, p,0.001). In a logistic model with relevant predictors, zinc deficiency was positively
associated with gender and with serum albumin level. The prevalence of zinc deficiency in the patient group was
significantly higher in patients without depression (i.e. with other diagnoses) than in patients with depression as a main
diagnosis or comorbid depression (x
2
= 4.36, df= 1, p = 0.037).
Conclusions:
Zinc deficiency is quite common among psychogeriatric patients and appears to be even more prominent in
patients suffering from other psychiatric disorders than depression.
Limitations:
This study does not provide a clear answer as to whether the observed differences represent a causal
relationship between zinc deficiency and psychiatric symptoms. The blood sample collection time points varied in both the
control group and the patient group. No data regarding zinc supplementation were collected.
Citation: Grønli O, Kvamme JM, Friborg O, Wynn R (2013) Zinc Deficiency Is Common in Several Psychiatric Disorders. PLoS ONE 8(12): e82793. doi:10.1371/
journal.pone.0082793
Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan
Received August 1, 2013; Accepted October 28, 2013; Published December 19, 2013
Copyright: ß2013 Grønli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was funded with grand from Northern Norway Regional Health Authority. The funders had no role in study design, data collection and
analysis, decision to publish or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: ole.gronli@unn.no
Introduction
Zinc is a trace element that is essential for the optimal function
of the human body, especially the brain. The highest concentra-
tions of zinc in the brain are found in the hippocampus and
amygdala regions [1]. Zinc is an important cofactor in more than
300 cellular enzymes influencing various organ functions [2].
Furthermore, a lack of zinc can lead to immune insufficiency,
infection, diarrhea, skin eruptions and dermatitis [3].
Important sources of zinc include meat and fresh fish [4]. Zinc
deficiency occurs in all age groups and nationalities [1]. A study
conducted in five European countries revealed zinc deficiency in
31% of people over 60 years of age [4]. In addition, the study
found significant differences between countries. Among hospital-
ized elderly individuals, a prevalence of 28% has been demon-
strated [5].
Several studies have revealed a connection between low plasma
zinc levels and depression [4,6–8]. Animal studies have demon-
strated that zinc deficiency in rodents enhances depression-like
symptoms [9,10]. In animals, depression-like symptoms that are
related to zinc deficiency, appear to be reversed by antidepressant
treatment [10,11].
Several randomised controlled trials (RCT) have been conduct-
ed to explore the impact of zinc supplementation on depressive
symptoms. Two trials have examined zinc supplementation as an
adjunct to antidepressant drug treatment in patients with clinical
depression. In a study by Nowac et al., 14 patients received an
antidepressant and either placebo or zinc supplementation. Zinc
supplementation significantly reduced scores on the Beck Depres-
sion Inventory (BDI) and the Hamilton Depression Rating Scale
(HADRS) after 6 and 12 week of supplementation compared with
placebo treatment [12]. This finding led to a larger RCT in which
60 patients received an antidepressant (imipramine) and either
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placebo or zinc supplementation. In this study, the researchers did
not find a significant difference in the BDI or HADRS scores
between adjunctive treatments with placebo or zinc supplemen-
tation [13]. However, in a subgroup of 21 patients with treatment-
resistant depression, a significantly greater reduction in depression
scores was exhibited by the group that received zinc compared to
the placebo group. These trials were rather small, but the results
have been supported by animal studies. Zinc deficiencies in rats
and mice have been demonstrated to induce depressive symptoms,
that are refractory to antidepressant treatment [11,14].
Most studies of zinc deficiency have focused on depression.
However, zinc has also been linked to a possible role in the
pathogenesis of Alzheimer’s disease (AD), but a causal role in AD
has not yet been demonstrated [15]. There is no evidence of a
difference in serum zinc concentration between patients with AD
and controls [16–18]. Patients with dementia in a psychogeriatric
population are characterized by psychiatric symptoms and
behaviour disturbances, and we have not found any studies
investigating zinc deficiency in this subgroup of demented patients.
Furthermore, the relation between zinc and psychosis is unclear.
However, to our knowledge, no studies have investigated zinc
deficiency and zinc levels in older patients with psychosis.
Moreover, to our knowledge, no studies have compared the zinc
status of a psychogeriatric population (exhibiting a broad range of
psychiatric disorders) with that of healthy controls. It is important
to examine whether zinc deficiency is common elderly patients
with diagnoses other than depression. A better knowledge of zinc
status in the elderly is important beyond the possible association
between low zinc levels and psychiatric disorders. Low zinc levels
are also associated with poor wound healing and an impaired
immune response [19,20]. Studies of nursing home residents, for
example, suggest that low zinc levels may be a risk factor for
pneumonia in the elderly [21].
Aims of the present study
The aims of this investigation were 1) to compare the prevalence
of zinc deficiency in patients referred to a psychogeriatric
department and in a control group and 2) to compare the
prevalence of zinc deficiency in patients with depression and in
patients with other psychiatric diagnoses.
Methods
Study population
Patients older than 64 years who were referred to a psychiatric
hospital in the northern part of Norway during the study period of
March 2010 to December 2011 were eligible for inclusion in the
study. The hospital covers a population of 255,000. We excluded
patients with ongoing infections or who were not able to
communicate due to their medical condition (i.e., severe demen-
tia). In total 107 patients were asked to participate in the study,
and five patients refused to participate. Two patients were
excluded due to ongoing physical illness (infection). The partic-
ipants were diagnosed using the structured Mini International
Neuropsychiatric Interview (MINI+) [22], the Montgomery-
Asberg Depression Rating Scale (MADRS) [23], the Mini Mental
State Examination (MMSE) [24], the Clock-drawing Test [25],
clinical interviews, observations, and medical records. Because of
the medical conditions (e.g.,dementia), it was not possible to
administer the MADRS to all patients: thus the Cornell Scale for
Depression in Dementia [26] was used for 22 patients. Diagnoses
were set according to ICD-10 criteria (WHO, 1992). Blood
samples were drawn in the morning (before 10 AM), within the
first three days of the stay and were analyzed for zinc and albumin.
In addition, a wide range of other tests were performed, but not
analyzed in the present study.
The control group included persons who were recruited from a
population-based health study in Tromsø, a town with 70,000
inhabitants in northern Norway (The 6
th
Tromsø Survey, 2007–
2008). We restricted the analysis to participants older than 64
years. In total, 4017 men and women in this age group
participated in the study, resulting in an overall participation rate
of 66%. Non-fasting blood samples were drawn, and serum from
all participants was frozen. Serum zinc and albumin from a
random selection of 882 individuals were later analyzed and used
for further comparison with the patient group.
Zinc and albumin analyses
In both the patient group and the control group, venous blood
samples were collected for the measurement of zinc and albumin.
For the zinc analysis, trace-metal-free tubes and special gloves
were used to avoid contamination. The samples were frozen and
stored at 270 C. Serum zinc was subsequently analyzed using a
flame atomic absorption at 213.9 nm (Perkin Elmer A-Analyst 800
Atomic Absorption Spectrophotometer).
In the patient group, blood samples were collected in the
morning (before 10 AM). However, due to other considerations,
64% of the samples were collected after patients fasted overnight
and 36% of the samples were collected under non-fasting
conditions. In the control group, all samples were collected under
non-fasting conditions between 8 AM and 12 AM. The
International Zinc Nutrition Consultative Group (IZiNCG) [27]
has recommended different serum zinc cut-off values depending
on the patient’s gender, fasting or non-fasting state, and time of
measurement (i.e., AM or PM). We applied the cut-off values for
zinc deficiency as defined in the IZiNCG guidelines (Table 1). A
large proportion of zinc in serum is bound to albumin [28].
Therefore, we performed an additional assessment of serum
albumin using the brom-cresol green method (Hitachi Modular P,
Roche). The lower reference level for serum albumin was 34.0 g/
L.
Statistical analyses
For the statistical analysis, SPSS 20 (SPSS, Inc., Chicago,
Illinois, USA) was used. Descriptive analyses were conducted to
describe the characteristics of the sample, and the Kolmogorov-
Smirnov test was used to examine assumptions of normal
distributions. Due to a difference in the cut-off values in the
fasting and non-fasting conditions, we based the statistical between
group tests (patient vs. control) on a dichotomously defined zinc
deficiency score (0-no deficiency, 1-deficiency). Differences in
baseline characteristics between patients and controls were
analyzed using Chi-square tests (dichotomous data) and indepen-
dent samples t-tests (continuous data). Differences in the preva-
lence of zinc deficiency between different patient groups were
analyzed with Chi-square tests. The association between zinc
deficiency and the sample (patient vs. control) was expressed as an
Table 1. Lower cut-off levels for zinc deficiency (mmol/L).
Females Males
Am fasting 10.7 11.3
Am non-fasting 10.1 10.7
PM 9.0 9.3
doi:10.1371/journal.pone.0082793.t001
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odds ratio (OR) with 95% confidence intervals (CI) from a logistic
regression analysis. Differences in zinc levels across different
patient groups were tested using one-way analysis of variance. A p-
value ,0.05 was accepted as statistically significant.
Ethical considerations
All patients who were deemed candidates for participation were
provided oral and written information about the study. For
patients who were unable to provide consent alone due to their
medical conditions, their next of kin were provided similar
information. Patients and the next of kin (when relevant) provided
written consent prior to inclusion in the study. Competency to
provide consent was assessed according to previously established
guidelines [29]. The Regional Medical Ethics Committee for
North Norway (REK North) approved the current study.
Results
The 100 psychogeriatric patients (62 females/38 male) included
in the present study suffered from a range of disorders, including
dementias, psychotic disorder, bipolar disorder, unipolar depres-
sive disorder, and anxiety disorders. We found that 41 patients had
a depressive disorder (mean MADRS = 25.3 (7.9)), as a first time
depressive episode, recurrent depression or as part of a bipolar
disorder. We also identified 20 patients who had depression
comorbid with another diagnosis, such as dementia or organic
mood disorder (mean MADRS = 19.9 (10.4)). In 39 of the patients,
we did not identify any depressive disorders (mean MADRS = 4.9
(3.7)). In this group, 20 patients had dementia (10 cases of
Alzheimer’s disease), 11 patients had a psychotic disorder, and 8
patients had other non-depressive disorders. The diagnostic
distribution in these three groups is presented in Table 2. The
rate of antidepressant use in the three patient groups (depression,
comorbid depression and other diagnoses) were, respectively,
76%, 75% and 25%.
The prevalence of zinc deficiency
The prevalence of zinc deficiency in the psychogeriatric patient
group was compared to the prevalence in a control group of 882
persons (444 females/438 males). Table 3 lists the characteristics of
the patient group and the control group. In the patient group,
41.0% (41/100) had zinc deficiency, compared with 14.4% (127/
882) in the control group. This difference was significant (n = 982,
x
2
df = 1
= 44.81, p,0.001). We found a non-significant difference
in the prevalence of zinc deficiency between males (47.4%) and
females (37.1%) in the patient group. In the control group, the
prevalence of zinc deficiency was 18.5% in males and 10.4% in
females, which was a significant difference (n = 882,
x
2
df = 1
= 11.83, p,0.001).
The median zinc level in the non-fasting patient group (n = 36)
was 10.7 mmol/L compared to 12.2 mmol/L in the control group
(also non-fasting). The median zinc levels in the fasting patient
group was 11.2 mmol/L. In the patient group, the prevalence of
zinc deficiency was 42.2% in the fasting group and 38.9% in the
non-fasting group, which was a not a significant difference.
The association between zinc deficiency and the patient or the
control group status was further analyzed with logistic regression
analyses. Zinc deficiency was associated with depression/comorbid
depression and other psychiatric disorders after adjusting for the
fasting condition, gender and age (Table 4). Both age and gender,
but not the fasting condition, made a small contribution to the
model (OR(gender) = 2.0 (1.4–2.8), p,0.001, OR(age) = 1.05
(1.0–1.1), p = 0.003). In a multivariate model that adjusted for
age, gender, smoking status, living alone, body mass index (BMI),
albumin and fasting condition, only gender (OR = 2.2 (1.5–3.2),
p,0.001) and albumin (OR = 1.3 (1.2–1.4), p,0.001) made
significant contributions to the model. The analyses without
albumin are likely the most relevant, as we discuss below.
Zinc deficiency in relation to psychiatric diagnosis
We identified zinc deficiency in 41.0% of the psychogeriatric
patients. The prevalence rates of zinc deficiency and zinc levels in
the three main diagnostic groups are presented in Table 5. The
difference in the prevalence of zinc deficiency between patients
with depression as the main diagnosis and patients with other
psychiatric diagnoses was not significant. However, when we
Table 2. Diagnoses of patients.
Diagnoses
N (male/female)
Patients with depression as the main
diagnosis
First time depression 6 (4/2)
Recurrent depression 27 (11/16)
Bipolar depression 8 (3/5)
Patients with depression secondary to
other diagnoses
Alzheimer’s dementia 10 (4/6)
Vascular dementia 2 (1/1)
Other organic mental disorders 2 (1/1)
Psychotic disorders 1 (1/0)
Anxiety disorders 5 (1/4)
Patients with no depressive symptoms
Alzheimer’s dementia 10 (7/3)
Vascular dementia 4 (2/2)
Other dementia 6 (1/5)
Other organic mental disorders 3 (1/2)
Psychotic disorders 11 (2/9)
Bipolar disorder, manic episode 2 (0/2)
Anxiety disorders 2 (2/0)
Somatoform disorders 1 (0/1)
doi:10.1371/journal.pone.0082793.t002
Table 3. Characteristics of the patient and control groups.
Patients Controls
p-values
Female/male (%) 62/38 (62.0/38.0) 444/438 (50.3/49.7) p = 0.027*
Age (SD) 76.5 (7.2) 72.2 (5.7) p,0.001**
Living alone (%) 53.0 37.1 p,0.001*
Smoking (%) 29.9 13.6 p,0.001*
BMI (SD) 25.3 (5.2) 27.0 (4.2) p,0.001**
Albumin g/L (SD) 41.0 (3.4) 45.0 (2.3) p,0.001**
Zinc deficiency–
males (%)
47.4 18.5 p,0.001*
Zinc deficiency-
females (%)
37.1 10.4 p,0.001*
Notes. *x
2
= Chi-square test, ** t = Student’s t-test.
doi:10.1371/journal.pone.0082793.t003
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compared all patients with depressive symptoms (main or
comorbid depression) to patients with other psychiatric diagnoses,
the prevalence was significantly higher in the latter group (Table 5).
The difference in the prevalence of zinc deficiency between
patients with depression as their main diagnosis and patients with
depression as a comorbid diagnosis was not significant. These
associations were not confounded by age, sex, smoking status,
living alone, BMI, fasting/non-fasting state or albumin levels as
these variables did not differ significantly between the three patient
groups. The Pearson correlation between zinc levels and MADRS
scores in the patient group was not significant. This was also the
case when we separately analyzed the patient subgroups with
depression as either main diagnosis or comorbid diagnosis. Among
the patients with dementia (n = 32, including 20 with Alzheimer’s
disease), we identified zinc deficiency in 48.5% of the patients, but
this prevalence was not significantly different from patients without
dementia.
Discussion
The major findings of this study were as follows: 1) There was a
significantly higher prevalence of zinc deficiency in the psycho-
geriatric patients compared with the elderly controls. 2) The
prevalence of zinc deficiency was significantly higher in patients
without depression compared with patients with depression as the
main or comorbid diagnosis. 3) There was no significant
relationship between zinc levels and MADRS scores in patients
with depression as the main or comorbid diagnosis.
Zinc and psychiatric disorders
We found a high prevalence of zinc deficiency in the patient
group compared with the control group. Several studies have
demonstrated lower zinc levels in patients with depression than in
healthy controls [6,8,30]. However, there is limited knowledge
about zinc deficiency in patients with diagnoses other than
depression. The current study found an even higher prevalence of
zinc deficiency in patients with other psychiatric diagnoses than in
patients with depression or comorbid depression. Dementia and
psychosis accounted for the largest diagnostic groups among these
patients. Zinc has been linked to a possible role in the pathogenesis
of Alzheimer’s disease (AD), but a causal role in AD has not yet
been definitively demonstrated [15]. Research has mainly focused
on abnormal zinc homeostasis, which may be involved in b-
amyloid plaque formation [31,32]. To the best of our knowledge,
there is no established link between serum levels of zinc and the
development of dementia. In one study, patients with AD were
compared with patients who exhibited mild cognitive impairment
and with normal controls, but no significant differences in the
serum zinc concentrations were found [18]. This result is in line
with other studies that revealed no significant differences in serum
zinc levels between controls and AD patients [16,17,33]. However,
the individuals with dementia in the current patient group
presented severe behavioral disturbances or psychiatric symptoms
(i.e., psychosis, depression, or anxiety), and were, therefore, not
representative of ‘‘typical’’ demented patients. Notably, nearly
50% of the patients in this group had zinc deficiencies. Thus, one
could speculate whether the lack of zinc contributes to behavioural
problems and psychiatric symptoms in dementia. The group of
patients with dementia was rather small and heterogeneous, so it is
of course difficult to draw any firm conclusions. The significance of
zinc in relation to psychosis is unclear. To our knowledge, no
studies have investigated zinc levels in relation to psychosis in the
elderly. Previous investigations have compared the zinc level of
patients with schizophrenia to that of healthy controls. One study
found no significant difference [34] whereas another study
revealed a difference [35], thereby reflecting the diverging results
found in previous studies [34].
Research in the field of zinc status and psychiatric disorders has
primarily focused on depression. Several studies have found a
connection between low zinc levels and depression [4,6–8], but a
few studies have not confirmed these findings [36,37]. A main
question is whether zinc deficiency actually contributes to the
development of depression, or if zinc deficiency is simply caused by
a change in diet due to the onset of depressive symptoms. Animal
studies, however, suggest that zinc deficiency induces depression-
like symptoms. When rodents are fed a zinc-deficient diet, they
Table 4. Adjusted odds ratio (95% CI) for the association between zinc deficiency and the patient/control status.
Group
Zinc deficiency, OR (95% CI)
Adjusted for age, gender and fasting condition
Multivariate adjusted*
Control 1.0 (reference) 1.0 (reference)
Depression or comorbid depression 2.5 (1.1–5.5) p = 0.024 1.0 (0.42.4) p = 0.95
Other psychiatric disorders 5.8 (2.314.4) p,0.001 2.4 (0.96.8) p = 0.09
*Adjusted for age, gender, BMI, smoking status, living alone, albumin levels and fasting condition.
doi:10.1371/journal.pone.0082793.t004
Table 5. Zinc levels and prevalence of zinc deficiency in the three diagnostic groups.
Depression as the
main diagnosis
Depression as co-morbid
diagnosis Other psychiatric diagnoses
Zinc deficiency (%)* 36.6 25.0 53.8
Zinc levels mmol/L(SD)** 11.4 (1.7) 11.7 (1.4) 10.7 (2.1)
*Significant difference in zinc deficiency between patient groups with depression/comorbid depression and other psychiatric diagnoses (x
2df = 1
= 4.36, p = 0.037).
**No significant differences betwee n the three patient groups, using one-way analysis of variance (F = 2.63, df = 2, p = 0.078). Distribution between fasting/non-fasting
conditions was equal in the three patient groups.
doi:10.1371/journal.pone.0082793.t005
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develop depression-like symptoms, including anorexia, anhedonia,
increased anxiety behaviour, and increased periods of immobility,
which have been reported in a number of studies [9,10,38].
Animal experiments have demonstrated that zinc can enhance the
action of antidepressants in depressive models, such as the forced-
swim test and the tail suspension test, and in chronic unpredictable
stress [39–41]. This finding has also been supported by treatment
studies in humans. Two RCTs have revealed potential benefits of
zinc supplementation as an adjunct to conventional antidepressant
drug therapy [12,13].
In the present study, the serum zinc levels in patients with
depression did not correlate with the MADRS scores. Although
the findings might suggest that the magnitude of the serum zinc
decline did not reflect the severity of the depression, other
explanations for these results are plausible. The present findings
correspond to similar results in two other studies [6,8], but stand in
contrast to those reported by Maes [30], who detected a
statistically significant correlation between zinc levels and HADS
scores. The first two studies [6,8], included patients with
treatment-resistant depression, whereas the latter study did not
[30]. In addition, it has been proposed that the lack of a
correlation between zinc levels and the severity of depression
might be explained by the fact that all of the patients belong to a
group of severely depressed individuals [8]. Patients who were
included in the current study had a marked severity of depression,
as they had been admitted to a psychiatric hospital. These subjects
were also predominantly treatment-resistant, but we did not
explore this aspect further.
To our knowledge, no previous studies have examined zinc
deficiency across a broader range of psychiatric disorders among
elderly people. The present findings are interesting because they
suggest that zinc may play a role in a wide range of psychiatric
disorders. Among patients with thyrotoxicosis, some individuals
develop anxiety, others develop depression or psychosis, and still
others, do not develop psychiatric disorders at all [42]. We find the
same pattern in for example patients with hyperparathyroidism
[43,44] and in patients with low levels of vitamin B12 [45]. These
results suggest that unknown individual factors may make certain
people more vulnerable than others to developing psychiatric
symptoms due to alterations in these hormones and micronutri-
ents.
Several hypotheses may explain the relation between depression
and zinc deficiency. Zinc can down regulate the glutamate
response by inhibiting post-synaptic N-methyl-D-aspartate recep-
tors (NMDA) [46], and is also involved in regulating brain-derived
neurotrophic factor (BDNF) expression in the brain [47]. Reports
have shown that zinc can increase the density of 5-HT1A and 5-
HT2A serotonin receptors in the hippocampus and frontal cortex
[48]. However, there is also mounting evidence that zinc plays an
important role in the immune system and zinc deficiency has been
reported to increase levels of pro-inflammatory cytokines [49].
This increase of pro-inflammatory cytokines also increases levels of
the heavy-metal-binding protein metallothionein. Furthermore, it
has been suggested that this mechanism contributes to the reduced
zinc levels that are observed in patients with depression [50].
There is some evidence that alterations in the immune system may
play a role in several types of psychiatric disorders [51], but it is
unclear whether this factor might explain the current findings.
Dietary intake of zinc
The present study did not include dietary data for the patient or
control groups. Therefore, differences in the dietary intake of zinc
might have contributed to the findings. Several studies have
supported a connection between low dietary zinc and depression;
however, no studies have investigated whether there is an
association between low dietary zinc levels and a broader range
of psychiatric disorders. A study of Europeans aged 60–84 years
found a relationship between low dietary zinc intake, plasma zinc
status and depressive symptoms [4]. A study of 402 postgraduate
students in Malaysia, found a relationship between a low dietary
intake of zinc and depression [52]. In one study, a low dietary zinc
intake was positively associated with depression in women, but not
in men [53]. A population study of habitual diets and mental
health in women revealed an association between dietary zinc
levels and depressive symptoms, but no such association with
anxiety disorders [54]. These investigations do not present clear
evidence for a causal relationship between low dietary zinc levels
and depression; however, they support similar findings in animal
studies. One could argue that psychiatric disorders are accompa-
nied by decreased appetite and, therefore, a decreased overall
dietary intake, including that of zinc. However, in the current
investigation, BMI was not a significant predictor. Moreover, prior
studies have not found an association between anorexia or weight
loss and low zinc levels [30].
Zinc and albumin
In the present study, the level of albumin was lower in the
patient group than in the control group. In a logistic regression
model, albumin and gender were significant predictors of zinc
deficiency. In a model without albumin, belonging to the patient
group was the strongest predictor. The relationship between zinc
and albumin is complex. It has been argued that reduced albumin
levels only partially explain a reduction in zinc levels [50]. There is
increasing evidence that depression and other psychiatric disorders
are accompanied by an activation of the inflammatory response
system (IRS) [51,55]. Activation of the IRS is known to lower the
zinc level (due to increased production of metallothionein), but
also lowers the albumin level [50]. Plasma zinc is primarily bound
to albumin (70%) and to a2-macroglobulin (18%), with the
remainder bound to other proteins and amino acids [56]. Only 1
of every 50 albumin molecules is bound to a zinc atom, and it has
been argued that this fact renders it difficult to ascertain how a
reduction in albumin could lead to significantly reduced zinc levels
[28]. The IZInc group reported that only hypoalbuminemia (,34
g/L) may significantly influence zinc levels [27]. We conclude that
the different levels of albumin in the current patient and control
groups cannot fully explain the large difference in the prevalence
of zinc deficiency. Therefore, analyses with only age, gender and
fasting condition as confounders might provide the most
interesting results (Table 4).
Strengths and limitations
A major strength of this study was the inclusion of patients who
suffered from different psychiatric disorders and the comparison of
these individuals with a large group of controls. The diagnostic
procedures that were applied to the patient group were extensive.
In addition to diagnostic instruments, clinical observations and
data from medical records were used. Another strength of the
study was that we controlled for confounding factors, including
age, gender, smoking habits, BMI, albumin levels, and whether the
patient was living alone or with another individual. These factors
have allowed us to make interesting observations regarding the
zinc levels in elderly psychiatric patients and in elderly controls.
Although we do not believe that zinc supplementation is
common among the elderly in our uptake area, we lacked data on
zinc supplement intake in the control group. We also lacked data
regarding psychiatric symptoms in the control group. However,
this group was quite large and unlikely to include a substantial
Zinc Deficiency
PLOS ONE | www.plosone.org 5 December 2013 | Volume 8 | Issue 12 | e82793
number of persons with severe psychiatric illness. In addition, the
blood-sampling time point differed in the two groups. Zinc levels
tend to decrease slightly during the day, as reflected in Table 1.
This fact might have increased the control group’s (for which the
blood sampling lasted until 12 AM) risk of being categorized as
zinc deficient. Nevertheless, this situation would strengthen the
present findings. The prevalence of zinc deficiency was similar in
the fasting and non-fasting patient groups. We also controlled for
the fasting/non-fasting condition (using a logistic regression
analysis) and this factor did not appear to influence the main
results.
Conclusions
In this study, we found that zinc deficiency is quite common
among psychogeriatric patients and appears to be even more
prominent in patients without depression. However, the present
investigation does not provide a clear answer as to whether the
observed differences represent a causal relationship between zinc
deficiency and psychiatric symptoms. Although the causes of the
differences in zinc deficiency rates are unknown, we propose
several possible explanations. Differences in albumin levels may
explain a smaller part of the differences in zinc levels. Another
factor might be differences in the dietary intake of zinc. Prior
studies have suggested potential differences in the dietary intake of
zinc between depressed patients and controls. This factor might
also apply to patients with other psychiatric disorders compared
with controls. Increased levels of inflammatory factors might also
contribute to lower levels of zinc in depressed patients; however, it
is unknown whether this could also be a factor in patients with
other psychiatric disorders. Although there might be different
causes of low zinc levels, animal studies [40,41] and intervention
studies [57] have suggested that the administration of zinc to
depressed patients zinc may yield a positive effect. The etiology of
psychiatric disorders is complex, and biological, environmental,
medical and possibly modifiable risk factors may all play a role
[58]. Additional research on this topic is necessary to further
explore the role of zinc in the treatment of depression and to
further investigate whether zinc may be of importance to other
psychiatric disorders.
Acknowledgments
We thank the laboratory staff at the Department of Laboratory Medicine,
University Hospital of North Norway for their contributions to this study.
We also thank the participating patients.
Author Contributions
Conceived and designed the experiments: OKG RW JMK. Performed the
experiments: OKG. Analyzed the data: OKG JMK RW OF. Contributed
reagents/materials/analysis tools: OKG RW JMK OF. Wrote the paper:
OKG RW JMK OF.
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... Nowadays, most of the studies investigating the correlation between Zn 2 status and mental disorders have been focused on depression, whereas the relation between Zn 2+ and other psychiatric disorders is still uncertain (71). Indeed, since the late 1980s, Zn 2+ deficiency was mainly found to be correlated with depression in animal and human samples (72) and several brain homeostatic systems have been linked to the maintenance of extra-and intracellular Zn 2+ at nontoxic concentrations, including in brain regions involved in the physiopathology of depression (73). ...
... Specifically, a recent meta-analysis found significantly lower serum Zn 2+ concentrations in schizophrenic patients than in controls (58). Moreover, a study found a higher prevalence of Zn 2+ deficiency in patients with other psychiatric diagnoses, such as psychosis, than in patients with depression (71). ...
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