ARTICLE
Auteur(s) : Lazaro Barragán-Rodríguez, Martha
Rodríguez-Morán, Fernando
Guerrero-Romero
FACP, Siqueiros 225 esq/Castañeda, 34000 Durango, Dgo.,
Mexico; and Biomedical Research Unit of the Mexican Social Security
Institute at Durango, Mexico
Depression in the elderly isusually persistent and relatedto
medical comorbidity and disability that may be associated with
long-term declines in medical and functional status [1, 2],
Furthermore, depression in elderly patients is not only highly
prevalent but frequently it is neither recognized nor treated [2],
negatively affects the course of diabetes, and is associated with
an increased risk of mortality [3].
Recently, based on a meta-analysis that recorded 39 studies
having a combined total of 20 218 subjects, Anderson et al. [4]
reported that diabetes doubles the odds of depression in the
elderly. Because physical and psychosocial changes occur as people
enter old age, the elderly are in a developmental phase of life
with its own unique challenges that affect the management of both
diabetes and depression [5, 6]. In this regard, evidence suggests
that depression is related to poorer glycemic control [7] and that
depression and diabetes, particularly in older people, have a
synergistic interaction that worsens its prognostic [8]. Thus,
identifying and treating depression in the elderly with diabetes is
strongly recommended [9].
Total magnesium is significantly lower during depression and
increases after recovery, among depressed patients [10]; in
addition, the psychiatric symptoms of magnesium deficiency are
unspecific, ranging from apathy to psychosis [11]; and more
recently, results from an age- and gender-matched case/control
study strongly suggests that hypomagnesemia is independently
associated with depressive symptoms in the elderly with diabetes
[12]. These findings raise the possibility that magnesium
deficiency is the cause of major depression and related to mental
health problems [13]; however, systematic clinical data about
magnesium levels in major depression patients according to
psychological profile are not available [14]. Thus, the aim of this
study was to evaluate the efficacy and safety of oral magnesium
supplementation, with magnesium chloride (MgCl2), in the
treatment of newly diagnosed depression in the elderly with type 2
diabetes and hypomagnesemia.
Materials and methods
With the approval of the protocol by the Mexican Social Security
Institute Research Committee, and after obtaining the subject’s
informed consent, a randomized, active control equivalent trial was
carried out. Individuals were recruited from the outpatient Primary
Level Medical Care offices in Durango, a city in northern Mexico.
Elderly subjects, aged 60 years or more, were eligible to
participate if they had type 2 diabetes hypomagnesemia, and newly
diagnosed depression.
Twenty-three eligible subjects were randomly allocated to
receive either magnesium supplementation or imipramine for
12-weeks. Because MgCl2 solution shows a higher
bioavailability than other commercial magnesium preparations [15],
the MgCl2 solution (50 g of MgCl2 per 1
000 mL of solution - 5% solution) was the magnesium supplement
used. In fasting conditions, subjects in the MgCl2 group
drank 50 mL of the 5% solution daily to receive 2.5 g of
MgCl2, equivalent to 450 mg of elemental magnesium.
Subjects in group B received 25 mg of imipraminedaily, which was
increased according to their response until a maximum of 150 mg per
day during 12 weeks. Computer-generated random numbers were used to
assign participants to magnesium supplementation or imipramine
groups. The final distribution was as follows: 12 subjects with
MgCl2 (Group A) and 11 subjects with imipramine (figure 1).
Widowhood or divorce in the last six months, alcoholism,
degenerative illnesses of the nervous central system, diagnosis of
diabetes ≤ 6 months, chronic diarrhea, use of diuretics, and
reduced renal function were exclusion criteria; in addition,
because of interactions between magnesium and psychotropic drugs
[16], previous or current treatment with antidepressants were also
exclusion criteria. Before their inclusion in the study, all the
subjects were clinically evaluated and laboratory tested in order
to determine the presence of exclusion criteria.
High blood pressure was identified in 10 (83.3%) and 8 (72.7%)
of the subjects in the magnesium and imipramine groups, p = 0.64.
During the 12 weeks of intervention, to control glycemia, all the
patients received standardized doses of glibenclamide (5 mg t.i.d)
and a low fat diet based on 21% of daily energy intake from fat,
less than 10% of daily energy intake from saturated fat, 21% from
protein, and 58% from carbohydrates. Total caloric intake was
calculated based on 30 kcal per kg per day ideal body weight
[17].
The primary trial end point was the improvement of depression
symptoms. Sample sizes were estimated based on a statistical power
of 80%, alpha value 0.05, and allowing non-improvement of
depression symptoms in 30% of the subjects receiving
MgCl2 or imipramine. The required sample size to detect
a treatment effect was 11 subjects in each group.
Definitions
Hypomagnesemia was defined by serum magnesium levels < 1.8
mg/dL. Diagnosis of depression was performed using the scale of
Yasavage and Brink [18] which recognizes symptoms of depression and
is validated for use in the elderly Mexican people. A score of
21 to 30 points is indicative of moderate to severe depression, 11
to 20 points mild depression, and 0 to 10 points absence of
depression. The scale has a sensitivity and specificity of 0.91 and
0.72 [19]. Eligible subjects for this study were required to have a
Yasavage and Brink score equal or greater than 11 points.
Measurements
At baseline and the end of the study, the Yasavage and Brink scale
was applied, and fasting glucose levels, glycosylated hemoglobin
(HbA1c), and lipid profile were measured. In addition, serum
magnesium levels were measured every 4 weeks. The person assessing
outcomes was blinded to the group assignment.
Anthropometric measurements were assessed using conventional
protocols. Height and weight were taken with the subjects in light
clothing and without shoes. The body mass index (BMI) was
calculated as weight (in kilograms) divided by height (in meters
squared). Waist circumference was taken as the minimum
circumference at umbilicus level.
Adherence to pharmacological treatment was assessed every month
by personal interview, and tablet count.
Assays
Serum magnesium was measured by colorimetric method, with intra-
and interassay variations of 1.0 and 2.5%, respectively.
Serum glucose was measured by the glucose-oxidase method; its
intra- and inter-assay variations were 1.5% and 2.1%. The lipid
profile was measured by enzymatic methods; the intra- and
inter-assay variations were 2% and 3.0%.
All measurements were performed in a Data pro Plus clinical
auto-analyzer (Arlington TX, USA).
Statistical analysis
The pre-planned intention-to-treat analysis of the primary study
end-point, the improvement of depression symptoms, were carried out
for all the randomly allocated participants who satisfactorily
completed the follow-up. To establish the differences between the
groups we used Mann-Whitney U test and Fisher’s Exact test.
A p value < 0.05 defined the level of statistical
significance. The data were analyzed using the SPSS 12.0
statistical package (SPSS Inc., Illinois USA, 1998).
Results
A total of 265 elderly with type 2 diabetes were screened.
Prevalence of depression, hypomagnesemia, and depression plus
hypomagnesemia was 44.9, 38.9, and 13.2%, respectively.
Thirty-five subjects fulfilled the inclusion criteria. Of these,
8 refused to participate and 23, 12 women and 11 men, were enrolled
and randomly allocated, 12 in the group of MgCl2 and 11
in the group of imipramine. Overall, the average Yasavage and Brink
score and serum magnesium levels were 17.0 ± 4.7 and 1.3 ± 0.3
mg/dL, respectively. A total of 16 (69.6%) individuals had
light and 7 (30.4%) moderate to severe depression.
The average dose of imipramine required to achieve a beneficial
effect on depressive symptoms was 50 mg daily. All the subjects in
the imipramine group had at least one drug-related adverse event
such as dry mouth, constipation, sweating, hot flashes, disorders
of visual accommodation and blurred vision, urination disorders,
fatigue, somnolence, increased anxiety, sleep disorders, confusion,
disorientation and auditive hallucinations, fine tremor, headaches
and dizziness, sinus tachycardia, nausea, anorexia, and itch. Two
(18.2%) individuals dropped out by the side effects of imipramine.
On the other hand, mild abdominal pain and diarrhea were present in
3 (25%) individuals who received MgCl2; there were no
dropped-outs due to MgCl2. Adherence was achieved by
91.7% and 72.7% of the subjects in the MgCl2 and
imipramine groups, respectively.
The preplanned intention-to-treat analysis of the primary study
end-point was performed in the 21 participants who completed the
follow-up. There were no differences by age (69 ± 5.9 and 66.4 ±
6.1 years, p = 0.39) and duration of diabetes (11.8 ± 7.9 and 8.6 ±
5.7 years, p = 0.33), in the groups with MgCl2 and
imipramine, respectively. The distribution of light (66.7 and
66.7%) and moderate to severe depression (33.3 and 33.3%) was
similar in the groups of MgCl2 and imipramine.
Table 1 shows the clinical
characteristics of the participants at baseline and at the end of
follow-up. At baseline, serum magnesium and Yasavage and Brink
scores were similar in both groups; at the end, subjects who
received magnesium supplementation significantly increased their
serum magnesium levels. The Yasavage and Brink score significantly
decreased in both groups; at the end of follow-up there were no
significant differences between the groups.
A total of 7 (58.3%) and 9 (81.2%) patients in the groups of
MgCl2 and imipramine significantly improved their
symptoms of depression, p = 0.37.
Table 1 Basal and end characteristics of elderly with
type 2 diabetes who received magnesium chloride (MgCl2)
or imipramine.
|
Baseline
|
End
|
|
MgCl2
|
Imipramine
|
MgCl2
|
Imipramine
|
|
N
|
(12)
|
(9)
|
(12)
|
(9)
|
|
Yasavage and Brink score
|
17.9 ± 3.9
|
16.1 ± 4.5
|
11.4 ± 3.8a
|
10.9 ± 4.3a
|
|
Fasting glucose, mg/dL
|
194.3 ± 59.0
|
183.4 ± 68.0
|
191.1 ± 59.7
|
183.1 ± 74.3
|
|
HbA1c, %
|
8.9 ± 1.6
|
9.0 ± 1.7
|
8.8 ± 1.2
|
8.9 ± 1.4
|
|
Systolic blood pressure, mm Hg
|
134.1 ± 19.2
|
141.0 ± 20.1
|
135.2 ± 20.5
|
143.7 ± 19.9
|
|
Diastolic blood pressure, mm Hg
|
77.2 ± 3.9
|
84.7 ± 6.1
|
77.0 ± 3.6
|
87.6 ± 6.4
|
|
Creatinine, mg/dL
|
1.0 ± 0.4
|
1.0 ± 0.3
|
0.9 ± 0.4
|
1.1 ± 0.3
|
|
Triglycerides, mg/dL
|
169 ± 53.8
|
148.0 ± 77.3
|
122 ± 52.6a
|
142.7 ± 51.9
|
|
HDL-Cholesterol, mg/dL
|
45.6 ± 20.6
|
41.0 ± 12.5
|
49.2 ± 15.4a
|
44.6 ± 10.8
|
|
Serum magnesium, mg/dL
|
1.3 ± 0.04
|
1.4 ± 0.04
|
2.1 ± 0.08a
|
1.5 ± 0.07b
|
ap < 0.005 between baseline and end conditions for
the subjects in the same group.
bp < 0.0005 between magnesium chloride and
imipramine groups.
Discussion
Our results show that oral magnesium supplementation with
MgCl2 is as effective in the management of depressed
elderly type 2 diabetics with hypomagnesemia as imipramine 50 mg
daily. In addition, our results also show the safety of
MgCl2 in the treatment of the elderly and that it is
better tolerated than imipramine. These findings support the
statement that serum magnesium should be determined when there are
symptoms of depression, particularly in the elderly with diabetes.
Major depression is a mood disorder that can adversely affect a
person’s life and sometimes to such an extent that suicide is
attempted. Therefore, recognizing and treating depression is an
important issue in the management of the elderly (5). However,
antidepressant drugs are not always effective and have been
associated with severe side effects and adverse events [20,
21].
Because magnesium ions regulate calcium ion flow in neuronal
calcium channels, helping to regulate neuronal nitric oxide
production and neurotransmission, magnesium deficiency has been
related to the pathogenesis of neuropathologies such as depression
[13, 22]. Based on case histories showing a rapid recovery (less
than 7 days) from major depression using 125-300 mg of magnesium
(as glycinate and taurinate) with each meal and at bedtime,
recently Eby et al. [13] hypothesized that magnesium treatment
could be effective in treating major depression resulting from
intraneuronal magnesium deficits. However, to the best of our
knowledge, this is the first randomized clinical trial that
presents evidence on the efficacy and safety of MgCl2 in
the treatment of depression.
In addition, it has been reported in animal models, that
increasing the intracellular magnesium concentration, stimulation
of sodium/magnesium antiports at a physiological intracellular
magnesium concentration, result in an inhibition of
sodium/magnesium antiports, improving the effect of imipramine on
depression symptoms [23].
During this study, to control hyperglycemia, all the patients
received the maximum doses of glibenclamide and a low fat diet;
however, antidiabetic treatment, that was individually evaluated
and adjusted at end of intervention, was clearly insufficient for
achieving adequate glycemic levels. This finding suggests that the
improvement of depression, in the elderly with type 2 diabetes,
seems to be independent of their glycemic status.
Some potential limitations of this study deserve to be
mentioned. First, the study was designed as an active control
trial. In this regard, a placebo should be administered, whenever
possible, to participants in control groups for assessing the
efficacy of new treatments in those clinical conditions for which
no effective treatment exists [24]. Because imipramine is an
effective treatment for depression [25] we compared two active
treatment groups without placebo, which is an acceptable way for
evaluating the efficacy and safety of a therapy, without ethical
implications [26-28], and obtaining reliable information about the
new therapy [28]. In addition, the less the study-to-study
variability in outcomes, and the few instances of unexplained
failure of the control agent are also persuasive reasons for using
the active-control trial design [24]. Second, we measured the
magnesium confined to serum which is a relatively minor compartment
of total body magnesium. However, taking into account that serum
magnesium levels shows a high correlation with intracellular free
magnesium concentration [25, 26], and boththe clearly conveyed aim
and primary trial end point of this study, this limitation did not
influence our conclusions. Third, the small sample size could be
related to the possibility of a type II error in the analysis of
data; however, the sample size had the power to show significant
differences intra- and inter-groups when baseline and end
conditions were compared, thus, the possibility of type II error is
minimal.
Conclusion
Our results show for the first time the efficacy and safety of
MgCl2 for the treatment of depression in the elderly
with type 2 diabetes and hypomagnesemia, supporting the statement
that serum magnesium should be determined when there are symptoms
of depression, particularly in the elderly with type 2 diabetes.
Acknowledgments
This work was supported by grants from the Consejo Nacional de
Ciencia y Tecnología de México (FOSIVILLA 20020402014) and by
grants from the Mexican Social Security Institute Foundation, Civil
Association.
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