Relationship between blood magnesium and psychomotor retardation in drug-free patients with major depression

Eur

Original

article

1998 ; 13 : 90-7

Psychiutq

0 Elsevier,

Paris

Relationship between blood magnesium and psychomotor retardation in drug-free patients with major depression J Widmer I, JG Henrotte2, Y Raffin l, D Mouthon D Chollet l, R Stepanian I, P Bovier I

l,

’ Department of Psychiatry, Division of Neuropsychiatry. Laboratory of Biochemistry. Psychiatric Hospital, University of Geneva, Chemin du Petit Bel-Air 2, CH-1225 Ch@ne-Bourg, Genre, Switzerland; 2 Institut de Chimie des Substances Naturelies, CNRS, F-91 198 G(f-sur-Yvette, France

(Received

7 March

1997; accepted

3 October

1997)

Summary - In previous reports, we have observed that blood magnesium was significantly higher in drug-free patients with major depression when compared to healthy controls. This was especially true for erythrocyte magnesium. Furthermore, the most severely depressed patients had the highest intracellular magnesium content, showing that intracellular magnesium rate was related to the intensity of symptoms, We report here the results of blood magnesium measured in 88 major depressed patients as compared to 61 controls. We show that the mean erythrocyte and also plasma magnesium contents are both increased in these patients. We observe that about 40% of male and female patients have a very significant increase (25%) in intracellular magnesium content as compared to controls. However, about 60% of the hospitalised depressed patients have normal values. None of the controls has high erythrocyte magnesium. This is less evident concerning the plasma magnesium. No differences are observed between patients when classified according to the intensity of moral pain or anxiety. In contrast, the patients with mild to high psychomotor retardation score, which is an index of hypoexcitability, have significant higher erythrocyte magnesium values compared with other patients. The results of male patients without psychomotor retardation do not differ from control values. Our study suggests that central hypoexcitability might be related to an increase in intracellular magnesium observed at the peripheral level, keeping in mind that hyperexcitability, as observed in various conditions such as stress and cardiovascular disorders, is frequently associated, in contrast, with a decrease in blood magnesium. 0 1998, Elsevier, Paris. affective

disorders

/ magnesium

/ erythrocyte

/ psychomotor

retardation

INTRODUCTION Electrolytes play a key role in the general metabolism of monoamines, which are involved in the pathophysiology of affective disorders. Changes in the ionic environment, either at the central or at the peripheral level, may modify precursor availability, thus enhancing neurotransmitter metabolism. Plasma and erythrocyte contents, as well as electrolyte movements across the membrane of this cell, have been measured in mood disorders. Several investigators have reported a decreased erythrocyte Na/K adenosine triphosphate (ATP)ase activity in major depressed patients [33]. High total plasma calcium has been observed in longstanding depressed patients; this rate was normalised after clinical improvement [27]. Blood sodium and potassium have also been found modified in some reports, but unchanged in others [9, 18, 29, 301. These discrepancies may be due to various factors.

/ symptoms

The patients were often under treatment and not classified according to sex. Differences in erythrocytic electrolytes were clearly described between sexes in healthy controls [26, 46, 481. Furthermore, in many of these studies, the intensity of symptoms estimated by an appropriate rating scale was not taken into account. In previous studies,we showedthat plasmaand erythrocyte magnesiumcontentswere increasedin major drugfree, depressedinpatients. In contrast, with only a few exceptions, there were no clear differences between patientsand controls in blood sodium,potassiumand calcium, measuredat the sametime as magnesium[44,45]. In a previous report, we observed that the most severely depressedpatients had the highest intracellular magnesium content, suggesting that this electrolyte may be related to the intensity of clinical symptoms[46]. The aim of this study was to show if somespecific clinical items, measuredby appropriaterating scales,could be related to blood magnesiumstatus in major depressedpatients.

Magnesium and symptoms in major depressed patients Table

91

I. Sex distribution of magnesium contents in patients with major depression and in controls. Controls

Females Males

43.2 44.5

f 2.l(n = 33) k I .7 (n = 28)

MgE

Females Males

2.040* 2.047

0.027

+ 0.028

MgP

Females Males

Patients

0.800+0.009(n 0.814 +O.O14(n

(n = 33) (n = 28)

= 33) = 28)

vs controls

0.006

NS

(P)

Pafients

50.1k1.3(n=61) 48.3 f 2.4 (n = 27)

0.000 1 0.001

2.242 f 0.031 2.254eO.05

0.005 0.03

0.842 0.863

(n = 61)

1 (n = 27)

f 0.010 (n = 61) eO.011

(n = 27)

Data are given as mean f SEM. Erythrocyte magnesium (MgE) is in mmol/L of cells and plasma magnesium (MgP) in mmol/L. n: number of subjects; P: significant differences (Student’s t-test). NS: non significant.

SUBJECTS AND METHODS Subjects Eighty eight depressed inpatients (61 females and 27 males), selected according to the Diagnostic and Statistical Manual (DSM)-IIIR [8] criteria (major recurrent: code 296.3x), and bipolar patients, all in a depressive state (code: 2965x), entered the study. This experiment was done in agreement with the ethics committee of the Department of Psychiatry of Geneva, and the patients gave their written informed consent. There were hospitalised in the same hospital unit and received the same type of food. All patients abstained from antidepressant drugs for at least 2 weeks (wash-out period) before the experiment. All were normotensive, without renal failure and non-diabetic. None of the patients had ever received lithium therapy. The severity of clinical symptoms was estimated by the Manual for the Assessment and Documentation of Psychopathology (MADP)-depression rating scale 161, based on items ranging from 0 to 4; 0 = absent; 1 = weak; 2 = mild; 3 = high; and 4 = very high. The MADP contains specific items giving a reliable estimation of psychomotor retardation, moral pain and anxiety. This scale has been considered by clinicians as more appropriate than the classical Hamilton scale, based on fewer items. Therefore, this latter scale was not used in our study. The major recurrent (unipolar) and depressive bipolar patients were grouped together (table I) since no significant differences between both groups were observed in the measurement of blood magnesium in previous studies, and since all bipolar patients were in a depressive episode [45]. As for the frequency distribution for erythrocyte and plasma magnesium (table II), the patients and controls were divided in two classes as follows: erythrocyte magnesium (MgE) lower than 2.30 mmol/L and higher than 2.30 mmol/L of cells; plasma magnesium (MgP) lower than 0.84 mmol/L and higher than 0.84 mmol/L. This was

calculated according to the histogram of the data for erythrocyte and plasma magnesium in all subjects (data not shown). The patients (P) were also divided into clinical subgroups as follows: Pl (table III) included 28 females and 1 I males with absence or very low psychomotor rating score (range: 0 to 5 points; the maximum score at this scale is 28). P2 included 33 female and 16 male patients with mild to high score (range 6 to 20 points). The following items were used to charactetise psychomotor retardation: inhibition and flagging of thoughts, decrease and inhibition of energy, asthenia, and laconismtrs. P3 (table IV) included 21 females and seven males with absence or very low moral pain rating score (range: 0 to 7 points; the maximum score at this scale is 44). P4 included 40 females and 20 males with mild to high score (8 to 33 points). This scale includes: loss of hope, sadness, culpability, and suicide attempts. P5 (fable V) included 25 females and eight males with absence or very low anxiety score (range 0 to 5 points; the maximum score at this scale is 24). P6 included 36 females and 19 males with mild or high score (range: 6 to 18 points). This scale includes: psychological and muscular tension, observed anxiety and agitation. The separation of the patients in those clinical subgroups was performed according to the practice and to the experience of the clinicians. Thus, the assessment of the categorisations was performed in blinded conditions relative to the biochemical results. In table VI, we tested by factor analysis the influence of age, sex and intensity of psychomotor-retardation in blood magnesium results. The patients were separated into two subgroups of age, those younger than 51 years and these older than 51 years, to take the possible influence of menopause into account in blood magnesium levels. The control group (C) included 28 healthy males, mean age: 44.5 years, and 33 females: mean age: 43.2 years, chosen among the hospital staff, taking no medication of any type, and without any history of affective disorders.

92 Table

J Widmer II. Distribution

of patients MgE

and controls

et al

with low or high erythrocyte

< 2.3 mmoWL

(MgE)

and plasma magnesium

MgE 2 2.3 mmoVL

(MgP)

contents,

Total

x2

m

Females Patients Controls Total

38 33 71

23 0 23

61 33 94

10.5

0.01

Males Patients Controls Total

16 28 44

11 0 11

27 28 55

14.3

0.001

A4gP < 0.84 mmoUL

A4gP > 0.84 mmoWL

Total

Females Patients Controls Total

34 25 59

27 8 35

61 33 94

4.7

0.05

Males Patients Controls Total

11 18 29

16 10 26

27 28 55

2.8

NS

Data are given as number of subjects. Female and male patients as well as controls are separated according to low or high erythrocyte (MgE) and plasma magnesium (MgP) contents. See Methods for more details. Chi square (x2) is used to test the significant differences in the distributions observed. (P): significant differences; NS: non significant; MgE overall patient vs control group: ~2 = 30.2; P < 0.0001. MgP overall patient vs control group: x2 = 13.1; P < 0.001.

Table III. Magnesium motor-retardation. Subjects

contents

for controls

c

(C) and depressed

patients

PI vs c (P)

lP) separated

PI

into two sub-groups

according

P2 vs PI (P)

to the intensity

P2

of psycho-

P2 vs c (P)

Age Females Males MgE Females Males

43.2 f 2.1 (n = 33) 44.5 f I .7 (n = 28)

0.05 NS

47.8 + 1.7 (n = 28) 44.8+3.7(n= 11)

2.04 f 0.03 (n = 33) 2.05 f 0.03 (n = 28)

0.005 NS

2.17*0.04(n=28) 2.13&0.07(n=

0.80 i 0.01 (n = 33) 0.81 i 0.01 (n = 28)

NS NS

0.001 NS

52.3 * 1.8 (n = 33) 50.7 r 3.4 (n = 16)

0.001 NS

11)

0.02 0.03

2.30 ZJZ0.04 (n = 33) 2.32 f 0.07 (n = 16)

0.000 1 0.0005

0.83 + 0.01 (n = 28) 0.84 + 0.03 (n = 11)

NS NS

0.85 f 0.01 (n = 33) 0.87 + 0.02 (n = 16)

0.005 0.03

MgP Females Males

Results are given as mean + SEM. Pl are patients with absence or very low psychomotor high score. Erythrocyte magnesium (MgE) is in mmol/L of cells and plasma magnesium significant; (P): significant differences (ANOVA).

Methods The sampling procedures and techniques are described elsewhere [45]. Briefly, 20 mL of whole blood from controls and patients were collected at 8 am by venipuncture with heparinate as an anticoagulant, and kept no longer than half an hour at room temperature before manipulation. After centrifugation for 10 min at 4 “C in order to separate plasma, the erythrocyte pellet was washed three times in an isotonic solution (NaCl 0.9%) to eliminate the trapped plasma and

retardation score and P2 are patients with mild to (MgP) in mmol/L. II: number of subjects: NS: non

other blood elements. The plasma was centrifuged for 10 min at 3,500 g at room temperature to remove residual blood platelets and white cells. Plasma and erythrocyte magnesium were measured in triplicate by the usual atomic absorption spectrometry with minor modifications and adaptations (AAS, Perkin Elmer, Norwalk, CT, USA [2]). The coefficient of variation for five repeated

measures

for the same

sample

was less that

3% for

both plasma and erythrocyte magnesium concentration. All reagents and standards were from Sigma, St Louis, MO,

Magnesium Table

IV. Magnesium

Subjects

contents

for controls

c

Age

Females Males

MizE Females Males

M@

Females Males

and symptoms

(C) and depressed

patients

P3 “S C(P)

V. Magnesium

Subjects

Females Males

MgE

Females Males

depressed

separated

into two sub-groups

P3

patients

93 according

P4 vs P3 (P)

to the intensity

of moral pain.

P4

P4 vs c (P)

43.2 + 2.1 (n = 33) 44.5 + I .7 (n = 28)

0.001 NS

51.9 + 2.5 (n = 21) 44.7 + 2.4 (n = 7)

NS NS

49.3 * 1.4 (n = 40) 49.6 t 1.7 (n = 20)

0.00 1 NS

2.04 + 0.03 (n = 33) 2.05 f 0.03 (n = 28)

0.005 NS

2.24 + 0.05 (n = 21) 2.15 + 0.08 (n = 7)

NS NS

2.25 + 0.03 (n = 40) 2.28 f 0.07 (n = 20)

0.0005 0.005

0.80 2 0.01 (n = 33) 0.81 r 0.01 (n = 28)

0.01 NS

0.85 2 0.02 (n = 2 I) 0.84 2 0.03 (n = 7)

NS NS

0.84 + 0.01 (n = 40) 0.86 + 0.02 (n = 20)

Results are given as mean f SEM. P3 are patients with absence Erythrocyte magnesium (MgE) is in mmol/L of cells and plasma (P): significant differences (ANOVA).

Table

in major

contents

for controls

(C) and depressed

or very low moral magnesium (MgP)

patients

PS vs c (P)

c

(P) separated

0.05 0.0 1

pain score and P4 arc patients with mild to high score. in mmol/L. n: number of subjects; NS: non significant;

into two sub-groups

PS

according

to the intensity

P6 vs P5 (p)

P6

of anxiety P6 vs C

(P)

43.2 f 2.1 (n = 33) 44.5 f 1.7 (n = 28)

0.05 NS

48.4 t 2.5 (n = 25) 51.4 + 2.3 (n = 8)

NS NS

5 1.2 k 1.3 (n = 36) 47.0” 1.7 (n = 19)

0.00 1 NS

2.04 f 0.03 (n = 33) 2.05 f 0.03 (n = 28)

0.005 0.04

2.24 + 0.04 (n = 25) 2.25 + 0.10 (n = 8)

NS NS

2.26 + 0.04 (n = 36) 2.24 + 0.07 (N = 19)

0.0005 0.0 I

0.80 r 0.01 (n = 33) 0.81 f 0.01 (n = 28)

0.005 NS

0.85 2 0.01 (n = 25) 0.83 t 0.02 (n = 8)

0.00 1 NS

0.84 + 0.01 (n = 36) 0.86 + 0.02 (n = 19)

0.001 0.0 I

MgP Females Males

Results are given as mean f SEM. P5 are patients with absence or very low anxiety score and P6 are patients with mild to high score. Erythrocyte magnesium (MgE) is in mmol/L of cells and plasma magnesium (MgP) is in mmol/L. n: number of subjects; NS: non significant; (P): significant differences (ANOVA).

Table VI. Sex and age (two sium (ANOVA; P values). Blood component MgE (two factors) MgE (three factors) MgP (two factors) MgP (three factors)

factors)

and sex and age and psychomotor-retardation

Age

sex

Age * Sex

0.3896 0.6740 0.0555 0.0525

0.9691 0.9854 0.5460 0.4135

0.652 1 0.6196 0.4979 0.6740

(PMR;

PMR

three factors)

interactions

Age * PMR

effects

Sex * PMR

in blood

magne-

Sex *Age

* PMR

0.0100

0.395 I

05637

0.3015

0.6784

0.1232

0.9780

0.4058

Results are given as P values. ANOVA: analysis of variance. Patients are separated into younger than 5 1 and older than 5 1 years old. PMR: psychomotor-retardation. See Table III and Methods for more details. MgE: erythrocyte magnesium. MgP: plasma magnesium. *: interactions.

USA. The analysis of variance (ANOVA, Fischer test) was used to compare the data (mean 2 standard error of mean [SEMI) between patients separated into clinical sub-groups, between patients and controls and between males and

females. Student’s t-test was used for the comparison

of two

groups (all the patients vs controls; ruble I). ANOVA for 2 or 3 factor

analysis

(age

table

and sex; age, sex and psychodone as seen on table VI.

motor-retardation) was also Finally, chi square statistics were used to compare the frequency distributions between patients and controls.

J Widmer

94 RESULTS

I shows that female and male patients have much higher mean erythrocyte and plasma magnesium contents than control subjects. These results confirm our previous reports based on fewer patients and controls. Female patients are older than female controls (P < 0.006). This difference is mainly due to the difficulty in recruiting female controls over age 50 who are taking no medication. Table II shows the distribution of patients and controls separated into low or high erythrocyte and plasma magnesium contents. It can be seen that 11 males (40% of them) and 23 female patients (38%) have very high erythrocyte magnesium levels. This represents an increase of about 25% as compared to the control mean values (P < 0.0001). In contrast, none of the male and female controls shows an erythrocyte magnesium content above 2.30 mmol/L. This difference is less pronounced for plasma magnesium, although the overall group difference (C vs P) is significant. Table III clearly shows that patients with psychomotor retardation (P2) have much higher erythrocyte and plasma magnesium than either other patients (PI) or controls (C). This is observed in both sexes. Female patients are older than either other female patients and than controls. This is not the case for male patients. Furthermore, the erythrocyte magnesium of male patients without psychomotor retardation does not differ from male controls. The differences in plasma magnesium content between both female and male patients and controls are smaller but still significant. In table IV and tuble V there are only very few and non significant differences in erythrocyte magnesium between patients separated into classesof moral pain and anxiety. This is also the case for either females or males and for plasma magnesium. Mean female patients are older than female controls. As seen in tuble VI, psychomotor-retardation is the only factor that is clearly associated with erythrocyte magnesium modification (P < 0.01). Indeed, neither age nor sex are related to blood magnesium levels in our study. Furthermore, neither intensity of anxiety nor intensity of moral pain influence blood magnesium status in depressedpatients (data not shown). Finally, we separatedthe patients who are suffering or not either from psychomotor retardation and moral pain. In this case, erythrocyte magnesium content is 2.25 mmol/L of cells for female patients 07 = 11) suffering either from psychomotor retardation and moral pain (P < 0.005 vs controls); 2.19 mmol/L for females (n = 21) with absenceor low scoresat these both scales (P < 0.01 vs controls). Male patients (IZ= 13) with these two symptoms have 2.25 mmol/L of erythrocyte magnesium (P < 0.01 vs controls) and 2.08 mmol/ when Table

et al

these symptoms are absent (n = 6). The last result does not differ from control values. Finally, neither plasma magnesium nor age were different between these two last subgroupsof patients nor between controls. DISCUSSION The significantly higher erythrocyte and plasma magnesium levels observed in our drug-free major depressed inpatients (n = 88) is in good agreement with our previous reports conducted with fewer patients (n = 53; in which all of them are included in this present study) and controls [45, 461. The majority of the studies dealing with blood magnesium and affective disorders were done using plasma magnesium only, as a routine clinical dosage, although it has been well known for a long time ago that magnesium exerts its physiological activities into cells. Conflicting results are found in the literature. Some authors have described decreased [21], unchanged [5 I] or increased plasma magnesium [27] in depressed patients. Small and non-existent significant increase in erythrocyte magnesium (2.06; II = 55 vs 1.95 mmol/L in controls; II = 46) in unipolar depressedpatients was observed in only one study [I l]. Unfortunately, in many of these studies, the patients were not characterised according to clinical sub-groups, to the severity of the symptoms, sex and age. Finally, most of the patients were receiving treatment at the beginning of these studies. In a study conducted with 1.55psychiatric inpatients, plasma magnesium was shown to be below (22.4%) and above (10.4%) the normal range, while others (67.2%) had normal levels. There were no control groups in this report, and the normal range was given by literature data. No clear correlations between clinical symptoms were observed. Finally, erythrocyte magnesium was not measured in this last study [22]. Differences have been observed in intracellular sodium and potassium between female and male patients and controls, clearly suggesting a need for sex separation in all such biochemical studies [26, 45, 481. An increase in erythrocyte and plasma magnesium was observed in female controls after menopause in some, but not all, studies [ 12, 401. In previous studies (along with the present one) (table VZ) we have tested without successthe influence of age and sex in blood magnesiumconcentration. This was also recently observed in a study conducted with 50 healthy subjects 1361.In contrast, a small difference (4.5%) was described in erythrocyte magnesium between young (n = 138; 18 to 29 years; 2.02 mmol/L) and old female controls (n = 95; 50 to 65 years; 2. I I mmol/L), in a study conducted with 1,050 healthy sub.jects1401.No differences between old and

Magnesium

and symptoms

young males were observed (2.17 vs 2.17 mmol/L). Furthermore, we suggest to carefully test the influence of age and sexes in such similar further biochemical studies. Finally, except for female controls (P < O.Ol), erythrocyte and plasma magnesium were not correlated (P = 0.15 to 0.35) in all clinical subgroups (data not shown). The fact that the relative low range observed in our control subjects (that is 1.95 to 2.28 mmol/L; the normal range collected from various other reports is about 1.9 to 2.4 mmol/L) is an argument that erythrocyte magnesium is well regulated in healthy subjects. Conversely, the fact that about 40% of the depressed patients have much higher magnesium content (range 2.29 to 2.95 mmol/L; mean about 2.55 mmol/L) than the controls while the other 60% have normal values is clearly in favour of an heterogeneity in the distribution of erythrocyte magnesium in affective disorders. Indeed, there are two groups of patients: those with normal range (the majority of them), and those with much higher erythrocyte magnesium content (+ 25%). This phenomenon is actually not understood, but may be due to other biochemical parameters, such as abnormalities in magnesium transport systems across the membranes of such cells. We have observed an increase in magnesium efflux in erythrocytes from depressed patients, suggesting a membranopathy in mood disorders, as seen for other electrolyte movements [46]. Erythrocyte as well as plasma magnesium concentrations have also been shown to depend upon several genetic factors, one of them being associated with the human leukocytes antigen (HLA) system [ 14. 151. Conversely, it is well known that an increase in plasma catecholamines, occurring in strenuous effort and in all stress situations, can lower blood magnesium. Intravenous epinephrine infusion also induces a decrease in plasma magnesium [37, 431, suggesting that hypomagnesemia is associated with hyperadrenergic activity. Hypermagnesemia is only seen in a few conditions, such as chronic renal failure, antacid therapy, excessive magnesium intake, or perfusion in case of overmedication against eclampsia [24,42]. We have clearly shown that the highly depressed patients (estimated by the AMDP total depression scale) had the highest erythrocyte magnesium values 1471. Psychomotor retardation as estimated by an AMDP-subscale is considered by clinicians as the index of the hypoexcitability status of the patients. Thirty-three (52%) female and 26 male (48%) patients enter this category. The fact that patients with psychomotor retardation have the highest erythrocyte magnesium content suggests that hypoexcitability syndrome is associated with hypermagnesemia, as observed at the peripheral level. It might be due to central low catecholaminergic activity in those patients. Other

in major

depressed

patients

95

factors might be taken into account concerning the role played by magnesium within the central nervous system. It is well established in animals that lowering magnesium increases central hyperexcitablity due to the desinhibition of the N-methyl-D-aspartate (NMDA - an excitatory amino acid) receptor ionotropic channels and by its activation of the gammaaminobutyric acid (GABA),-gated chloride channels [38]. In contrast, as recently shown, magnesium infusion in human could be of interest as an adjuvant to postoperative analgesia 1411, a situation which resembles that of our patients suffering from psychomotorretardation. Other central receptors, such as the muscarinic ones (cholinergic type), or AZ+, adenosine receptors require physiological magnesium levels for normal functioning 13, 281. Furthermore, magnesium plays a key role in the cell signalling, by acting through the G protein complex system, which is known to be involved in mood disorders [3, 201. It is then obvious that our patients who show a strong increase in erythrocyte magnesium could have other abnormalities in central neurotransmitter and neuromodulator systems in which magnesium is involved. Furthermore, our group has observed a negative correlation between blood magnesium and the density of alpha adrenergic receptor binding sites in blood platelets from depressed patients, showing that magnesium is involved also in the regulation of such peripheral receptors [ 19 1. It is well known that many situations related to hyperexcitability, such as cramps, tetany, various functional disorders, diabetes mellitus, acute myocardial infarction, spasmophilia, panic attack, cardiac arrythmias, preeclampsia/eclampsia, hearing loss induced by noise exposure, and pre-menstrual syndrome are related to or accompanied by a deficiency or a loss of magnesium as measured at the peripheral level [35, 391. Thus, magnesium oral intake or infusion could improve many of these clinical symptoms [ 10, 231. This is especially true for the management of eclampsia [ 1, 321. These clinical results provide good arguments that magnesium could be able to cross the brain blood barrier, as seen in animal studies in which magnesium sulfate infusion could have central anticonvulsant effects, by directly acting as an potent inhibitor of the NMDA receptors 17, 1.31. Recent interesting studies have shown that mice with genetically low erythrocyte and plasma magnesium levels exhibited more active behaviour, greater sensitivity to stress, more gastric ulcers, increased blood pressure, norepinephrine secretion, and norepinephrine concentrations in the brain than mice with high blood magnesium content [4, 16, 17, 3 I].

J Widmer

96

Furthermore, mouse-killing behaviour in magnesiumdeficient rats is inhibited by pharmacological doses of magnesium salts [5]. These animal strains may serve as a potential model to study the relationship between magnesium and behaviour. In our study, the patients suffering or not from moral pain or anxiety are not different in their erythrocyte magnesium content. This is also shown when the patients are suffering either from psychomotor retardation and moral pain. Thus, psychomotor retardation, or hypoexcitability syndrome, seems to remain the main and only sub-group of clinical items which explains why the patients with the most severe depressive syndrome have the highest erythrocyte magnesium content as previously reported 1461. In contrast, with only a few exceptions, depressed patients studied in the same conditions and suffering from high psychomotor retardation do not differ from the others and from controls concerning blood sodium, potassium and calcium, as we have recently reported, showing that magnesium might be the most attractive blood electrolyte to be studied in mood disorders at the present time [49]. Nevertheless, some points remain to be clarified. Psychomotor retardation, and therefore increases of erythrocyte magnesium as observed in many of our patients, might be due to low physical activity rather than to the illness, remembering that intensive and strenuous effort is often associated, in contrast, to magnesium depletion [34]. Second, further experiments must be done in animals to establish if blood magnesium status is indeed representative of the central magnesium level. In humans, magnesium in autopsy brain samples from patients with multiple sclerosis was shown to be lower than those of controls [50]. In contrast, no differences were found in magnesium contents in postmortem brain tissue from schizophrenic patients as compared to healthy controls [25]. Except for such few studies, magnesium contents in the human brain, in different sites, both in physiological and in pathophysiological conditions, still remain very poorly investigated at that time.

et al 2

3

4

5

6 I

8

9 10

11

12

13

14

15

16

17

18

ACKNOWLEDGEMENTS 19 We thank script.

Dr

J Golaz

for

the critical

reading

of the manu20

REFERENCES 21 1 Abi-Said D, Annegers JF, Combs-Cantrell D, Suki R, Frankowski RF, Willmore LJ. A case control evaluation of treatment efficacy: the example of magnesium sulfate prophylaxis against eclampsia in patients with preeclampsia. J Clin Epidemiol 1997 ; 50 : 419-23

22 23

Archer WH, Emerson RL, Reusach CS. Quantification of ervthrocvte magnesium and potassium using atomic absorption sp&opiotom&y. Anal Let&-s 1972 ; 26 : 689-707 Avissair S, Murphy DL, Schreiber G. Magnesium reversal of lithium inhibition of beta-adrenergic and muscarinic receptor coupling to G proteins. Biochem Pharmacol 1994 ; 1 : 171-5 Aymard N, Leyris A, Monier C, Fran&s, Boulu RG, Henrotte JG. Brain catecholamines, serotonin and their metabolites in mice selected for low (MgL) and high (MgH) blood magnesium levels. Mug Res 1994 : 8 : 5-9 Bat P, Pages N, Herrenknecht C, Teste JF. Inhibition of mousekilling behaviour in magnesium-deficient rats: effects of pharmacological doses of magnesium pidolate, magnesium aspartate, magnesium lactate, magnesium gluconate and magnesium chloride. Mug Res 1995 ; 8 : 37-45 Bobon DP. L.e q&me AMDP. Manuel de Documentation et de Quantification de la Psychopathologic. LiBge: Bobon; 198 1 Cotton DB, Hallak M, Janusz C, Irtenkauf SM, Berman RF. Central anticonvulsivant effects of magnesium sulfate on Nmethyl-D-aspartate induced seizures. Amer J Obstet Gynaecol 1993 ; 974-8 American Psychiatric Association. DSM IIIR. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed, revised. Washington, DC: American Psychiatric Press; 1987 Esche I, Joffe RT, Blank DW. Erythrocyte electrolytes in psychiatric illness. Acta Psych& Stand 1988 ; 78 : 695-7 Fachinotti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazrani AR. Oral magnesium successfully relieves pre-menstrual mood changes. Obsret Gynecoll991 ; 78 : 177-81 Frazer A, Ramsey TA, Swann A, Bowden C, Brunswick D, Garver D, Secunda S. Plasma and erythrocyte electrolytes in affective disorders. J Afsect Dis 1983 ; 5 : 103- 13 Gueux E, Duch&ne-Marullaz P, Rayssiguier Y. Plasma and erythrocyte magnesium levels in a French population. Mag Bull 1988 ; 10 : 77-80 Hallak M, Irtenkauf S, Cotton DB. Effects of magnesium sulfate on excitatory amino acid receptors in the rat brain. Am J Obstet Gynaecoll996 ; 175 : 575-81 Henrotte JG, Pla M, Dausset J. HLA and H-2 associated variations of intra-and extracellular magnesium content. Proc Nut1 Acad Sci USA 1990 ; 87 : 1894-8 Henrotte JG. Genetic regulation of cellular magnesium content. In: Birch NJ, ed. Mugnesium and the cell. London: Academic Press; 1993. p 177-99 Henrotte JG, Aymard N, Leyris A, Monier C, Franc& H, Boulu RG. Brain weight and noradrenaline content in mice selected for low (MgL) and high (MgH) blood magnesium. Mag Res 1993 ; 6 : 21-4 Henrotte JG, Franck G, Santorromana M, Fran&s H, Mouton D, Motta R. Mice selected for low and high blood magnesium levels: a new model for stress studies. Physiol Behav 1997 ; 61 : 653-8 Joffe RT, Blanck DW, Berrettini WH, Post RM. Erythrocyte sodium and potassium in affective illness. Acta Psyrhiatr Stand 1986 ; 73 : 416-19 Karege F, Bovier P, Widmer J, Gaillard JM, Tissot R. Platelet membrane alpha2-adrenergic receptors in depression. Psych&t Res 1992 ; 34 : 243-52 Karege F, Bovier P, StCpanian R, Malafosse A. The effect of clinical outcome on platelet G proteins of major depressed patients. Eur Neuropsycho; in press Kirov GK, Tsachev KN. Magnesium, schizophrenia and manicdepressive cbsease. Neuropsychobiology 1990 ; 23 : 79-81 Kirov GK, Birch NJ, Steadman P, Ramsey RG. Plasma magnesium levels in a population of psychiatric patients : correlations with symptoms. Neuropsychobiology 1994 ; 30 : 73-8 Knudson K, Abrahamsson J. Antianhythmic effects of magne-

Magnesium

24

25

26

27

28

29

30

31

32 33

34

35

36

37

and symptoms

sium sulphate. Report of three cases. Actu Anaesth Stand 1995 ; 39 : 850-4 Kojima S, Kanashiro M. Intracellular free magnesium of red blood cells in patients with renal diseases. Nephron 1992 ; 61 : 89-93 Komhuber J, Lange KW, Kruzik P, Rausch WD, Gabriel E, Jellinger K, Riederer P. Iron, copper, zinc, magnesium, and calcium in post-mortem brain tissue from schizophrenic patients. Biol Psychiat 1994 ; 36 : 3 l-4 Lasker N, Hopp I, Grossman S, Bamforth R, Aviv A. Race and sex differences in erythrocytes Na+, K+, and Na+-K+ adenosine triposphatase. J CZin Invest 1985 ; 75 : 18 13-20 Linder Brismar K, Beck-Friis J, SILf J, Wettenberg L. Calcium and magnesium concentrations in affective disorders: differences between plasma and serum in relation to symptoms. Actn Psych& Stand 1989 ; 80 : 527-37 Mazzoni, MR, Martine C, Luchacchini A. Regulation of agonist binding to A2A adenosine receptors: effects of guanine nucleotides and magnesium ions. Biochem Biophys Acta 1993 ; 1120 : 76-84 Naylor GJ, McNamee HB, Moody JP. Changes in erythrocyte sodium and potassium on recovery from a depressive illness. Br JPsychiat 1971 ; 118 : 219-23 Naylor GJ, Dick DAT, Dick EG, Le Poidevin D, Whyte SF. Erythrocyte membrane cation carrier in depressive illness. Psychol Med 1973 ; 3 : 502-8 Osborne-Pellegrin MJ, Henrotte JG. The variability of blood pressure in mice selected for low (MgL) and high (MgH) blood magnesium levels. Mag Res 1994 ; 8 : 1 l- 17 Raman NV, Rao CA. Magnesium sulfate as an anticonvulsivant in eclampsia. Int J Gyneco[ Obsr 1995 ; 49 : 289-98 Reddy PL, Khanna S, Subhash MN, Channabasavanna SM, Sridhara Ramo Rao BS. Erythrocyte membrane sodium-potassium adenosine triphosphatase activity in affective disorders. J Neurul Transm 1992 ; 89 : 209- 18 Resina A, Brettoni M, Gatteschi L, Galvan P, Orsi F, Rubenni MC. Changes in the concentrations of plasma and erythrocytes and of 2,3 diphosphoglycerate during a period of aerobic training. Eur JAppl Physiol 1994 ; 68 : 390-4 Resnick LM, Altura BT, Gupta RK, Laragh JH, Alderman MH, Altura BM. Intracellular and extracellular magnesium depletion in Type 2 (non-insulin-dependant) diabetes mellitus. Diabetol 1993 ; 36 : 767-70 Ryschon TW, Rosenstein DL, Rubinov DR, Niemela JE, Elin RJ, Balaban RS. Relationship between skeletal muscle intracellular ionized magnesium and measurements of blood magnesium. JLab ClinMed 1996 ; 127 : 207-13 Ryzen E, Servis KL, Rude RK. Effects of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentration measured by nuclear magnetic resonance. JAmer Co11 Nut 1990 ; 9 : 114-19

in major

depressed

patients

97

38 Schwartz RD. Wagner JP, Yu X, Martin D. Bidirectionnal modulation of GABA-gated chloride channels by divalent cations: inhibition by Ca++ and enhancement by Mg++. J Neurochem 1994 ; 62 : 916-22 39 Singh RB, Rastogi SS, Ghost S. MA. Dietary and serum magnesium levels in patients with acute myocardial infarctions, coronary artery disease and noncardiac diagnosis. J Amer Call Nut 1994 ; 13 : 139-43 40 Speich M, Gelot S, Auget JL. Plasma and erythrocyte magnesium, calcium, zinc, copper, phosphorus and cholesterol in a population of 1050 healthy adults. Mug Bull 1995 ; 17 : 62-8 41 Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiol 1996 ; 84 ; 340-7 42 Vormann J, Gunther T, Perras B, Rob PM. Magnesium metabolism in erythrocytes of patients with chronic renal failure and after renal transplantation. Eur J Clin Chem Clin Biochem 1994 ; 32 : 901-4 43 White K.. Addis GJ, Whitesmith R, Reid JL. Adrenergic control of plasma magnesium m man. Clin Science 1987 ; 72 : 135-8 44 Widmer J, Bovier P, Karege F, Raffin Y, Hilleret H, Gaillard JM, Tissot R. Evolution of blood magnesium, sodium and potassium in depressed patients followed for three months. Neuropsychobioiogy 1992 ; 26 : 173-9 45 Widmer J, Stella N, Raffin Y, Bovier P, Gaillard JM, Hilleret H, Tissot R. Blood magnesium, potassium, sodium, calcium, and cortisol in drug-free depressed patients. Mag Res 1993 ; 6 : 33-41 46 Widmer J, Henrotte JG, Raffin Y, Bovier P. Relationship between erythrocyte magnesium, plasma electrolytes and cortsol, and intensity of symptoms in major depressed patients. J Affect Dis 1995 ; 34 ; 201-9 47 Widmer J, F&ray JC, Bovier P, Hilleret H, Raffin Y, Gaillard JM, Garay R. Sodium-magnesium exchange in erythrocyte membranes from patients with affective disorders. Neuropsychobiology 1995 ; 32 : 13-18 48 Widmer J, Raffin Y, Mouthon D, Chollet D, Gaillard JM. Simultaneous measurement of plasma and erythrocyte sodium, potassium and magnesium; plasma calcium; blood platelet magnesium and calcium as a tool in studying peripheral electrolyte status. In: Halpem H. ed. Current Research In Magnesium. London: John Libbey; 1996. p I3- 16 49 Widmer J, Mouthon D, Raffin Y, Chollet D, Hilleret H, Malafosse A, Bovier P. Weak association between blood sodium, potassium and calcium and intensity of symptoms in major depressed patients. Netiropsychobiology 1997; 36: 164-71 50 Yase M, Yase Y, Ando K, Adachi K, Mukoyama M, Ohsugi M. Magnesium concentration in brains from multiple sclerosis patients. Acta Neural Stand 1990 ; 8 1 : 197-200 51 Young LT, Robb JC, Levitt AJ, Cooke RG, Joffe RT. Serum Mg2f and Ca2+/Mg2+ ratio in major depressive disorder. Neuropsychobiology 1996 : 34 : 26-8