Prog. Neuro-PsychopharmocoI. 6 BioI. Psychic& 1990, Vol. 14, pp. 171-180 0278-5846190 $0.

00 + so
Printed in Great Britain. All rights reserved @I 1990 Pergamon Press plc

A PILOT STUDY OF MAGNESIUM ASPARTATE

~DROC~O~DE ~G~SI~~~~ AS A MOOD
STABILIZER FOR RAPID CYCLING BIPOLAR
AFFECTIVE DISORDER PATIENTS

GUY CHOUINARD1,2, LINDA BEAUCLAIRl, RITA GEISER3 AND PIERRE ETIENNE3

lResearch Centre, Louis-H. Lafontaine Hospital

University of Montreal, Montreal, Canada;
2Allan Memorial Institute, McGill University, Montreal, Canada;
and 3Research Department, CIBA-GEIGY US, Summit, NJ, USA.

(Final form, September 1989)

Abstract

Chouinard, Guy, Beauclair, Linda, Geiser, Rita and Etienne, Pierre: A pilot study of
magnesium aspartate hydrochloride (Magnesiocarde) as a mood stabilizer for rapid cycling
bipolar affective disorder patients. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1990,
2:171-180

1. Nine severe rapid cycling manic-depressive patients were treated with a magnesium
preparation, Magnesiocard~ 40 mEq/day in an open label study for a period up to 32
weeks.
2. Magnesiocard@ was found to have clinical results at least equivalent to those of
lithium in about 50% of these patients. These results were obtained in an exploratory
study and should be interpreted with caution.
3. The possibility that Magnesiocarde could replace or improve the efficacy of lithium as
a preventive treatment of manic-depressive illness merits further clinical
investigation.

Keywords: Bipolar illness, lithium, manic-depressive illness, magnesium, rapid cycler.

Abbreviations: Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression of

Depression (CGID), Clinical Global Impression of Mania (CGIM), Hamilton Psychiatric Rating
Scale for Depression (HAM-D), Magnesium (Mg), Manic State Rating Scale (MMS), lithium (Li).

Introduction

Magnesium is the fourth most abundant cation in the body, and the second most abundant
intracellular cation. The body contains about 20 to 28 grams of magnesium, of which
approximately 55% is present in bone, 27% is present in muscle, and the remaining 18% is
distributed in nonmuscular soft tissue and body fluids. The vast majority (85%) of
magnesium is intracellular, bound in the form of a magnesium-ATP complex. Magnesium is a
co-factor for ATP and an essential activator of many enzyme systems. Therefore, it is
important in ATP-dependant oxidative phosphorylation, as well as in controlling such
processes as carbohydrate synthesis. Magnesium also interacts with other important
cations. Chronic depletion of magnesium will result in a loss of cellular potassium and a
gain in cellular calcium. The evidence also suggests that magnesium may function
physiologically as a calcium antagonist, modulating the activity of calcium. These various
actions help to explain the Clinical manifestations of magnesium deficiency (See Ebel and
Gunther, 1980; Levine and Coburn, 1984; for a review). In the CNS Mg plays a very
important role in the control of excitatory aminoacid neurotransmission through its

171
172 G. Chouinard et al.

interaction with NMDA (N-methyl-D-aspartate) receptors which are regulated by

voltage-dependent binding of magnesium ions inside the channel (Mayer et al., 1984; Mayer
and Westbrook, 1987; for a review). The NMDA receptor complex is*involved in long-term
potentiation and some forms of learning in mature animals (See Landfield and Deadwyler,
1988 for review.); burst firing and the generation of patterned activity in neuronal
networks; use-dependent stabilization of synaptic connectivity in young animals, and such
pathologies as epilepsy, spasticity, ischemic neuronal death and neurodegeneration (See
Fagg et al., 1986 for a review). A deficient maturation of NMDA receptors has been
proposed as the primary cause of schizophrenia (Etienne and Baudry, 1987). In spite of
this array of possible roles for magnesium, the link between psychiatric symptomatology and
magnesium is unclear (Ananth and Yassa, 1979; Frazer et al., 1983). Exceptions are
alcoholic and other organic brain syndromes which are clearly associated with

hypomagnesemia. As a treatment, magnesium remains a therapeutic indication in eclampsia

(Pritchard, 1955), a condition associated with general CNS hyperexcitability. In
veterinary medicine, magnesium is used as an anti-stress agent. In recent years, there has

been an increasing interest in magnesium in almost several ideas of medicine including

obstetrics-gynecology, sports medicine and cardiology.

Lithium, like sodium, potassium, calcium and magnesium has a widespread effect on enzyme
systems and may act in part by substituting for these ions. The effects of lithium are
ubiquitous and they are manifested on neurotransmitters, endocrine glands and behavior.
Lithium inhibits and prevents episodes of manic excitement and to a lesser degree inhibits
and prevents episodes of depression in manic depressive psychosis (Schou, 1968). It can

also inhibit a variety of agressive behavior in man and animals (Sheard, 1978). It is not
possible at the present time to relate precisely the behavioral effects of lithium on its
many biochemical changes, but magnesium and calcium may be involved in lithium effects
(Pavlinac et al., 1979), as lithium can result in an increase in plasma Mg and a positive

whole-body magnesium balance (Plenge and Rafaelsen, 1982).

Thus it appeared that treatment with an orally available and well tolerated magnesium

salt was worth investigating as an alternative to lithium in patients who responded poorly
to lithium given in conjunction with conventional therapy and who presented with rapid

cycling clinical features. In this exploratory study, we selected 9 such patients and
replaced lithium with Magnesiocardo.

Methods

Patients Characteristics

Nine patients suffering from bipolar illness according to the DSM-III criteria, and
hospitalized at Louis-H. Lafontaine Hospital, Montreal, were included. Informed written

consent was obtained from all subjects. The hospital diagnosis of manic depressive illness

was confirmed by the research psychiatrist. All patients were classified as rapid cyclers,
having had at least four cycles in the previous year, and were considered by the treating
 Magnesiocard@ 173

physician to be poor responders to conventional therapy. Schizophrenic patients, patients

suffering from mental retardation, alcoholism, epilepsy, drug abuse problems and severely
suicidal patients were excluded. Also excluded were patients presenting with serious,
acute or chronic medical problems. All patients included were female although this was not
a criterion of selection. Patient characteristics were as follows: The mean age of the
patients was 4326 (range: 35-52 years). The total number of prior hospitalizations ranged
from 39 to 4 (mean: 16.2 times), and the length of prior hospitalizations ranged from 8 to
117 months) (mean: 51.8 months). During the year that preceded the Magnesiocarde trial,
the number of hospitalizations ranged from 1 to 3 (mean: 2.5 times), and the length of
hospitalization ranged from 1 to 52 weeks (mean: 21.6 weeks). The age of onset of the
illness ranged between 17 and 32 (mean: 24.3). Before entering into the study all
patients were on lithium carbonate with a dosage ranging from 900 to 1800 mg (mean:
1150 mg per day). In addition to lithium, three patients received antidepressants, seven
patients received antiepileptics (clonazepam and carbamazepine), and four patients received
neuroleptics.

Medication

Magnesiocarde (mono-Magnesium L-aspartate hydrochloride trihydrate, C4H6ClNO4Mg.3H20,

MW:245.9,) is a well absorbed magnesium preparation, manufactured by Verla-Pharm, Tutzing,
West Germany.

Magnesiocarde was given four times a day in tablets containing 5 mEq of magnesium. All
patients had their medication gradually increased over a period of 1 to 4 weeks from a dose
of 20 mEq per day to 40 mEq per day and thereafter patients were maintained on the maximum

daily dose of 40 mEq per day. All patients started with 20 mEq except for one patient in
whom the initial dose was 15 mEq per day.

Study Design

The original study was designed as an open label 8-week treatment starting after
withdrawal of all prior medications including lithium. The patients were seen at weekly
intervals. The target enrollment was 10, only 9 were included because of administrative
reasons. Because 7 patients (of the 9 enrolled) appeared to benefit from their 8-week
treatment with Magnesiocarde, a 24-week maximum prolongation study was added with
evaluations at week 10, 12, 16, 20, 24, 28 and 32.

Safety Measures

A physical examination was performed on the first day of the study, at week 4, 8 and upon
study termination. Vital signs were taken on days 0, 1, 3 and at all subsequent
evaluations/visits. Routine laboratory tests were performed on days 0, 4, 8 and upon
termination.

Special Laboratory Measurements

Potassium, sodium, calcium and magnesium were measured in plasma by atomic absorption
spectroscopy at all evaluations/visits.
174 G. Chouinard et al.

Outcome Measures

Two psychiatrists and two research nurses were involved in the evaluation of the
patients. Each patient was evaluated by the same nurse throughout the study and 75% of all
the psychiatric evaluations were done by the senior investigator (GC).

The psychiatrists rated the patients with the following instruments: The Hamilton
Psychiatric Rating Scale for Depression, 24 items (HAM-D) (Guy, 1976), two (Global
Impression of severity of illness) g-point evaluation scales, one for mania , one for
depression (CGIM, CGID), the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham,
1962) and the Brief Manic Scale (Chouinard et al., 1983), which included 5 items derived
from the Inpatient Multidimensional Psychiatric Scale (Lorr and Klett, 1966#) (motor
hyperactivity, euphoria, pressure of speech, logorrhea and insight) (Table I).

The research nurses rated the patients with the Special Scale for Manic Depressive
(Bunney and Hamburg, 1963) and the Manic State Rating Scale (MMS) (Blackburn, 1977).

Data Analyses

This was an exploratory study and the data analysis was not specified in the original

protocol. All analyses were therefore post-hoc. Upon completion of the study, it seemed
approriate to have two types of exploratory analyses with different aims: 1. To assess
the impact of the treatment during the study itself. For this purpose, comparisons of
scores at baseline, at the end of the original study and at the end of the follow up period
were made. 2. To do a retrospective assessment of the impact of the treatment against the
context of the "natural" course of illness for a period of one year preceding the beginning
of this study. For this purpose, a common assessment method was developed to compare the
status of patients during the years which preceded the rial and during the trial itself.

The period of treatment (up to one year) which preceded the Magnesiocardo trial was
reviewed for all patients. The status of each patient, as described in the hospitalization
and interim visits progress notes, was assessed by one of the research nurses who
participated in the project, and classified into five categories: manic (M), borderline
manic (BM), euthymic (E), borderline depressed (BD) and depressed (D). The total number of
days spent in any of those five states was then calculated.

Similarly, the entire duration of the Magnesiocard trial was also reviewed for all
patients. The status of each patient at each visit as described in the rating scales, was
reassessed by the principal investigator, and classified with the same five categories.
The transformation of rating scale data into categories was made according to the following
operational definitions: BMS 2 18 and CGIM 2 4 = M; BMS 2 10 and CGIM 2 3 = BM; HAM-D 2 18
and CGID > 4 = D; HAM-D 2 10 and CGID > 3 = BD. In the case of the simultaneous presence
of both manic (borderline manic) and depressed (borderline depressed) elements, the highest
of the two CGI scores overruled. In the case of equivalent CGI scores, the highest score
obtained in the other scale used in the formula overruled. The total number of days spent
in any of those five states was calculated with the understanding that each evaluation
 175

truly represented the clinical state during the preceding week. The scores obtained at
visits made at week I, 2, 3, 4, 5, 8, fD, 12, 16, 20, 24, 26, 28 and 32 therefore
represented cumulative survey periods of 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 and
91 days. A difficulty arose with the unequal spacing between visits. In order to obviate
it, a separate analysis was made for the equally spaced visits (Z-week intervals) made on
week 2, 4, 6, 8, 10 and 12. Finally, in order to compare the results obtained in patients
whose participation in the Magnesiocard trial ranged from 8 weeks to 32 weeks, a percentage
conversion was used.

Table 1

Brief Hanic Scale (5MS)

Circle the column headed

by the term which best
describes the patient's Not Very Moderately Extremely
present condition Present Mild Mild Moderate Severe Severe Severe

Motor Overactivity:
Exhibits overactivity, 0 12 3 4 5 6
restlessness, andior
acceleration fn body
movements? Faces or
shifts restlessly.
Bearing, posture suggest
excitement or agitation,

El evated Mood :
Exaggerated sense of 0 1. 2 3 4 5 6
well-being, euphoria

Pressure of Speech:
Manifest speech that is 0 12 3 4 5 6
hurried, accelerated or
pushed? "Pressure of
Speech'".

Logarrhea: Exhibits an 0 12 3 4 5 6
excess of speech?
Difficult to stop flow
of speech once started.
Difficult to get a word
in edgewise. Judge the
amount of speech and not
fts rate of relevance.

Insight: Shows a lack of 0 12 3 4 5 6

insight regarding himself
or an ability to recognize
that he has problems?
Offers physical illness as
an explanation. Believes
he is in a rest home or
prison. Denies illness or
need for trea~ent.
176 G. Chouinard et al.

Results

Evaluable Patients

The study lasted from May 1986 to January 1988. Nine patients were enrolled. One
patient completed only two weeks of treatment. She was not included as this period was
short to draw any conclusions about Magnesiocard" as a mood stabilizer. The remaining
eight patients completed the first part of the study (8 weeks of treatment). One patient
was withdrawn after 8 weeks because of no response. The remaining patients entered the
prolongation study (maximum duration 32 weeks).

Course of Illness

Six patients were sufficiently improved during the first 8 weeks to be dischargd from
hospital (one more patient could have been discharged if she had found a place to live).
One patient (patient 7) only completed the first 2 weeks of the study because of the
continuation of a severe manic episode.

Of the patients who were discharged, 3 completed the 6-month follow-up period as
outpatients and were judged to have benefited from the medication in the sense that it
appeared at least as efficacious as lithium. The other 3 could not be successfully

maintained as outpatients.

Concomitant Medication

In addition to Magnesiocarde, the 6 patients who entered the prolongation study needed to
resume the similar adjuvant medication that they had received prior to the trial i.e.

clonazepam and L-tryptophan. Four of the 6 also received neuroleptics on a prn basis. One
patient needed a short-term course of an antidepressant drug during the follow up phase of
the study.

Rating Scales

Changes During the Original Study. Eight patients completed the original study. On the
HAM-D, there was an overall improvement when comparing the initial scores to the scores
obtained at the end of the 8-week period. The mean score went from 7 to 3.75. On the BMS,
and the MMS, there was also a small improvement from the initial score to the end score.
The mean BMS score went from 7.25 to 5.5 and the mean MMS score, from 13.3 to 12.1. The
mean BH score, on the other hand, remained unchanged: 48.8 vs. 50.8.

Changes During the Prolongation Study. Three patients completed the 24 week
prolongation/follow-up. These three patients continued to improve on all the rating scales
compared to the second baseline i.e. the beginning of the follow-up period. The mean HAM-D
score went from 5.3 to 2.66; the mean BMS score from 2.0 to 1.66; the mean MMS score from
5.3 to 3.3; the mean BH score from 44.3 to 31.3

Evaluation of the Study Related Changes in the Context of the Previous Year. For
patients I to 9, the total % of time spent in any of the five states during the trial as
 Magnesiocard@ 177

compared to the previous year is shown in Table 2.

Table 2

Non-stabilized Stabilized
D BD BM M E BD+E Days
+BM Surveyed
% % % % % %

Patient 1.
Previous year 44 16 18 14 8 42 341

Weeks
Entire 2,4,6,8,10,12
trial (32 wks) 1; 00 00 00 100
85 100
85 ::

31 354
1; ; 40
17 :; 49 :: 42
15 0 24 15 46 70 91

Patient 3.
Previous year 0 10 0 24 66 1;: 323
Weeks 2,4,6,8,10,12 00 17 :; 00 66 42
Entire trial (20 wks) 9 73 100 77

Patient 4.
Previous year 47 359
Weeks 2,4,6,8,10,12 20 33 8 00 83 1:: 42
Entire trial (32 wks) : 17
8 0 0 84 92 91

Patient 5.
Previous year 5 0 25 0 70 95 349
Weeks 2,4,6,8 0 0 25 25 50 75 28

Patient 6.
Previous year 38 0 20 15 27 47 362
Weeks 2,4,6,8,10,12 33 0 17 50 8 17 42
Entire trial (16 wks) 33 0 22 45 22 63

Patient 7. (Not included in summary analyses)

Previous year 21 0 0 24 55 55 338
Entire trial (3 wks) 0 0 0 100 0 0 14

Patient 8.
Previous year 8 330 22 19 374
Weeks 2,4,6,8,10,12 33 0 42
Entire trial (20 wks) 0 20 40 10 30 90 70

Patient 9.
Previous year 0 0 3 16 81 84 350
Entire trial (9 wks) 15 0 57 0 28 85 49

These data are concordant with the clinical course. If one looks at the time spent in
the euthymic stage, the first 4 patients were found to be euthymic for a longer period of
time than when on lithium. In addition two out of three patients (patient 1 and 4) who
completed the prolongation study as outpatients had a marked increase in the percentage of
the time spent in a stabilized state i.e. a clinical state other than mania or depression.
Patient 3 also spent relatively more time in a stabilized state but did not complete the

trial.
178 G. Chouinard et al.

Plasma Tonic Concentrations

As expected, plasma sodium, potassium, calcium and magnesium were left unchanged with
treatment.

Side Effects

The side effects encountered during the study were mild and consisted mostly of soft

stools and diarrhea.

Discussion

This was an exploratory study and no firm conclusion can be drawn from it. One should

bear in mind that the patients were treated by a specialized clinical psychopharmacology
team during their Magnesiocarde treatment. The impact of the research treatment team on
the well being of the patients, as opposed to the impact of the new drug itself, is of
course impossible to assess without a control group.

If we assume that Magnesiocarda treatment, in this small sample of severe manic

depressive patients, was clinically equivalent to their previous treatment for one year, we
are still unable to demonstrate the clinical therapeutic value of Magnesiocarda as the
efficacy of the previous treatment cannot be proven in these patients.

A review of the literature after 1945 did not reveal published reports of treatment of
manic depressive illness with magnesium salts. Their use, however, was reported in the

pre-war literature. Unlike other reports which describe their use for acute
tranquillization of manic patients, one report (Mestrallet et al., 1932) clearly suggests
the use of i.v. magnesium sulfate weekly as a preventive treatment against the recurrence
of manic-depressive attacks.

The question of the unique properties of Magnesiocarde versus other magnesium salt
preparations cannot be answered by this study. It is unlikely that the nature of the
aspartate-magnesium complex in the intact preparation, rather than magnesium itself, had
much to do with the results obtained as the complex is broken into its components in the
gut, and plasma aspartate levels are not affected by treatment (CIBA-GEIGY data).

In spite, or because of these uncertainties, we believe that this study merits a

controlled follow up study. Unfortunately, a confirmatory (or infirmatory) study of the
therapeutic value of Magnesiocard @ in this indication would require a large sample size and
a longer duration (one year at least) to be considered conclusive.

Conclusion

In conclusion, a magnesium salt preparation, Magnesiocardm was found to be equivalent to

lithium in a small group of severe manic-depressive patients, and perhaps superior to
lithium in about one third of these patients. These results were obtained in a pilot study
 Magnesiocard@ 179

and should be interpreted with caution. The possibility that Magnesiocarde could replace

or improve the efficacy of lithium as a preventive treatment of manic-depressive illness

merits, as suggested by this study, verification in a controlled study.

Acknowledgement

We thank Lorraine Paradis, R.N. and F. Brunelle, R.N. for their invaluable contribution
to this study.

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Inquiries and reprint requests should be addressed to:

Dr. Guy Chouinard

Clinical Psychopharmacology Unit
Allan Memorial Institute
1025 Pine Avenue West
Montreal, Quebec, Canada, H3A 1Al