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02_5221_paper

Anna Serefko1, Aleksandra Szopa1, Piotr WlaŸ2, Gabriel Nowak3,4,Maria Radziwoñ-Zaleska5, Micha³ Skalski5, Ewa Poleszak1 Chair and Department of Applied Pharmacy, Medical University of Lublin, ChodŸki 1, PL 20-093 Lublin, Poland Department of Animal Physiology, Faculty of Biology and Biotechnology, Maria Curie-Sk³odowska University,Akademicka 19, PL 20-033 Lublin, Poland !Department of Neurobiology, Institute of Pharmacology, Polish Academy of Science, Smêtna 12,PL 31-343 Kraków, Poland "Department of Cytobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland#Department of Psychiatry, Medical University of Warsaw, Nowowiejska 27, PL 00-665 Warszawa, Poland Correspondence: Ewa Poleszak, e-mail: ewa.poleszak@umlub.pl and Micha³ Skalski,
Abstract:
Magnesium is one of the most essential mineral in the human body, connected with brain biochemistry and the fluidity of neuronal
membrane. A variety of neuromuscular and psychiatric symptoms, including different types of depression, was observed in magne-
sium deficiency. Plasma/serum magnesium levels do not seem to be the appropriate indicators of depressive disorders, since ambigu-
ous outcomes, depending on the study, were obtained. The emergence of a new approach to magnesium compounds in medical
practice has been seen. Apart from being administered as components of dietary supplements, they are also perceived as the effective
agents in treatment of migraine, alcoholism, asthma, heart diseases, arrhythmias, renal calcium stones, premenstrual tension syn-
drome etc. Magnesium preparations have an essential place in homeopathy as a remedy for a range of mental health problems.
Mechanisms of antidepressant action of magnesium are not fully understood yet. Most probably, magnesium influences several sys-
tems associated with development of depression. The first information on the beneficial effect of magnesium sulfate given hypoder-
mically to patients with agitated depression was published almost 100 years ago. Numerous pre-clinical and clinical studies
confirmed the initial observations as well as demonstrated the beneficial safety profile of magnesium supplementation. Thus, mag-
nesium preparations seem to be a valuable addition to the pharmacological armamentarium for management of depression.
Key words:
magnesium, depression, antidepressant-like effect, antidepressant therapy
Introduction
is localized in bones while the rest is found in soft tis-sues and plasma/serum [33]. According to literature Magnesium, one of the most essential minerals in the [20, 64] magnesium is widely connected with brain human body, a co-factor of many enzymatic reactions biochemistry as well as the fluidity of neuronal mem- [43, 54], is known to be involved in proper function- brane. Thus, a variety of neuromuscular and psychiat- ing of cardiovascular, alimentary, endocrine and os- ric symptoms (i.e., hyperexcitability, agitation, tetany, teoarticular systems. An adult contains about 24 headaches, seizures, ataxia, vertigo, muscular weak- grams of magnesium, of which more than 50 percent ness, tremors, irritability, anxiety, insomnia, nervous Pharmacological Reports, 2013, 65, 547–554 fits, lipothymias, fatigue, confusion, hallucinations, erythrocyte magnesium concentration and the clinical depression) was observed in magnesium deficiency.
progress of this disorder was also noted [60, 89]. In All of them were reversible by restoration of normal contrast, Nechifor et al. [60] showed a decrease of brain magnesium level [66, 84]. Experimentally in- erythrocyte magnesium in patients with severe and duced magnesium deficiency resulted in depression- medium major depression. Magnesium decrease was like behavior in rodents [57, 78, 80, 88], which was positively correlated with the severity of clinical effectively managed by antidepressants [78, 88].
symptoms measured by Hamilton scale. The same The diet of depressed people appears to be impov- author [59] observed lower erythrocyte magnesium erished in magnesium [41]. Jacka et al. [41] found an level (versus the control group) in adult patients with inverse relationship between magnesium intake and major depression who had received antidepressant depressive symptoms in community-dwelling adults.
therapy before hospital admittance. On the other However, the authors wonder if the poor quality of hand, antidepressant therapy with amitriptyline or ser- depressives’ diet was a causative factor or a conse- traline increased concentration of erythrocyte magne- quence of their mental disorder. Apart from malnutri- sium level [60]. Data of another trial showed that sig- tion, low magnesium level in the body may occur due nificantly lower erythrocyte magnesium level in to defects in its absorption or as a result of its renal patients with major depression was associated with loss (for example in case of diabetes, alcoholism, diminished magnesium plasmatic level as well as treatment with antidiuretics, aminoglycosides, fluoro- increased plasmatic concentration of copper [59].
quinolones, cisplatin, digoxin, cyclosporine, ampho- A positive correlation between serum level of magne- tericin B) [34]. Acute emotional stress and stressful sium and thyroid hormone T4 [42] along with the in- activities increase magnesium excretion as well [22].
volvement of an imbalance in the serum magne- It has also been proposed that the transfer of large sium/copper ratio have been found in depressed amounts of this element from mother’s blood to fetus patients [96]. Opposing results were obtained by with other nutrients may contribute to occurrence of Hasey et al. [32], who noticed an inverse correlation postpartum depression [20]. Some authors try to asso- between serum magnesium concentration and T3 and ciate a long-term insufficient intake of magnesium T4 levels. No relationship was demonstrated between with development of systemic inflammation, which in zinc and magnesium or/and copper concentrations or turn is likely to aggravate the symptoms of depression [23, 49, 50, 67, 86]. Major and suicidal depression Plasma/serum magnesium levels do not seem to be particularly seems to be related with magnesium in- appropriate indicators of depressive disorders, since sufficiency. Literature data indicate that cerebrospinal ambiguous outcomes, depending on the study, were fluid magnesium concentration was low in patients obtained. There are several reports on higher concen- with history of suicidal behavior [4, 5] while serum tration of magnesium in depressed patients [8, 37, 48] and cerebrospinal fluid calcium to magnesium ratios and more than a few on the lower magnesium level [6, were usually elevated in acutely depressed individuals 38, 75, 96]; some authors claim that there is no differ- when compared to the healthy subjects [46]. As pointed ence in the serum/plasma concentrations of magne- out by Eby and Eby [20], this connection is not so obvi- sium ion or calcium/magnesium ratios between the af- ous for “melancholy”, depression developed as a re- fected subjects and the control group [46, 93]. Levine sult of hormonal imbalance, low cholesterol, food al- et al. [46] compiled data from multiple researches on lergy, Wilson’s disease and other ailments or depres- plasma/serum levels of magnesium and calcium in de- sion being an adverse reaction to drugs.
pressives. Similar non-consistency of results wasnoted in relation to magnesium plasma/serum levelsafter initiation of antidepressant drug therapy – Frizelet al. [29] showed a significant increase of magne- Magnesium levels in depression
sium concentration while Naylor et al. [58] found nodifferences. Most probably, all these divergences oc- There is evidence of rise in erythrocyte magnesium curred because of the influence of distinct factors and levels in severely and moderately depressed people methodology of clinical trials on the obtained results versus the slightly depressed ones and healthy indi- [46, 60]. One of them might have been the imple- viduals [28, 89–91]. Positive correlation between mented therapy – for example, some studies demon- Pharmacological Reports, 2013, 65, 547–554 Magnesium in depression
strated that neuroleptics [2, 40], antidepressants [5, dietary supplements but also they are perceived as the 90] and lithium treatments promote alterations in effective agents in treatment of migraine, alcoholism, plasma/serum levels of magnesium [37]. These diver- asthma, heart diseases, arrhythmias, renal calcium gent results have made recognition of depression as stones, premenstrual tension syndrome and many being caused by magnesium deficiency nearly impos- others [3, 17, 19, 27, 44, 52, 77, 94, 95]. The role of sible to the clinician and have very greatly retarded magnesium preparations in management of a range of research. Eby et al. [22] suggested that tissue magne- mental disorders as well as emotional problems [20, sium level is a much better indicator than magnesium 55] cannot be neglected. For many decades magne- plasma/serum concentration. Iosifescu et al. [38] and sium has had its essential place in homeopathy as Nowak et al. [62] reported the link between reduced a remedy for a range of mental health problems, content of magnesium in brain and depression. Phos- including depression [20]. Promising preclinical and phorus magnetic resonance spectroscopy seems to be clinical reports support therapeutic potential of currently the best tool for in vivo assessing magne- diverse magnesium compositions in different kind of sium level in the human brain [39]. It has a potential depression (Tab. 1). Antidepressant activity of mag- to become a reliable method that could help in diag- nesium was observed after both short-term and nosis of different pathological conditions associated chronic administration [69, 81, 82].
with low brain magnesium, e.g., major depression Mode of action of antidepressant-like effect of magnesium is not fully understood yet [10]. There isstrong evidence that magnesium influences severalsystems associated with development of depression.
This cation is known to modulate the activity ofNMDA and GABA receptors, play an important role Mechanism of antidepressant action
in suppression of hippocampal kindling and release ofadrenocorticotropic hormone and interact with the The emergence of a new approach to magnesium limbic-hypothalamus-pituitary-adrenal (HPA) axis, compounds in medical practice has been seen. Not frequently dysregulated in depressives [56]. Besides, only are they administered as components of ordinary it probably affects access of corticosteroids to the Tab. 1. Preclinical and clinical reports supporting the involvement of magnesium in treatment of depression
Magnesium deficiency and depression-like behavior in rodents Antidepressant activity of magnesium after short-term and chronic administration in post-traumatic depression (decreased incidence and severity) Effect of joint administration of magnesium and other agents enhancement of the antidepressant-like activity of magnesium by NMDA antagonists inhibition of the antidepressant-like activity of magnesium by NMDA agonists synergistic antidepressant-like effect of magnesium and fluoxetine, imipramine, citalopram, tianeptine, bupropion Efficacy of magnesium treatment/supplementation in reducing depressive symptoms in chronic fatigue syndrome in reducing depressive symptoms in women with premenstrual syndrome in elderly depressives with hypomagnesaemia and type 2 diabetes Pharmacological Reports, 2013, 65, 547–554 brain via influence on P-glycoprotein, participates in ago [87]. Administration of magnesium sulfate to rats inactivation of protein kinase C neurotransmission subjected to traumatic brain injury significantly de- and stimulates activity of Na+/K+ATPase [1, 31, 35, creased both incidence of post-traumatic depression 55, 76, 92]. Depletion of magnesium, a physiological and its severity [30]. Decollogne et al. [16] and voltage-dependent blocker of NMDA receptor ion Poleszak et al. [69, 72–74] observed that the immobil- channel, allows calcium and sodium ions to enter the ity time in forced swimming test in mouse and rat postsynaptic neuron and to exit potassium ions [21, models was significantly reduced by magnesium ions.
51, 53]. Increased influx of calcium ions leads to pro- The obtained results were comparable to those re- duction of toxic reactive oxygen species and toxic corded for imipramine and MK-801 [16]. Moreover, amount of nitric oxide radicals as well as neuronal the ineffective doses of NMDA antagonists (MK-801, swelling and neuronal death [9, 21, 51]. Neuronal CGP 37849, L-701,324, D-cycloserine) given jointly dysfunction and depression as a consequence of an with a low and also subactive dose of magnesium hy- excessive leak of calcium into cells triggering the syn- droaspartate shortened the immobility time in the FST aptic release of glutamate, depolarization of neurons [71]. On the other hand, the agonists of different bind- and further increase of calcium ions is also observed ing sites of the NMDA receptor complex (i.e., NMDA in ATP insufficiency in neurons. Magnesium ions are and D-serine) abolished the magnesium-induced known to take part in a proper formation and utilisa- antidepressant-like effect [70, 71]. Co-treatment of tion of ATP [12, 21]. Some authors confirmed that the magnesium salts and antidepressants from different shortage of magnesium ions along with the excess of classes (i.e., fluoxetine, imipramine and bupropion) calcium ions and glutamate are the cause of brain cell results in the synergistic antidepressant-like effect, synaptic dysfunction leading to mood and behavioral measured by the standard broadly accepted FST, used disorders, including depression [20]. Although the an- in behavioral experiments [10, 74]. Similar outcomes tidepressant activity of magnesium is predominantly were also observed by Poleszak [68] for combination attributed to the blockade of NMDA receptor [14, 63], of magnesium ions and citalopram or tianeptine.
animal studies performed by Carsodo et al. [10] con- Depression-like behavioral disturbances induced in firmed that various receptors from several other sys- rats by magnesium-deficient diet were reversed by tems: serotonergic (5 HT1A-, 5 HT2A/2C-receptors), treatment with Mg L-aspartate and magnesium chlo- noradrenergic (a1-, a2-receptors) and dopaminergic ride hexahydrate combined with vitamin B$ [80].
(D1-, D2-receptors) are relevant, as well. Involvement Similar results were obtained after joint administra- of serotoninergic system in anti-depressant action of tion of magnesium and pyridoxine hydrochloride in magnesium ions was also demonstrated by Poleszak experiments carried out in animal model of chronic [68] in the forced swimming test (FST) in mice – an alcoholism [36]. According to Singewald et al. [78], anti-immobility activity of magnesium was dimin- chronic oral administration of desipramine or hype- ished by pre-treatment with p-chlorophenylalanine, an ricum extract as an addition to a 21-day magnesium- inhibitor of serotonin synthesis. Since it was shown deficient diet prevents development of depression- that 15 mg/kg of magnesium moderately stimulates like behavior disturbances. In experiments performed the reward system in rats [45], there are some suppo- by Nikseresht et al. [61] on female mice, a single joint sitions that the brain reward system may contribute to administration of zinc, magnesium and vitamin B the antidepressant effect of magnesium [45, 60]. Sup- 3 days after delivery improved depressive behavior.
plementation of magnesium ions prolongs duration of Co-administration of a high dose of sildenafil cit- slow wave sleep which is decreased in the course of rate (20 mg/kg) with magnesium hydroaspartate thor- oughly inhibits the antidepressant properties of thelatter [79]. Because of the sedative activity of magne-sium, caution is advised when anesthetic drugs andthis element are given together. Reduction in anes- Pre-clinical and clinical studies
Eby and Eby [20] observed the efficacy of magne- The first information on the beneficial effect of mag- sium supplementation in patients with postpartum and nesium sulfate given hypodermically to patients with major depression. Magnesium treatment also im- agitated depression was published almost 100 years proved symptoms of depression in chronic fatigue Pharmacological Reports, 2013, 65, 547–554 Magnesium in depression
syndrome [13] and in women with premenstrual syn- topical application of 25% magnesium chloride solu- drome [25]. Randomized clinical trial performed by tion to the chest and back was proposed as well [20, Barragan-Rodriguez et al. [7] demonstrated that 12- 83], since this route can result in increases in brain week oral administration of 5% solution of magne- sium chloride to elderly depressives with hypomagne- Given that standard antidepressant therapies, semia and type 2 diabetes exerts therapeutic effect though varied but with numerous side effects, do not similar to imipramine 50 mg daily. A recovery within meet clinical expectations [15, 65] in about 60% of less than 7 days from major depression after taking patients [22], magnesium preparations with their magnesium glycinate and magnesium taurinate with overall beneficial safety profile seem to be a valuable each meal and at bedtime, was reported for several addition to the pharmacological armamentarium for cases [20]. However, some authors wonder to what management of depression. As a prevention strategy, degree magnesium given alone may decrease the in- Eby et al. [22] recommended daily intake of 600 to tensity of depression symptoms [60]. Depressive 800 mg of magnesium, with the exception of ineffec- states and paresthesia immediately resolved after in- travenous administration of magnesium sulfate to 69-year-old woman with Gitelman’s syndrome [24].
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Pharmacological Reports, 2013, 65, 547–554
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