Elsevier

Medical Hypotheses

Volume 74, Issue 4, April 2010, Pages 649-660
Medical Hypotheses

Magnesium for treatment-resistant depression: A review and hypothesis

https://doi.org/10.1016/j.mehy.2009.10.051Get rights and content

Summary

Sixty percent of cases of clinical depression are considered to be treatment-resistant depression (TRD). Magnesium-deficiency causes N-methyl-d-aspartate (NMDA) coupled calcium channels to be biased towards opening, causing neuronal injury and neurological dysfunction, which may appear to humans as major depression. Oral administration of magnesium to animals led to anti-depressant-like effects that were comparable to those of strong anti-depressant drugs. Cerebral spinal fluid (CSF) magnesium has been found low in treatment-resistant suicidal depression and in patients that have attempted suicide. Brain magnesium has been found low in TRD using phosphorous nuclear magnetic resonance spectroscopy, an accurate means for measuring brain magnesium. Blood and CSF magnesium do not appear well correlated with major depression. Although the first report of magnesium treatment for agitated depression was published in 1921 showing success in 220 out of 250 cases, and there are modern case reports showing rapid terminating of TRD, only a few modern clinical trials were found. A 2008 randomized clinical trial showed that magnesium was as effective as the tricyclic anti-depressant imipramine in treating depression in diabetics and without any of the side effects of imipramine. Intravenous and oral magnesium in specific protocols have been reported to rapidly terminate TRD safely and without side effects. Magnesium has been largely removed from processed foods, potentially harming the brain. Calcium, glutamate and aspartate are common food additives that may worsen affective disorders. We hypothesize that – when taken together – there is more than sufficient evidence to implicate inadequate dietary magnesium as the main cause of TRD, and that physicians should prescribe magnesium for TRD. Since inadequate brain magnesium appears to reduce serotonin levels, and since anti-depressants have been shown to have the action of raising brain magnesium, we further hypothesize that magnesium treatment will be found beneficial for nearly all depressives, not only TRD.

Introduction

Neuropsychiatric disorders account for 36% of all non-communicable conditions, are the leading cause of all disability (more than twice that of cardiovascular diseases and malignant neoplasms) in the United States and Canada, with depressive disorders causing 40% of all neuropsychiatric disorders [1]. Major depression is expected to affect up to 25% of the American population at some point in their lives. Patients suffer in many areas of their lives, including sleep, eating, relationships, school, work, and self-image.

Americans are developing major depression at higher rates and younger ages than ever before [2]. People born around 1900 rarely had childhood or early adult depression and only about 1% ever developed depression. People born between 1935 and 1944 had a 1% incidence of depression by age 15, a 2% rate of depression by age 25 and 9% incidence by age 45. People born in 1955, had a 1% incidence of depression by age 15, a 6% incidence by age 25, and a lifetime incidence of 25%. The onset of depression has greatly increased in incidence, and it is affecting people much earlier in their lives during the late 20th century and early 21st century than before the 20th century [2].

Among those who seek professional help for clinical depression, some patients find relief for their condition using selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic anti-depressants, herbal 5-HTP, omega-3 EFAs and various medical and psychiatric treatments. The clinical efficacy of current anti-depressant drug therapies is unsatisfactory; anti-depressants induce a variety of unwanted side effects, and, moreover, their therapeutic mechanisms are not clearly understood. Thus, a search for better and safer agents is continuously in progress [3].

A large proportion of the burden caused by depression is attributable to treatment-resistant depression (TRD). TRD itself is common, as high as 60% if TRD is defined – as it probably should be – as absence of remission from psychiatric medical and drug treatment. Duration and severity of illness are higher in TRD. In the short term, TRD is highly recurrent with as many as 80% of those requiring multiple treatments relapsing within a year of achieving remission. For those with a more protracted illness, the probability of recovery within 10 years is about 40%. Patients with TRD are more likely to suffer from comorbid physical and mental disorders, to experience marked and protracted functional impairment, and to incur higher medical and mental healthcare costs. Thus, in order to reduce the substantial burden caused by depression, TRD is one of the central focuses of medical research [4].

We hypothesize that there is a different cause for TRD relative to treatable depression, a cause perhaps resulting from changes in the diet, and that magnesium-deficiency is involved as the main factor. For a long time it was not accepted that food could have any influence on brain structure and its function including cognitive, mood and intellectual development. However, it is now very certain that magnesium plays important roles in all the major metabolisms in oxidation–reduction and in ionic regulation, among other roles in the brain [5]. Experience taught us the value of bioavailable oral magnesium in effectively and rapidly treating depression [6] and we hypothesized that magnesium treatment would be broadly effective, be of wide clinical benefit in TRD and reports of its efficacy would be readily and widely found in the literature. We searched for reviews and found that there were none that were comprehensive and all inclusive, and that such review was needed.

Section snippets

Methods

To prepare this review, which we purport to be a comprehensive and all inclusive English-language review, we conducted a PubMed/Medline search for the terms magnesium and depression (1309 articles – only 76 related to mental health), magnesium and: “affective disorders” (40 articles), “treatment-resistant depression” (0 articles), “clinical depression” (0 articles), “major depressive disorder” (13 articles), and “major depression” (15 articles). The neurobiochemistry of magnesium and depression

Discussion

Our hypothesis that the benefits of magnesium in treating human depression, and especially TRD, would be found to be well known in the medical literature was not well supported. However, we found substantial information that − when taken together − shows a significant rationale for treatment of TRD with magnesium, continued research and more randomized, double-blind, placebo-controlled clinical trials of magnesium for TRD.

Conclusions

Due to its safety and efficacy, physicians should prescribe magnesium for TRD without further delay, even though much more clinical research is needed to confirm and extend this important line of research.

Conflicts of interest statement

None declared.

Acknowledgements

We thank the George and Patsy Eby Foundation for financial support.

References (132)

  • E. Poleszak et al.

    Antidepressant- and anxiolytic-like activity of magnesium in mice

    Pharmacol Biochem Behav

    (2004)
  • E. Poleszak et al.

    NMDA/glutamate mechanism of antidepressant-like action of magnesium in forced swim test in mice

    Pharmacol Biochem Behav

    (2007)
  • D.V. Iosifescu et al.

    Brain bioenergetics and response to triiodothyronine augmentation in major depressive disorder

    Biol Psychiatry

    (2008)
  • A. Frazer et al.

    Plasma and erythrocyte electrolytes in affective disorders

    J Affect Disord

    (1983)
  • L. Herzberg et al.

    Sex difference in mean serum-magnesium levels in depression

    Lancet

    (1972)
  • J. Widmer et al.

    Relationship between erythrocyte magnesium plasma electrolytes and cortisol and intensity of symptoms in major depressed patients

    J Affect Disord

    (1995)
  • L. Barragan-Rodríguez et al.

    Depressive symptoms and hypomagnesemia in older diabetic subjects

    Arch Med Res

    (2007)
  • R.L. Cundall et al.

    Plasma and erythrocyte magnesium levels in affective disorders

    Lancet

    (1972)
  • M.S. George et al.

    CSF magnesium in affective disorder: lack of correlation with clinical course of treatment

    Psychiatry Res

    (1994)
  • C.M. Banki et al.

    Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts

    Biol Psychiatry

    (1985)
  • J. Levine et al.

    Increased cerebrospinal fluid glutamine levels in depressed patients

    Biol Psychiatry

    (2000)
  • M.P. Freeman

    Complementary and alternative medicine for perinatal depression

    J Affect Disord

    (2009)
  • R.T. Joffe et al.

    The thyroid, magnesium and calcium in major depression

    Biol Psychiatry

    (1996)
  • World Health Report. Changing history annex table 3: burden of disease in DALYs by cause, sex and mortality stratum in...
  • J.S. Meyer et al.

    Psychopharmacology: drugs the brain and behavior

    (2005)
  • B. Szewczyk et al.

    Antidepressant activity of zinc and magnesium in view of the current hypotheses of antidepressant action

    Pharmacol Rep

    (2008)
  • J.M. Bourre

    Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain part 1: micronutrients

    J Nutr Health Aging

    (2006)
  • F.N. Jacka et al.

    Association between magnesium intake and depression and anxiety in community-dwelling adults: the Hordaland Health Study

    Aust N Z J Psychiatry

    (2009)
  • Heart gains from whole grains

    Harv Heart Lett

    (2002)
  • M.S. Seelig et al.

    The magnesium factor

    (2003)
  • R.L. Blaylock

    Food additive excitotoxins and degenerative brain disorders

    Med Sentinel

    (1999)
  • P.G. Weston

    Magnesium as a sedative

    Am J Psychiatry

    (1921–22)
  • M.F. Bear et al.

    Neurotransmitter systems

  • M. Yasui et al.

    Magnesium-related neurological disorders

  • W.F. Langley et al.

    Central nervous system magnesium deficiency

    Arch Intern Med

    (1991)
  • R.J. Macgregor

    Quantum mechanics and brain uncertainty

    J Integr Neurosci

    (2006)
  • R.M. Sapolsky

    Stress the aging brain and the mechanisms of neuron death

    (1992)
  • L.P. Mark et al.

    Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging

    AJNR Am J Neuroradiol

    (2001)
  • E.R. Kandel et al.

    Synaptic integration

  • K.A. McMenimen et al.

    Probing the Mg2+ blockade site of an N-methyl-d-aspartate (NMDA) receptor with unnatural amino acid mutagenesis

    ACS Chem Biol

    (2006)
  • B. Alberts et al.

    Molecular biology of the cell

    (2002)
  • E. Carafoli

    Calcium – a universal carrier of biological signals

    FEBS J

    (2005)
  • Gillessen T, Budd SL, Lipton SA. Excitatory amino acid neurotoxicity. In: Alzheimer C, editor. Molecular and cellular...
  • M.W. Hollmann et al.

    Modulation of NMDA receptor function by ketamine and magnesium part II: interactions with volatile anesthetics

    Anesth Analg

    (2001)
  • J. Durlach et al.

    Mechanisms of action on the nervous system in magnesium deficiency and dementia

  • K. Krnjevic et al.

    Intracellular divalent cations and neuronal excitability

    Can J Physiol Pharmacol

    (1979)
  • M.E. Morris

    Brain and CSF magnesium concentrations during magnesium deficit in animals and humans: neurological symptoms

    Magnes Res

    (1992)
  • H. Murck

    Magnesium and affective disorders

    Nutr Neurosci

    (2002)
  • K. Held et al.

    Oral Mg(2+) supplementation reverses age-related neuroendocrine and sleep EEG changes in humans

    Pharmacopsychiatry

    (2002)
  • H. Murck et al.

    Mg2+ reduces ACTH secretion and enhances spindle power without changing delta power during sleep in men – possible therapeutic implications

    Psychopharmacology (Berl)

    (1998)
  • Cited by (0)

    View full text