Magnesium for treatment-resistant depression: A review and hypothesis
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)
- et al.
What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies
J Affect Disord
(2009) - et al.
Rapid recovery from major depression using magnesium treatment
Med Hypotheses
(2006) - et al.
Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population
Biol Psychiatry
(1993) - et al.
Intravenous magnesium
Crit Care Resusc
(1999) - et al.
Skeletal buffer function and symptomatic magnesium deficiency
Med Hypotheses
(1991) - et al.
Magnesium: nature’s physiologic calcium blocker
Am Heart J
(1984) - et al.
NMDA receptor complex blockade by oral administration of magnesium: comparison with MK-801
Pharmacol Biochem Behav
(1997) - et al.
Evidence for the involvement of the monoaminergic system in the antidepressant-like effect of magnesium
Prog Neuropsychopharmacol Biol Psychiatry.
(2009) - et al.
Kainic acid: a powerful neurotoxic analogue of glutamate
Brain Res
(1974) - et al.
Magnesium-deficient diet alters depression- and anxiety-related behavior in mice – influence of desipramine and Hypericum perforatum extract
Neuropharmacology
(2004)