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Pharmacist Continuing Education: The Use of Magnesium in Major Depressive Disorder Management

15 May 2019 2:35 PM | Mandy Garion (Administrator)

Authors:  Arianne MacGillivray, PharmD and Ijeoma Onyema, PharmD
PGY-1 Pharmacy Practice Residents

Mentor:   Anthony Lucido PharmD, BCPS
PGY-1 Pharmacy Practice Residency Director
SSM Health DePaul Hospital – Bridgeton, MO

Program Number:  2019-05-09
Approval Dates:  June 5, 2019 – December 4, 2019
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

  1. List the current antidepressants used in major depressive disorder
  2. Evaluate the impact magnesium has on depressive symptoms
  3. Identify the different theories regarding major depressive disorder pathophysiology
  4. Explain the mechanism of action of magnesium in major depressive disorder

Introduction

Major Depressive Disorder (MDD) is a debilitating mental disorder, with approximately 17.3 million adults in the United States and 216 million people worldwide experiencing at least one major depressive episode.8  This disorder is characterized by at least two weeks of low mood that is often accompanied by low self-esteem, anhedonia, fatigue, and possible suicidal ideation. The pathophysiology behind major depressive disorder has been explained by multiple neurobiologic factors.

Pathophysiology

Genetics has been thought to play a role as well as stressful life events. Chronic stress has been found to lead to increased amounts of corticotrophin-releasing hormone released from the hypothalamus and subsequent increases in cortisol levels. A lack of monoamines such as norepinephrine, dopamine, and serotonin has been found in depressed patients and increases in available monoamines is the main mechanism of action of the majority of current antidepressant therapy. Dysregulation in GABA and glutaminergic processes as well as the circadian rhythm has also been associated with depression. Additionally, depressed patients have been found to have structural neurobiologic abnormalities, such a smaller hippocampus.7

Secondary depression can be caused by diseases and/or medications. For example, endocrine disorders such as diabetes and hypothyroidism have been associated with depression. Low levels of vitamins and minerals have also been associated. Specially, a low level of vitamin D has been found to be closely linked to depressive states. Magnesium has also been linked to depression, and will be discussed in further detail throughout the rest of this publication. Medications such as glucocorticoids, interferons, opioids, and beta blockers have been associated with depression; however, evidence relating to medication-induced depression is conflicting. There is question whether or not medications actually induce depression or if the perceived changes in mood are just related to these medications’ side effects such as fatigue, insomnia, lack of appetite, etc.

Current Therapies

There are five classes of antidepressants that are indicated for use in major depressive disorder and are currently used in practice. These include: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIS), monoamine oxidase inhibitors (MAOIs), and “other” antidepressants such as bupropion, nefazodone, trazodone, and mirtazapine. Potential common side effects of antidepressants include: GI problems, anxiety, weight gain, sexual dysfunction, and/or sedation. The potential of these medications to cause these side effects has notoriously caused significant patient concern; however, the majority of these should subside within the first few weeks of initiation. Based on these side effects, cost, duration, and potential to cause drug interactions, the 2010 American Psychiatric Association Guidelines recommend that SSRIs, SNRIs, mirtazapine, and bupropion be utilized first line. According to these guidelines, patients will generally see improvement with these medications in the first 1-2 weeks of treatment, but the medications may take up to 12 weeks to see full effect. If a patient experiences some improvement in depressive symptoms within the first few weeks of an antidepressant initiation, but moderate improvement is not achieved after 4-8 weeks at the highest tolerated dose, a different medication may be considered.1 Nonprescription medications such as SAM-e and fish oil have been evaluated for antidepressive efficacy, but current research is inconsistent in regards to the validity and applicability of the data analyzed. 

MOA of Magnesium in Depression

The true mechanism that magnesium plays in depression is unknown; however, it likely serves as a multi-factorial contributor in the depression. This is because of its impact on many of the pathways, hormones, and neurotransmitters involved in mood regulation. In the chronic mild stress model, the levels of magnesium and cortisol have been shown to be inversely proportionate. Also, magnesium is a calcium antagonist via its voltage-dependent blockade of the N-methyl-D-aspartate (NMDA) channel. By inhibiting the influx of calcium ions, less toxic reactive oxygen species and nitric oxide radicals are produced, leading to a reduction in neuronal swelling and neuronal death. This then results in less neuronal dysfunction and improved synapse production and activity.Moreover, magnesium has some impact on the modulation of gamma-aminobutyric acid (GABA) receptors; it likely has an inhibitory effect on GABA. This action downregulates the inhibitory effect of GABA on hippocampal activity, which contributes to suppression of hippocampal kindling and adrenocorticotropic hormone release to the HPA axis, which is a frequent occurrence in depression. Magnesium has also been suggested to play a role in systemic inflammation and the production of ATP, which could validate the impact the mineral has within the chronic stress pathophysiology model of depression in future studies.

Guideline Recommendation

There are currently no guidelines that recommend the use of magnesium for major depressive disorder treatment. However, several studies have been done to confirm that there is a reduction in magnesium levels in depressed patients as well as evaluate magnesium’s effectiveness in patients with major depressive disorder.

Table 1 – Studies Evaluating Magnesium’s Impact on Depression

Summary of Clinical Evidence

The studies that have been performed to assess magnesium’s antidepressant efficacy are highly variable in methodology. Different assessment tools for determining depression were used; none of the studies assessed used the Montgomery–Åsberg Depression Rating Scale (MADRS), which is considered to many to be the gold standard for indicating depressive symptoms in research studies. This variety in assessment methods could compromise the generalizability of recommending magnesium to depressed patients. Due to the high ambiguity of the association of serum magnesium levels to depressive symptoms in these studies (as many studies in the past have shown increased, decreased, and normal levels of magnesium in depressed patients), it has been theorized that serum magnesium levels may not be the most appropriate indicators of magnesium’s impact on major depressive disorder. Specifically, the variability of magnesium levels seen in these studies have suggested that proved that not all magnesium compositions are equally absorbed into the bloodstream. Magnesium chloride, sulfate, glycinate and taurinate have been associated with higher bioavailability than magnesium oxide.18

Conclusion

Overall, more robust research and investigation into supplementation for behavioral health management is needed to truly determine magnesium’s place in depression management, specifically with larger diverse populations and different indicators used to evaluate the efficacy of magnesium in depression (i.e. tissue magnesium level as a proxy of bioavailability). While not currently recommended in any guideline for depression, magnesium supplementation could be considered for those with mild depressive disorder who are also using behavioral interventions or an oral antidepressant given future research produces more tangible data that confirms its antidepressive effects.

References

  1. American Psychiatric Association 2010 Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third edition.
  2. Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb; 202: 100-7.
  3. Cade JF: A significant elevation of plasma magnesium levels in schizophrenia and depressive states. Med J Aust, 1964, 1, 195–196
  4. Eby GA, Eby KL: Rapid recovery from major depression using magnesium treatment. Med Hypotheses, 2006, 67, 362–370.
  5. Enya M, Kanoh Y, Mune T, Ishizawa M, Sarui H, Yamamoto M, Takeda N et al.: Depressive state and paresthesia dramatically improved by intravenous MgSO4 in Gitelman’s syndrome. Intern Med, 2004, 43, 410–414
  6. Hasey GM, D’Alessandro E, Cooke RG, Warsh JJ: The interface between thyroid activity, magnesium, and depression: a pilot study. Biol Psychiatry, 1993, 33, 133–135
  7. Hasler, G. Pathophysiolgoy of Depression: Do we have any solid evidence of interest to clinicians? W Psych. 2010 Oct; 9(3): 155-161
  8. National Institute of Mental Health. Major Depression. https://www.nimh.nih.gov. Accessed March 20, 2019.
  9. Imada Y, Yoshioka S, Ueda T, Katayama S, Kuno Y, Kawahara R: Relationships between serum magnesium levels and clinical background factors in patients with mood disorders. Psychiatry Clin Neurosci, 2002, 56, 509–514
  10. Joffe RT, Levitt AJ, Young LT: The thyroid, magnesium and calcium in major depression. Biol Psychiatry, 1996, 40, 428–429
  11. Nechifor M: Interactions between magnesium and psychotropic drugs. Magnes Res, 2008, 21, 97–100.
  12. Nechifor M: Magnesium in major depression. Magnes Res, 2009, 22, 163S–166S
  13. Patten SB, Barbui. Drug-induced depression; a systematic review to inform clinical practice. Psychother Psychosom. 2004; 73(4):207.
  14. Rasmussen HH, Mortensen PB, Jensen IW: Depression and magnesium deficiency. Int J Psychiatry Med, 1989, 19, 57–63.
  15. Rotella F, Mannucci E. Diabetes mellitus as a risk factor for depression. A meta-analysis of longitudinal studies. Diabetes Res Clin Pract. 2013 Feb; 99(2):98-104
  16. Serefko Aet al. Magnesium in depression. Pharmacol Rep. 2013;65(3):547-54.
  17. Tarleton EK, Littenberg B, MacLean CD, Kennedy AG, Daley C (2017) Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS ONE 12(6): e0180067
  18. Walker AF, Marakis G, Christie S, Byng M: Mg citrate found more bioavailable than other Mg preparations in a randomised, double-blind study. Magnes Res, 2003, 16, 183–191.

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