Magnesium for depression

Major depression is a common mood disorder affecting people all over the world^[1]. It's one of the leading causes of disability^[2] worldwide, and a significant burden on those who it affects. It’s more than feeling down due to sad life events. Everybody gets the blues, but it becomes a medical issue when it exceeds normal grief and sorrow, with depressive episodes persisting for longer, being more intense, and oftentimes recurring^[3] more frequently than they normally would, suggesting an underlying vulnerability. Depression isn’t merely a single emotional state, but is multifaceted with varying severity of symptoms^[4] depending on the individual, including feelings of worthlessness, low energy, lack of pleasure, insomnia, and changes in appetite.

Depression hurts, and that alone would be bad enough, but it may also increase the risk of various life-threatening diseases, making it medically concerning in several ways. It’s typically managed with pharmaceutical antidepressants, psychotherapy, or both, with varying degrees of success depending on the individual. Pharmaceutical treatments can ease depression for many people, but not everyone can receive their full benefit. Some people don't respond to standard antidepressants, having treatment-resistant depression^[5], and may require a long period of experimentation with various medications to find the right one, if they do at all. The difference between medication and placebo in the general population of patients with depression doesn’t tend to be large, except in severe^[6] cases, suggesting a need for better treatment options.

Research into treatment-resistant depression using a novel class of drugs has yielded insights into its pathophysiology. The use of drugs that target NMDA receptors^[7] in the brain may offer an alternative approach to depression treatment. NMDA receptors (pictured in Figure 1) are ion channel proteins that sit on the edge of synapses. When bound by glutamate and glycine, these receptors play an important role in neural plasticity, allowing for the passage of ions, namely sodium and calcium, which leads to synaptic transmission. However, they can become dysfunctional. Studies suggest^[8] that abnormal NMDA function plays a part in the pathogenesis of depression, and NMDA antagonists have positive and potent effects on the symptoms of depression. Ketamine is the most widely known drug that specifically targets NMDA receptors, and has been observed to lead to a chain of events that are neuroprotective and enable plasticity, areas that may be relevant to depression.

Figure 1: Magnesium and ketamine are both NMDA ion channel blockers

Reference: Ghasemi et al. Neurosci Biobehav Rev. 2014 Sept.

Magnesium plays a role in blocking NMDA receptor ion channels under normal physiological conditions and it shares a number of similarities with ketamine^[9] in its effects on NMDA receptors. A low serum level^[10] of magnesium has also been correlated with depression. While not a knock-out case for the relevance of dietary magnesium, as there are differences between ketamine and magnesium, and a low intake of magnesium could go hand-in-hand with a worse overall diet and lifestyle, various researchers have become interested in a possible link. One small trial^[11] suggests that it performs roughly as well as the medication imipramine, but more trials are needed to test its efficacy and give us an idea of its effectiveness compared with a placebo. The study under review seeks to remedy that.

Evolving research into depression treatment suggests NMDA receptor antagonists to be a promising tool to treat depression and reverse some of the processes involved in it. Magnesium plays an important role in NMDA regulation and low magnesium levels could be contributing to depression in some people, leading researchers to investigate the possible connection.