Depression is a prevalent systems-level disability that widely overlaps or is comorbid with other disease states—mental and physical. Accordingly, multiple brain regions, pathways, and signaling molecules appear to be involved (Miller & Raison, 2016; Williams et al., 2016). Treatment-resistant depression (TRD) comprises a third or more of the depressed population. Reduced—it is the failure to achieve complete remission following adequate antidepressant therapy (Chamberlain et al., 2019; Fava, 2003; Gaynes et al., 2013). TRD patients are at high risk for physical and mental comorbid states, disease severity, and no effective treatment options (Eby III & Eby, 2010). Discord across research groups has slowed the advancement towards more definitive criteria for TRD due to aspects involving research design, lacking treatment response metrics, low inter-clinician reliability, and comorbidity—factors that perpetuate ambiguity around the predictors for TRD (Chamberlain et al., 2019; Gaynes et al., 2013). This review takes a broad look at immune system function in TRD with a special consideration towards magnesium (Mg) as an effective orthomolecular adjunct or treatment option for TRD within a Westernized population predisposed to malnutrition.
Depression gives rise to several neuroanatomical changes including negative volume and activity shifts in the hippocampus and prefrontal cortex (PFC), and hypertrophy of the amygdala (Pittenger & Duman, 2008; Zarate et al., 2013). Conventional antidepressant therapies focused on the molecular approach to disease and treatment—selective serotonin reuptake inhibitors (SSRI) and monoamine oxidase inhibitors (MAOIs), are based on the monoamine hypothesis and rely on increasing the synaptic availability of several key neurotransmitters —norepinephrine, serotonin, and dopamine, and promoting neurogenesis (Koo et al., 2010; Lacasse & Leo, 2005). Generally, only short-term antidepressant use seems to be effective, producing marginally significant effect sizes when compared to placebo and in certain cases of depression following weeks of treatment (Cipriani et al., 2018). Further, these antidepressants not only come with undesired side effects—cognitive impairments (Sayyah et al., 2016) and persistent sexual dysfunction (Csoka et al., 2008), as examples, but can remain long after discontinued use alongside symptomatic return (Cipriani et al., 2018; Davies & Read, 2019). The discovery of fast-acting antidepressants, such as ketamine or scopolamine (Berman et al., 2000; Wohleb et al., 2017), have lifted conservative eyes onto alternative pathways that can pause and reverse the injuries and brain changes governed by depression.
Origins and epigenetics
Mental illness often presents in early life (Kessler at al., 2010; Kim-Cohen et al., 2005). The main predictor of well-being in adults is childhood emotional health and stability (Cabaj et al., 2014; Kessler et al., 2010). In other words, childhood trauma increases the risk of adult mental health disorders, including depression, and seems to be a primary feature of TRD (Sachs-Ericsson et al., 2007; Williams et al., 2016). The diathesis stress model describes the increased risk for depression when an individual has a history of maltreatment and expresses two short alleles for the serotonin transporter gene (5-HTTLPR), rather than two long or one long plus one short allele (Caspi et al., 2003). This model has been examined in the context of generational stress, gender differences, and chronic stress leading to depression (Liu & Alloy, 2010).
Pathogen host defense (PATHOS-D) hypothesis
Within the modern gene pool are common, pro-inflammatory alleles linked to increased risk for depression (Raison & Miller, 2013). The persistence of depression risk alleles in the human genome is at odds with Darwinian evolution. Depression impairs reproduction and survival by its maladaptive effects on social functioning. In earlier times, infection led many humans to death before adulthood, therefore genetic alleles that promoted protective pro-inflammatory mechanisms were strongly selected for (Fumagalli et al., 2011; Gurven & Kaplan, 2007; Miller & Raison, 2016). The pathogen host defense (PATHOS-D) hypothesis suggests that these alleles, in connection to the immunological and behavioural responses to a wide scope of environmental threats, persist to enhance survival as they have for antecedent generations (Miller & Raison, 2016; Raison & Miller, 2013).
The reliable use of cytokines to induce or reverse depressive symptoms has gained much attention. Individuals at high risk for depression are consistently found to have higher levels of inflammatory markers when compared to low-risk individuals in a variety of populations including youth, chronic pain, and breast cancer patients (Kim et al., 2013; Kovacs et al., 2016; Raison et al., 2010; Tartter et al., 2015). Further, the height of the inflammatory response to a psychosocial stressor corresponds well to predictions of later depression development (Aschbacher et al., 2012; Pace et al., 2006; Quinn et al., 2020). Growing studies support the role of low-grade systemic inflammation in the pathogenesis of depression—namely TRD, psychosis, and other neuropsychiatric disorders (Chamberlain et al., 2019; Dantzer et al., 2008; Khandaker et al., 2015; Metcalf et al., 2017; Michopoulos et al., 2015; Raison et al., 2006; Raison et al., 2013; Wium-Andersen et al., 2013). Meta-analyses point to several cytokines—interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), tumor necrosis factor (TNF), and Creactive protein (CRP), as strong indicators of antidepressant treatment response (Gimeno et al., 2009; Goldsmith et al., 2016; Haapakoski et al., 2015; Howren et al., 2009; Khandaker et al., 2014; Metcalf et al., 2017; Miller et al., 2009; Osimo et al., 2019).
Elevating systemic cytokines through activation or deliberate administration to nondepressed subjects evokes sickness behaviour—a condition whose symptomatic repertoire is indiscernible from depression and can be reversed with antidepressants (Capuron et al., 2002; Dantzer, 2009; Raison & Miller, 2013). In other words, infections can be mistaken for depression, depression can be mistaken for infection, and these inflamed events can provide insight into the treatment resistance seen in TRD (Ratcliffe, 2013). Further, the depressive symptoms associated with other illnesses such as psoriasis, obesity, and rheumatoid arthritis are significantly reduced upon anti-cytokine therapy (Kappelmann et al., 2018; Menter et al., 2010; Soczynska et al., 2011; Tyring et al., 2006). While adaptive and innate immune systems appear to play instrumental roles in TRD, perspective into other non-drug interventions, predispositions, and factors affecting these immunological pathways is needed for progress and understanding.
Magnesium, cytokines, and depression
Micronutrient deficiencies, common in modernized cultures, are associated with poorer health outcomes such as cognitive decline, cancer, obesity, immune dysfunction, and depression (Wang et al., 2018). Magnesium (Mg) is an essential cofactor and mineral cation found primarily within cells. Due to its highly involved importance, it is kept within tight homeostatic control through dietary absorption, urinary output, and bone stores. There are numerous channels that can lead to changes in Mg absorption or excretion including consumption of alcohol or dietary compounds such as phytic acid or oxalates, malnutrition, medications, aging, smoking, diabetes, hypernatremia, hypercalcemia, disorders affecting the gastrointestinal system, and chronic stress—to name a few (Barbagallo et al., 2009; Dickerman & Liu, 2011; Eby and Eby, 2006; Kieboom et al., 2015; Pochwat et al., 2014; Tarleton, 2018; Topf & Murray, 2003; Volpe, 2013).
Low dietary Mg has been correlated with depression in young adults, adding a 50% increased risk for depression in those found at the lowest intake quintile (Tarleton & Littenberg, 2014). Mg deficiency has also been associated with elevations in IL-1ß, IL-6, TNF, and CRP (Dibaba et al., 2014; Nielsen, 2018; Sugimoto et al., 2012). Meta-analyses and other studies have revealed an inverse relationship between dietary Mg intake and serum CRP levels (Dibaba et al., 2014; King et al., 2005; Simental-Mendia et al., 2017).
Mg is a calcium antagonist and calcium channel blocker. Low or deficient Mg stimulates the opening of L-type calcium channels allowing an influx of calcium, a rise in intracellular calcium, and calcium release from the sarcoplasmic reticulum (Dacey, 2001; Gums, 2004; Lin et al., 2010). Increased intracellular calcium promotes the release of IL-1ß, IL-6, TNF or CRP, stimulating phagocytic cells and the production of reactive oxygen species (Libako, et al., 2010). Repletion of Mg has been found to effectuate a reversal of these calcium-inducing effects, consequently attenuating cytokine production (Lin et al., 2010; Sugimoto et al., 2012).
Animals depleted of Mg were also found to activate the N-methyl-D-aspartic acid (NMDA) receptor leading to an influx of intracellular calcium, production of substance P in C fibers, increased cytokines, and oxidative stress (Blache et al., 2006; Reynolds, 1998; Weglicki, 2012; Zarate et al., 2013). In the chronic mild stress (CMS) model of depression, particular glutamatergic subunits of NMDA receptors—GluN1, GluN2A, GluN2B and PSD-95, within the hippocampus, amygdala, and PFC— areas associated with depression, were found to be upregulated or downregulated upon administration of Mg under stressed conditions (Pochwat, 2014). The effects that Mg repletion impart on cytokine regulation appear to result from its antagonistic actions on calcium, calcium channel and NMDA receptor inhibition, and modulation of NMDA receptor expression (Lin et al., 2010; Lodge & Johnson, 1990).
Magnesium and TRD
While the relationship with depression and Mg to inflammation is convincing, the relation between Mg and depression remains unclear. Some studies have been unable to establish a link between Mg status and depressive outcome (Dickerman & Liu, 2011; Phelan et al., 2018; Wang et al., 2018), while other studies have determined a distinct inverse correlation between Mg and depression. In animal models, the behavioural despair endophenotype of depression was reproduced in mice using the forced swim test (FST), demonstrating that Mg depletion increases immobility whereas Mg repletion reduces immobility when compared to placebo (Poleszak et al., 2004; Singewald et al., 2004). In human models, the prevalence (cross-sectional) and incidence (longitudinal) of depression and Mg intake in self-reporting groups reveal a strong inverse relationship—Mg depletion exacerbates depressive symptoms and symptom improvement occurs upon Mg repletion (Eby & Eby, 2006; Jacka et al., 2009; Tarleton & Littenberg, 2015; Tarleton et al., 2017; Yary et al., 2016). Moreover, interesting results measured by phosphorus nuclear magnetic resonance (NMR) spectroscopy reveal that TRD subjects have significantly lower levels of intracellular Mg in the brain compared to non-TRD subjects (Eby III & Eby, 2010; Iosifescu et al., 2008).
Co-administration of Mg and antidepressants such as imipramine or citalopram, were reported to augment antidepressant efficacy (Poleszak et al., 2005; Szewczyk et al., 2008). The antidepressant-like effects promoted by Mg have been traced to its binding interactions with the serotonergic, noradrenergic, and dopaminergic systems (Cardoso et al., 2009; Eby III & Eby, 2010; Kantak, 1988). As low levels of brain Mg seem to decrease serotonin, and antidepressants appear to improve intracellular concentrations of brain Mg (Eby III & Eby, 2010), confidence surrounding this particular cofactor builds as a potential therapy for TRD.
The mechanism of action of Mg appears to be widespread, circuitous, and intricate, along with regulatory effects on the hypothalamic-pituitary adrenal (HPA) axis and adrenocorticotrophic hormone (ACTH)—other points of Mg control in depression that have been aptly described in previous work (Eby III & Eby, 2010; Murck, 2002; Sartori et al., 2012). In the Mg-depletion model of depression, inadequate Mg levels lead to NMDA overactivity, cytokine production, and increased symptoms of depression. Administering NMDA receptor antagonists like ketamine and Mg have been found to support: synaptogenesis, reversal of stress-induced atrophy, and symptomatic improvement in TRD (Berman et al., 2000; Zarate et al., 2013).
The data suggests that Mg repletion is a necessary or plausible treatment approach in TRD or depression in general, respectively. The current review sought to reconcile the shared mechanisms between magnesium and TRD while acknowledging the nutritional neglect often encumbering the depressed individual. Modern food practices over the last century have contributed to lacking dietary Mg density and intake estimated in Westernized populations (Gums, 2004). Low Mg food sources further predispose depressed subjects to nutrient deficiencies, as the disorder often directs poor dietary choices. The ubiquitary nature of stress and inflammation highlights a growing impact on gene expression and the call to identify sites of origin and maintenance. Mutual crossover points relating to cytokine production, Mg, and TRD suggest an increased likelihood that Mg supplementation would be a beneficial treatment option for TRD and depressed persons that are or are not medicated, excluding the elderly unless newly diagnosed with depression associated with type 2 diabetes (Blanchflower & Oswald, 2008; Eby III & Eby, 2010; Tarleton & Littenberg, 2015). The strong relationship between Mg and immune response emerging from the extant literature prompts continued investigation (Tam et al., 2003).
The majority of studies conducted on Mg included males and females across all ages and body types, improving the generalizability of the findings; however, gender-specific biases in Mg levels may not have been accounted for, e.g. contraceptive use (Stanton & Lowenstein, 1987). Studies that found positive correlations between depression and negative serum or cerebrospinal fluid (CSF) Mg levels were excluded due to methodological concerns regarding the use of serum or CSF Mg as an indicator of intracellular or total body Mg levels, as either can be within normal limits while the other is not (Arsenian, 1993; Elin, 1994; Purvis, 1992). For instance, in TRD, serum Mg can be high, normal, or low and unrelated to levels of brain Mg (Eby III & Eby, 2010), while depressed patients not on medication can have high erythrocyte Mg scores (Widmer et al., 1992; Widmer et al., 1995; Widmer et al., 1993). In other words, intracellular and extracellular Mg concentrations vary across tissue types and between individual temperament, physiological demand, and other health-related contexts. Further, the biological half-life of Mg is nearly six months (Elin, 1994), while repletion of Mg body stores through oral supplementation can take weeks or months (Gums-Dorup et al., 1993; Whang et al., 1994). It is possible that the symptomatic reduction and positive effects seen with acute Mg repletion in these studies would require repeat high doses of Mg over an extended period to maintain the observed effects until adequate intracellular brain levels were achieved, after which a lower dosage or proper dietary routine could suffice. Mg homeostasis is complex, therefore delayed clinical presentation of Mg deficiency within certain tissues is expected and comparable to the lagging clinical appearance of calcium deficiency in postmenopausal women (Gums, 2004). Such uncertain mechanics could explain the dissonant results found across studies using serum or CSF Mg levels prior to a clear understanding around how Mg levels shift within different tissues and physiological states.
Environmental stressors are known to influence gene expression, biological process, neural function, cognition, behaviour, and well-being. Over the past two decades, an integrated approach to understanding depression has led to several multilevel paradigms including the Social Signal Transduction Theory of Depression. This theory describes the proportional immune response, specifically increases in IL-6, that follows psychosocial stress, impairs executive function, and advances or worsens the development of depression (Quinn et al., 2020; Slavich & Irwin, 2014). The incidence of stress and depression has become a common social reality. For TRD sufferers, conventional medications are not an option; for others, philosophical or lifestyle choices drive the alternative wish to avoid the use of pharmaceutical drugs. For all those concerned, research around orthomolecular medicines that encourage recovery or stress-induced inflammatory resistance would benefit those hoping for improved outcomes. As well, focus on hygiene theory, gut microbiota, and the developing immune system of young children might lead to gentler, cost-effective, and preventative measures for TRD and general depression.
The immune system is a complex security and surveillance network regulating all matters of functional breach, averse to nutritional deficiencies that create openings for pathogenic insult. Low Mg is associated with various chronic conditions including major depression, postpartum depression, hypothyroidism, Alzheimer’s, stroke, hypertension, cardiovascular disease, migraine headaches, and type 2 diabetes mellitus (Eby & Eby, 2006; Kawano et al., 1998; Volpe, 2013). While inflammation plays a role in the aforementioned dysfunctions, the potential harm of pharmaceutical anti-inflammatory or anti-cytokine therapy in patients with or without inflammation must be acknowledged. The potential use of Mg as a therapeutic agent in TRD is tenable, safe, and practical for daily use to promote health and prevent disease in those predisposed to Mg depletion, stress, TRD, and depression (Eby III & Eby, 2010; Gums, 2004; Tam et al., 2003; Volpe, 2013); hypermagnesemia—a rare concern, with caution typically reserved for those inclined to renal failure. Prospective work confirming the efficacy of Mg in TRD must be pursued to authenticate its restorative value.
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