Review
Ketamine, magnesium and major depression – From pharmacology to pathophysiology and back

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Abstract

The glutamatergic mechanism of antidepressant treatments is now in the center of research to overcome the limitations of monoamine-based approaches. There are several unresolved issues. For the action of the model compound, ketamine, NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be involved in a mechanism, which leads to synaptic sprouting and strengthened synaptic connections. The link to the pathophysiology of depression is not clear. An overlooked connection is the role of magnesium, which acts as physiological NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine with that of high doses of magnesium in animal models, finally leading to synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as measured by an increase in slow wave sleep in humans. 3. Pathophysiological mechanisms, which have been identified as risk factors for depression, lead to a reduction of (intracellular) magnesium. These are neuroendocrine changes (increased cortisol and aldosterone) and diabetes mellitus as well as Mg2+ deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg2+ levels in comparison to health controls. 5. Experimental Mg2+ depletion leads to depression- and anxiety like behavior in animal models. 6. Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts to increase brain Mg2+ levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg2+ levels tend to be therapy refractory. Accordingly, administration of Mg2+ either alone or in combination with standard antidepressants acts synergistically on depression like behavior in animal models.

Conclusion

On the basis of the potential pathophysiological role of Mg2+-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg2+ levels. Furthermore, screening for compounds to increase neuronal Mg2+ concentration could be a promising instrument to identify new classes of antidepressants. Overall, any discussion of the glutamatergic system in affective disorders should consider the role of Mg2+.

Introduction

An interest in glutamatergic aspects in depression existed more than 20 years ago and important data were generated (Trullas and Skolnick, 1990; Paul et al., 1994). The renewed awareness of the limitations to treat depression with monoamine-based mechanism of action and the findings of a rapid antidepressant response to ketamine in patients with treatment resistance to these compounds has led to a paradigm shift for the development of new antidepressant compounds. First observations of the effects of ketamine in depression (Berman et al., 2000) were done more than 10 years ago. However, it was not until the mile-stone observations of Zarate et al. (2006), who demonstrated in a double blind placebo controlled study the effect of ketamine in patients, who did not respond to standard antidepressants, that this field got broader attention. During the last several years has the NMDA ergic system received marked attention in the context of developing new compounds for mood disorder (Li et al., 2011b). The mechanism of action of glutamatergic compounds is unraveling, but there are several unresolved issues.

Section snippets

Proposed mechanism of action of ketamine in depression

The recently proposed sequence of events involves blocking N-methyl-d-aspartate (NMDA) receptors on gamma-aminobutyric acid (GABA)-ergic interneurons. The dampening of their activity disinhibits glutamatergic neurons due to a lowered GABAergic inhibition. Within the given context of NMDA blockade the released glutamate primarily excites (-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) (AMPA) and kainite receptors (Fig. 1). It is important to keep in mind that this combination of

Comparison of the effects of Mg2+ and ketamine

The comparison of the effect of ketamine with the physiologically present NMDA antagonistic Mg2+ may provide further insights into the mechanisms in question. 1. Ketamine- and Mg2+ administration both lead to an increase in slow wave sleep in humans preferably at the beginning of the sleep period (Held et al., 2002; Duncan et al., 2012b). 2. Administration of an innovative Mg2+ compound with a high bioavailability leads to an increase in BDNF expression in the brain and finally to synaptic

NR2b antagonistic effect of Mg2+

Mg2+ is a naturally occurring NMDA-receptor antagonist and has effects in concentrations, which are physiologically occurring in the extrasynaptic space (see Murck, 2002). Of particular interest is the relative specificity of the Mg2+ block of the NMDA receptors based on their specific subunits. The NR1 receptor is ubiquitous, whereas different kinds of NR2 subunits exist. Of these the NR2c and NR2d are the least sensitive to the Mg2+ block, whereas NR2a and NR2b are more sensitive (Kuner and

Importance of regional differentiation

The regional differentiation of the biological effects of stress and antidepressant treatments is of critical importance (Tables 1 and 2): Opposite change of BDNF expression in the PFC vs. the amygdala occurs under stressful conditions (Yu and Chen, 2011). A similar regional specificity of the effects of ketamine and Mg2+ administration exists: Mg2+ administration leads to an increase in NR2b-receptor expression, as well as to CaMKII-phosphorylation, CREB-phosphorylation and BDNF expression,

Glutamatergic regulation of CNS Mg2+ content

It appears that the mechanism of action of ketamine and Mg2+ overlaps beyond the NMDA antagonistic effect of extracellular Mg2+. The question is, how may this happen? An interesting observation is that ketamine actually leads to an increase of intracellular Mg2+ in peripheral tissue (Kim et al., 2006), which involves an increase in ERK1/2 and p38 MAP kinase. Further ketamine and MK-801 reverses the decrease of brain Mg2+ after brain trauma (McIntosh et al., 1990; Shapira et al., 1993). The

Synoptic overview of rapid antidepressant interventions

As an overview of the discussed mechanism a comparison of the effects of the different manipulations is provided in Tables 1 and 2. Additional information on the effects of chronic stress, which can be regarded as a model of depression, is included (Kuipers et al., 2003; Laifenfeld et al., 2005; van Donkelaar et al., 2009; Knox et al., 2010; Lee and Goto, 2011; Quan et al., 2011; Yu and Chen, 2011; Chiba et al., 2012; Hemanth Kumar et al., 2012; Yuen et al., 2012; Zhang et al., 2012) as

Predictors of ketamine response

It is important to note that not all patients with depression can be expected to respond to ketamine. Studies have been done in patients with therapy refractory depression, who may represent a specific subtype of all depressed patients. In this population the number of patients needed to treat (NNT) is 3–5, which is an extremely good effect, however not complete (Aan Het Rot et al., 2012). Predictors of response for ketamine are being studied: Reduced SWS at the beginning of the sleep period,

Pathophysiological connections

If some forms of depression may be mediated via low intracerebral Mg2+ and ketamine potentially reverses these changes, the question is, what let to these low Mg2+ level? Is there a connection to established mechanism of depression? In fact, Mg2+ is excreted by an increased activity of the sympathetic nervous system and the hypothalamus–pituitary adrenocortical axis (Murck, 2002; Murck et al., 2012). It has been suggested that the pathophysiological changes targeted by ketamine originate from

Increase in intracellular Mg2+ as a mediator for antidepressant efficacy

I summarized the parallel effects between ketamine and Mg2+. I also provided evidence that Mg2+ is involved in pathways, which are connected to the known pathophysiology of depression. Further I described mechanisms, which lead to an increase in intracerebral intracellular Mg2+. The question is now, is there precedence for the action of standard antidepressants on Mg2+? There are several observations, which point into that direction: Of high interest is that imipramine, the first reuptake

Conclusion

What are the conclusions of the described relationships? These are at least threefold:

1. Reduced concentration of Mg2+ in several tissues or functional markers of reduced tissue Mg2+ content appear to indicate worse response to antidepressant therapy with standard, the monoamine system targeting compounds. Direct intracellular measures in peripheral cells, P-spectroscopy of the brain or functional markers, like the pattern of slow wave sleep may therefore be predictive for the response of

Conflict of interest

Harald Murck works currently for Covance Inc. Princeton, USA. He was formerly employed by Bristol-Myers Squibb, Novartis, Amarin and Lichtwer Pharma. There exists no conflict of interest. No funding for the preparation of this article was received.

Contributors

Harald Murck is the sole contributor to this article.

Role of the funding source

No funding was received for preparing this article.

Acknowledgment

I would like to thank Ronald Duman, Yale University and Carlos Zarate, NIMH, and Laura Zumpano, Pfizer, for their helpful comments.

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