Ketamine, magnesium and major depression--from pharmacology to pathophysiology and back.

UNLABELLED: 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 Mg(2+) deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg(2+) levels in comparison to health controls. 5. Experimental Mg(2+) 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 Mg(2+) levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg(2+) levels tend to be therapy refractory. Accordingly, administration of Mg(2+) 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 Mg(2+)-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg(2+) levels. Furthermore, screening for compounds to increase neuronal Mg(2+) 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 Mg(2+).