NMDA receptor antagonists antidepressants

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

In experimental studies, chronic antidepressant treatments have been shown to reduce the behavioural effects of the NMDA-glutamate receptor antagonist dizolcipine. This suggests that antidepressants may act as functional NMDA receptor antagonists and thereby reduce excitatory glutamate transmission which is mediated by NMDA receptors. 

In humans, the antidepressant activity of NMDA receptor antagonists has not been evaluated extensively (Skohiick 1999). In animal models of depression, NMDA receptor antagonists have been reported to exert positive effects in most studies (Trullas 1997). This concerns mainly the forced swim test (Maj 1992 Moryl et al. 1993 PrzegaUnski et al. 1997) and stress-induced anhe-donia (Papp and Moryl 1994). Amantadine but not memantine was effective against reserpine-induced hypothermia (Moryl et al. 1993). In the forced swim test, both amino-adamantanes produced specific antidepressive-like activity (Moryl et al. 1993). 

Papp M, Moryl E (1994) Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Em J Pharmacol 263 1-7... 

The concept of NMDA antagonists as antidepressants has generated considerable interest in the NMDA receptor as a target for new antidepressant therapies (85,86,87). Recent data indicate that c/s-1-phenyl-2-[1-aminopropyl]-N,N-diethylcarboxamide, a NMDA receptor antagonist and homologue of milnacipran, produces sustained relief from depressive symptoms. Several studies have shown that chronic antidepressant treatment can modulate NMDA receptor expression and function. Preclinical studies with this and other NMDA receptor antagonists have demonstrated their potential antidepressant properties. 

The combination of traditional antidepressant drugs (e.g., imipramine) and uncompetitive NMDA receptor antagonists (e.g., memantine) may produce enhanced antidepressive effects as a result of synergism. This observation may be of particular importance for the treatment of antidepressant-resistant patients. Most interesting was the observation that fluoxetine, which was inactive in the forced swimming test in rats when given alone, showed a positive effect when combined with memantine (2.5 and 5 mg/kg). 

Rogoz, Z., Skuza, G., Maj, J., and Danysz, W. 2002. Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42 1024-1030. 

Trullas R, Skolnick P Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185 1-10, 1990... 

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