Glutamate, the most prevalent excitatory neurotransmitter, plays a pivotal role in neural communication, learning, memory formation and more. Recent exploration has found imbalances in glutamate signaling in depression’s emergence, opening avenues for potential glutamate blocker application, such as ketamine and dextromethorphan, in addressing it. This article will examine glutamate’s role in depression and glutamate blockers’ therapeutic potential, referencing Nuedexta’s off-label usage and Auvelity’s recent FDA approval for depression.
The Glutamate Depression Link
Glutamate is paramount for proper brain function, but excessive or imbalanced glutamate activity can harm, leading to “excitotoxicity.” This excitotoxicity has been implicated in diverse neurological and psychiatric disorders, including depression. It is hypothesized that disrupted glutamate signaling may contribute to depressive symptom development by decreasing neural communication and suppressing neurogenesis and inter-neuronal connectivity in pivotal brain regions.
Glutamate Blockers: Ketamine and Dextromethorphan
Ketamine and dextromethorphan are two glutamate blockers exhibiting promise in treating depression. Both primarily act as N-methyl-D-aspartate (NMDA) receptor antagonists, blocking glutamate activity at these receptors (one of two major types for glutamate). Blocking them can help restore glutamate balance, promote neurogenesis, and improve inter-neuronal connectivity in brain regions tied to depression. Ketamine’s often rapid-onset antidepressant impact, specifically, has garnered significant attention in recent years [see ketamine deep dives].
Nuedexta and Auvelity: Glutamate Blockers Joined to Additional Medicines
Nuedexta is a combined prescription containing dextromethorphan with a tiny quantity of quinidine. While principally indicated by the FDA for a condition called “pseudobulbar affect”—unfortunately prevalent in dementia and multiple sclerosis—Sterling psychiatrists have used it off-label since its release for treating depression. Prior to its release, we have compounded personalized capsules of small quinidine dosages with over the counter dextromethorphan—ordinary cough medicine. Quinidine serves to boost the availability of dextromethorphan in the brain, enabling it to more successfully block excess glutamate signaling and alleviate depressive symptoms. It makes dextromethorphan more available by blocking its conversion to dextrorphan. Dextrorphan is a mild opioid that provides dextromethorphan its cough suppressant effect. Regretfully it additionally enables it to be misused. With quinidine, these effects disappear. Dextromethorphan by itself has no antidepressant effect.
Auvelity, lately approved by the FDA for depression, combines dextromethorphan with the existing generic antidepressant bupropion (Wellbutrin). In addition to its own effectiveness as an antidepressant, bupropion–like quinidine–stops the breakdown of dextromethorphan, permitting it to exert its glutamate-blocking effects in the brain. Before Auvelity came to market, Sterling psychiatrists recommended the mixture of bupropion and dextromethorphan as separate medications taken concurrently.
Conclusion
Glutamate performs a pivotal function in depression formation, with glutamate blockers such as ketamine and dextromethorphan offering a hopeful path for treatment. The off-label utilization of Nuedexta and the current FDA endorsement of Auvelity—both using the same mechanism: blockade of the conversion of dextromethorphan to dextrorphan—has provided psychopharmacology an entirely new set of tools to combat depression. Further research is required to completely comprehend the antidepressant effect of glutamate blockers.