By understanding the molecular and cellular mechanisms underlying ketamine’s robust antidepressant effects, scientists have been able to target and manipulate specific areas of the glutamatergic system to develop novel psychopharmacological treatments for depression.
The goal, in essence, is to develop a new generation of antidepressants that are similarly as rapidly efficacious as ketamine with sustained remission and no perceptual side effects.
Exploring Other Glutamatergic Agents for Depression
Memantine, marketed as Namenda, is presently used in the treatment of Alzheimer’s, but has also been of particular interest to the psychiatric community because it acts as a non-competitive NMDA receptor antagonist.
Unlike ketamine, Namenda lacks dissociative and psychotomimetic properties, making it a well-tolerated candidate for the treatment of depression.
However, when tested orally, Namenda’s antidepressant effects were not fast-acting. Its intracellular signaling appears to differ from ketamine in that it does not inhibit eEF2K or trigger BDNF synthesis when blocking NMDA receptor activity at rest.
Therefore, Namenda does not lead to long-term potentiation of synapses, which is critical for the elicitation of a rapid antidepressant response (Gideons, Kavalali, & Monteggia, 2014).
Despite its delayed antidepressant action, Namenda remains a powerful drug and is still being studied in augmentation with other psychiatric medications for the treatment of refractory depression and bipolar disorder.
The non-competitive NMDA receptor antagonist, Riluzole displays neuroprotective properties and is currently FDA approved for the pharmacological treatment of amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease).
It acts by inhibiting glutamate release (via voltage-dependent sodium channels) while activating both AMPA receptors and kainate receptors, resulting in the synthesis of BDNF proteins.
In 2004, Zarate and colleagues conducted an open-label study, testing the efficacy and tolerability of Riluzole when administered orally to patients with treatment-resistant depression. Participants experienced a delayed onset of antidepressant effects. Side effects were similar to those being treated for ALS, including headaches and gastrointestinal distress. No perceptual side effects were reported indicating a low risk profile for abuse (Zarate et al., 2004).
Larger controlled studies involving Riluzole have since focused on its use as an add-on treatment to other antidepressants, including maintenance to intravenous ketamine. Because of its anxiolytic and anti-obsessional properties, Riluzole is being tested in patients with obsessive compulsive disorder (OCD).