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Novel MDD Options
Exciting Times for Inhibiting Depression

Released: May 31, 2023

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Key Takeaways
  • Glutamate and GABA are major neurotransmitters that are being targeted in recent major depressive disorder treatment approaches.
  • These novel agents likely work in synergy with standard antidepressant therapy to exert their effects, but more research is needed to confirm this relationship.
  • This is an exciting time in neuropsychopharmacology that is providing healthcare professionals with rapid-acting options for their patients with difficult-to-treat depression.

At this point, we know that major depressive disorder (MDD) is not identical across the population—it is biologically distinct. Currently, the majority of treatments available for MDD focus on addressing monoaminergic mechanisms (ie, selective serotonin reuptake inhibitors [SSRIs], serotonin‒norepinephrine reuptake inhibitors [SNRIs], monoamine oxidase inhibitors [MAOIs], tricyclic antidepressants). However, approximately 30% of patients with MDD do not achieve an adequate response to monoaminergic therapies, leaving significant gaps in care. Enter: glutamate and GABA modulators. These are 2 relatively new approaches to addressing MDD that seem to be rapid acting and may help fill the gaps left in treatment response by monoaminergic agents.

Why Target Glutamate and GABA?
Glutamate and GABA are the major excitatory and inhibitory neurotransmitters in the brain, respectively. Given their abundance, it is reasonable to believe that they have a role in many disorders, including depression. Leading theories are that glutamate excitotoxicity and GABA deficiency may contribute to MDD pathophysiology. With the advent of NMDA antagonists (eg, ketamine, esketamine) to address glutamate signaling and neurosteroids (positive allosteric modulators of GABAA, eg, brexanolone, zuranolone) to address GABA signaling, we can see that targeting these neurotransmitters certainly has a place in MDD treatment.

Misconceptions
When suggesting these novel agents—or really any treatment option—to patients, it is important to emphasize that there are always other options and this is never the last resort. It is also important to address any misconceptions that they may have. For example, many patients have heard that esketamine acts quickly and is effective in patients who are treatment resistant. Although this is true, expectations should be tempered with reality: The drug has to be taken regularly for an extended period of time, does require clinic visits and a substantial amount of preparation and time, and, initially, may require increased administration to be effective. In addition, some patients still do not fully respond to esketamine. In some cases, esketamine therapy may dramatically improve suicidal ideation, but not other symptoms of depression—an important effect, but with room for improvement. Again, it is important to reinforce that this is not their last option and that a nonresponse or partial response to esketamine does not mean they will never find an effective medicine. Treatment is never one-size-fits-all.

Clinical Application and Future Directions
Currently, (es)ketamine and dextromethorphan/bupropion are the major NMDA antagonists being applied in MDD treatment. Ketamine/esketamine has FDA approval for use as an adjunct to antidepressant therapy in treatment-resistant depression or in MDD with active suicidal behavior/ideation, and dextromethorphan/bupropion has FDA approval as monotherapy in MDD. Another NMDA antagonist, esmethadone, also is being investigated for use in MDD.

It likely is not just the NMDA antagonism that has a role in the efficacy of these agents. Given their clinical application, it seems likely that there is a synergistic effect with monoaminergic agents. Nearly all patients who are receiving esketamine or ketamine treatment also are receiving monoaminergic antidepressant treatment—in fact, it is required by most third-party payers to have the esketamine treatment approved in the first place. In addition, the combination of dextromethorphan and bupropion intentionally exploits this synergism for its effects: It is believed that the NMDA antagonist action of dextromethorphan helps speed up the antidepressant effects of bupropion. In turn, as a cytochrome P450 2D6 inhibitor, bupropion inhibits the rapid first-pass metabolism that dextromethorphan typically undergoes, allowing adequate dextromethorphan serum levels to be reached for a prolonged period of time.

Regarding GABA modulators, brexanolone currently is approved for use in postpartum depression. Zuranolone is in late-stage clinical trials for MDD. Like NMDA antagonists, the neurosteroids have been studied in combination with standard antidepressant therapies, and a synergistic effect is thought to be at work here, as well.

This is an exciting time in neuropsychopharmacology, and it will be wonderful to see how targeting glutamate and GABA can positively change the treatment paradigm—hopefully allowing for more rapid and sustained improvements in MDD symptomatology. With the novelty of these agents, we are only just beginning to understand how to best apply them for MDD treatment. Future research likely will involve exploring the different combination possibilities: Will monotherapy emerge as a feasible approach? Will combining NMDA antagonists with neurosteroids yield an increased response?

Your Thoughts?
We seem to be on the cusp of a third wave of pharmacologic development as it applies to antidepressants. The first wave was the tricyclics and MAOIs, and the second was SSRIs and SNRIs. Now we are deviating from the monoaminergic pathway and exploring the NMDA antagonists and neurosteroids as a third wave of treatment options. Have you used glutamate or GABA modulators in practice yet? Answer the poll and join the discussion in the comments.

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