New Hope for Treatment-Resistant Depression: Glutamatergic Antidepressants (Part One)

Medications that target the serotonergic system are currently the first line of psychopharmacological treatment for major depressive disorder. Although many patients have derived great benefit from selective serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), there remains a large percentage of people who do not experience any relief from these drugs.

The psychiatric community has labeled these patients with “treatment-resistant depression.”

In other words, their frequency and longevity of depressive episodes cannot singularly be managed by achieving serotonergic homeostasis, even in cases when antidepressants are augmented with mood stabilizers.

The older classes of antidepressants – tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) – have also proven to be ineffective in patients with treatment-resistant depression.

This monoamine hypothesis has dominated our pathophysiological understanding and treatment of depression for the past 50 years. It postulates that balancing levels of serotonin, dopamine and norepinephrine is crucial in the psychopharmacological treatment of depression. However, the low response rate of these antidepressants suggests otherwise.

The latest clinical research supports the theory that primary excitatory amino acid neurotransmitters, known as glutamate, play a critical role in the pathogenesis of depression. Dysregulation of the glutamate system in the central nervous system has previously been linked to impaired cognitive function and neurodegeneration.

Drugs that specifically target N-methyl-D-aspartate (NMDA) receptors are currently being explored as novel antidepressant drugs.

Ketamine as a Rapid-Acting Antidepressant

Ketamine is a NMDA receptor antagonist, meaning that it works to inhibit the action of NMDA receptors.

When administered intravenously at sub-anesthetic doses, ketamine has shown to be efficacious in the treatment of depression within a few hours, whereas SSRIs and SNRIs typically require four to six weeks to take effect.

Ketamine also appears to display anti-suicide properties. And unlike the antidepressants that are used today, ketamine does not induce manic symptoms in bipolar patients.

We initially became aware of ketamine’s antidepressant potential in the 1990s when the first randomized, placebo-controlled, double-blinded study was conducted.

Although the sample size was very miniscule with only nine participants, the fast-acting nature of ketamine when compared to the saline solution created both enthusiasts and skeptics among the scientific community (Berman et al., 2000).

Similar studies were replicated and modified, both domestically and internationally, with much larger sample sizes that consistently produced statistically significant results in favor of ketamine therapy for treatment-resistant depression.

The stigma associated with ketamine halted much of the early research, as it is used recreationlally in high dosages to achieve disociative and hallucinogenic effects.

Breakthrough Therapy

In 2012, the FDA signed the Food and Drug Administration Safety and Innovation Act (FDASIA), which fast-tracked potential breakthrough drugs under Section 902.

A breakthrough therapy is defined as a drug that is “a) intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and b) preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

Ketamine was approved as one of these revolutionary breakthrough drugs, which is remarkable considering the aggressive War on Drugs in America. It is currently prescribed off-label for unipolar and bipolar depression. Today, there are roughly 20 ketamine clinics in operation in the United States, none of which accept health insurance.

Mechanism of Action

Ketamine acts as an antidepressant by inhibiting NMDA receptors while simultaneously activating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptors of the ionotropic glutamatergic system.

Its mechanism of action appears to produce plasma brain-derived neurotrophic factor (BDNF) proteins, which depressed individuals are severely deficient in. BDNF and its receptor, tyrosine kinase B (TrkB) work to mediate long-term potentiation of synapses.

In other words, specifically targeting and altering NMDA and AMPA receptors can be used to increase the density of small protrusions from a neuron’s dendrite, which helps strengthen and repair excitatory synaptic connections.

New Hope for Treatment-Resistant Depression: Glutamatergic Antidepressants (Part One)

Jenna Line

Jenna Line is an eating disorder activist and prospective MSW student with a undergraduate background in Social Psychology from the University of Maryland (College Park). You can find her on LinkedIn


APA Reference
Line, J. (2019). New Hope for Treatment-Resistant Depression: Glutamatergic Antidepressants (Part One). Psych Central. Retrieved on July 9, 2020, from


Scientifically Reviewed
Last updated: 25 Sep 2019
Last reviewed: By John M. Grohol, Psy.D. on 25 Sep 2019
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