How Does Ketamine and Esketamine (Spravato) Relieve Depression? - COPE

How Does Ketamine and Esketamine (Spravato) Relieve Depression?

How does ketamine act in the treatment of depression? Researchers are still exploring this relatively new treatment.  Below you will find an outline of our current understanding of how ketamine relieves depression.

The take home message is that we believe that ketamine may exert its antidepressant effect through correction of brain circuitry that is dysfunctional in patients with depression.

What We Thought Caused Depression

In former decades, depression was viewed as an insufficiency in the brain of neurotransmitters such as serotonin and norepinephrine. Antidepressants were believed to act by increasing the levels of these neurotransmitters in the brain.

We now understand that such explanations for depression and antidepressant action are simplistic. Merely filling a car with gas will not make it run. Similarly, merely increasing the levels of certain neurotransmitters will not make a depressed brain healthy again.

Current Understanding of What Causes Depression

Connections in the brain are not random. Rather, the connections are arranged in circuits with different circuits playing different roles. Dysfunctional brain circuitry has been identified in patients with depression.

Patients with Depression Display Different Brain Structure

Studies in animal models of stress and depression and in stressed and depressed humans have demonstrated three important structural changes in the brain:

1. A decrease in the formation of new nerve cells in a part of the brain known as the hippocampus.

2. A decrease in the branching and connectivity of nerve cells in the hippocampus.

3. A decrease in the number of supporting cells, known as glial cells.

The hippocampus is the seat of learning and memory, and therefore assists in adaptation to the environment. Depression may hence be viewed as a failure of adaptation resulting from hippocampal dysfunction. Structural changes occur in other parts of the brain as well, such as the prefrontal cortex, which is involved in higher cognitive functions.

Antidepressant treatments, including ketamine, have been shown to reverse many of the structural changes described above through a process is known as neuroplasticity.

Understanding Brain Chemistry

Neurons, neurotransmitters, synapses, and receptors

Nerve cells in the brain, also known as neurons, communicate with each other through small chemicals known as neurotransmitters.

Synapses are places where nerve cells meet. Neurotransmitters are released by nerve cells into synapses. Released neurotransmitters act on adjoining nerve cells by binding to structures known as receptors.


There are hundreds of neurotransmitters in the brain, one of the most important being a chemical called glutamate. Glutamate is an excitatory neurotransmitter, which means that it increases activity in the brain. In fact, glutamate is the most important and widely distributed excitatory neurotransmitter in the brain. Glutamate binds to many receptors, including receptors known as the NMDA and AMPA receptors.

How Does Ketamine and Esketamine (Spravato) Affect Glutamate?

Ketamine and Esketamine (Spravato) blocks the action of glutamate on NMDA receptors. As a result, the action of released glutamate on AMPA receptors may be disproportionately increased.

Ketamine and Esketamine (Spravato) may also block NMDA receptor-mediated activation of certain GABA interneurons. GABA interneurons are nerve cells that are inhibitory in function; they dampen the release of glutamate. Thus, ketamine-esketamine-mediated inhibition of these GABA interneurons could result in enhanced release of glutamate and hence greater action of glutamate on AMPA receptors.

Activation of receptors by glutamate is important because it results in synaptic changes and in neuroplasticity, as discussed in an earlier section.

Positive Effects of Ketamine and Esketamine (Spravato) on Connections in the Brain

Glutamate and its action on nerve cells bearing glutamate receptors is the starting point of the neuroplasticity cascade. Ketamine and Esketamine (Spravato) may strengthen connections between nerve cells and form new connections, resulting in downstream changes that correct the neurocircuitry that is faulty in depression.

Take Home Message

Ketamine and Esketamine (Spravato) may exert its antidepressant effect through correction of brain circuitry that is dysfunctional in depression.

Learn More

If you or someone you love is suffering from depression, we encourage you to reach out to COPE to learn more about our innovative, effective, evidence-based treatments. Please call our office at COPE to schedule an appointment.