Ketamine: Not A Simple Treatment, But a Worthy One


One doctor at the APA Virtual meeting explains how ketamine can rebuild spine and synaptic proteins in the brain, but may be difficult to actually prescribe to patients.

growing, depression, mood disorders



In his presentation at the 2021 American Psychiatric Association Virtual Meeting, Richard C. Shelton, MD, the Charles B. Ireland Professor in the Department of Psychiatry and Behavioral Neurobiology at the University of Alabama at Birmingham, and the Director of the UAB Depression and Suicide Center, discussed the functions and concerns of ketamine.

“This is not a simple treatment or a treatment to take lightly,” Shelton said during the Q+A portion of his presentation. “On the other hand, we’ve seen remarkable results.”

Shelton began with a discussion of ketamine’s functions in the brain, and how it restores the regulatory processes for patients with mood disorders, using a study by Li et al as an example.1

“Stressful experiences cause a reduction or retraction of spines and synapses. The brain is less able to control or regulate the emotional state,” Shelton explained.

With ketamine administration, there is an almost immediate increase in formation of critical spine and synaptic proteins.

“When you add ketamine to the system, you produce a rapid return and restoration of those spines and synapses. We see an effect within 24 hours,” Shelton continued. “Ketamine has the ability to restore the regulatory control to the brain and helps to theoretically normalize mood.”

Shelton shared data from 8 studies regarding ketamine, and how it produced a rapid, robust effect for patients with severe, resistant mood disorders,2-9 and further studies on how ketamine functioned for patients with suicidal ideation.10-13

“The good news: ketamine really seemed to work in these highly treatment-resistant patients,” Shelton said. 

Shelton also addressed key concerns regarding ketamine, especially how it may be a challenge to prescribe. First, the US Food and Drug Administration requires a “somewhat cumbersome” risk evaluation and mitigation strategy program, in which the clinic, provider, and patient must all be registered in the program. There are prior authorization hurdles, as well as reimbursement issues. Nonetheless, Shelton finds ketamine more than worth it.

“When I treated my first patient with IV ketamine in 2012, it was just amazing to see the effect occur within 24 hours,” Shelton said.


1. Li N, Liu RJ, Dwyer JM, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69(8):754-61.

2. Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47(4):332-337.

3. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.

4. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173(8):816-826.

5. Daly EJ, Singh JB. Adjunctive intranasal esketamine in treatment-resistant depression-reply. JAMA Psychiatry. 2018;75(6):654-655.

6. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.

7. Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: A randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.

8. Daly EJ, Trivedi M, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: A randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.

9. Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3).

10. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: A systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158.

11. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2018;175(7):620-630.

12. Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3).

13. Ionescu DF, Fu DJ, Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: Results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31.

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