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Tawny L. Smith, PharmD, BCPP
Assistant Professor, Department of Psychiatry
University of Texas Southwestern Medical Center at Austin
Seton Healthcare Family


The high rate of non-response and the delayed onset of action with antidepressants have led investigators to pursue alternative agents to address treatment resistant depression (TRD). N-methyl-D-aspartate (NMDA) antagonists, specifically ketamine, have been shown to produce rapid responses in TRD. During his session, Dr. Sanjay Mathew, Director of the Mood Disorders Research Program in the Mental Healthcare Line at the Michael E. Debakey Veteran’s Affairs Medical Center in Houston, TX, discussed the potential role that ketamine and other NMDA antagonist may have in treating TRD.

Treatment Resistant Depression

TRD is a challenge faced by many clinicians and patients. While major depressive disorder is thought to be one of the more treatable mental illnesses, many will not respond adequately to antidepressant treatment. TRD is defined as a failure to respond to 2 or greater adequate antidepressant trials and is seen in roughly 20-30% of patients with depression.1 Unfortunately, subsequent trial failure rates increase with each failed acute therapy, regardless of the treatment modality.2

Patients with comorbid anxiety or medical disorders are at elevated risk of TRD.1 Dr. Mathew also highlighted other risk factors, such as early onset depression.1 Dr. Mathew went on to discuss neurobiologic factors that have been associated with TRD, highlighting genetic polymorphisms in receptors and metabolic enzymes that have been implicated. Dr. Mathew advised that the genetic polymorphisms likely account for only a small portion of the differences in antidepressant response. Dr. Mathew also discussed evidence suggesting a loss of synapses in the prefrontal cortex leading to “barren” connectivity in TRD. This implicates involvement of the glutamate system since glutamate is responsible for 80% of neuronal activity.

Ketamine: The Evidence

In 2006, Zarate and colleagues3 published a study demonstrating the efficacy of single infusion ketamine for TRD. Because of the quick onset of action (separating from placebo at 110 minutes) and the high response rate (71% response rate at day 1), this study generated a great deal of interest in the use of ketamine for TRD. Several other single site studies support the rapid antidepressant effects of ketamine, but several limitations were identified by Dr. Mathew, such as cross-over design, saline as a placebo and small sample sizes. Additionally, while numerous studies have demonstrated a rapid response in the use of ketamine for TRD, the antidepressant effects do not persist over time for most patients.

To address some of these limitations, Murrough and colleagues4 conducted a two-site, parallel arm, randomized controlled trial of a single infusion ketamine compared to the active placebo (midazolam) in 73 patients with TRD. The ketamine group demonstrated statistically greater improvement in depressive symptoms at 24-hours post-treatment, compared to the midazolam group (P<0.0014). This effect was sustained even after adjusting for baseline score and site, with a 2-fold likelihood of response at 24 hours compared to midazolam (odds ratio 2.18, 95% CI 1.21 to 4.14; P<0.006; response rate 64% vs. 28%). Ketamine continued to demonstrate a significant response through 72 hours, but not after 7 days. In this study, the researchers were able to demonstrate the rapid antidepressant effects in a more optimal study design, providing additional support for ketamine as an approach for the rapid treatment of TRD. However, similar to the trials previously mentioned , response was not sustained.  

Ketamine appears to be a well-tolerated intervention. The only psychiatric side effect noted in the Murrough study was an increase in suspiciousness.3 Auditory hallucinations were not reported.  Dissociative side effects were noted, but short in duration. While not statistically significant, there was a notable trend in an association between response to ketamine and the amount of dissociation seen at 40 minutes. Dr. Mathew mentioned that this may indicate that ketamine dosing might require “tweaking” for each individual patient in order to provide adequate NMDA modulation to elicit a response.

Future Directions

Depressive symptom response is maintained for up to 7 days after a single infusion of ketamine, despite a very short elimination half-life of 2 hours. This would suggest that the neurobiological mechanisms underlying the antidepressant actions of ketamine are more multifaceted than simply NMDA receptor blockade. It is likely that ketamine initiates a cascade of events that results in a rapid response that is sustained even after the drug has been metabolized.  In rodent models, ketamine increased brain derived neurotropic factor (BDNF), leading to enhancement of cellular plasticity and synaptogenesis.5,6 It is likely that future research will look at signaling pathways to help explain the mechanism by which ketamine produces a rapid response. Additionally, future studies may focus more on specific symptoms, such as suicidality, as a primary outcome measure. Several other NMDA or metabotropic glutamate receptor modulators are currently being tested in phase II clinical trials.7

Cardinal References

  1. Keitner GI, Mansfield AK. Management of treatment-resistant depression. Psychiatr Clin North Am 2012; 35:249-65.
  2. Rush AJ, Trivedi MH, Wisniewski SR et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905-17.
  3. Zarate CA Jr, 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;63:856-64.
  4. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013;170:1134-42.
  5. Duman RS, Voleti B. Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 2012;35:47-56.
  6. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:35-41.
  7. Flight MH. Trial watch: phase II boost for glutamate-targeted antidepressants.Nat Rev Drug Discov 2013;12:897.
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