• Eighteen patients with depression that had not responded to at least one prior antidepressant trial received administrations of intranasal ketamine 50 mg or placebo in two sessions at least 7 days apart.
  • Depressive symptoms 24 hours after treatment administration were significantly improved with intranasal ketamine compared with placebo. A total of 8 of 18 ketamine patients met response criteria at 24 hours, compared with 1 of 18 placebo patients.
  • The percentage of responders with intranasal ketamine was lower than what has been observed in some prior studies of intravenous ketamine.

A new randomized, double-blind crossover study has found that a single 50-mg dose of intranasal ketamine was associated with rapid antidepressant response in patients with treatment-resistant depression, with a significant effect seen 40 minutes after administration.

The search for novel strategies for treatment-resistant depression has recently focused on the glutamate system. Several studies have found rapid antidepressant effects from intravenous ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, but there have been concerns about limitations of this route of administration because of factors such as its lack of availability in most clinical practices and patient resistance.

In order to examine whether an alternative route of ketamine administration might prove viable, a proof-of-concept trial examined the short-term effects of a 50-mg intranasal dose of ketamine in patients with depression who had not responded to at least one prior antidepressant trial.

Study details

Adults ages 21 to 65 with a primary diagnosis of chronic or recurrent depression were eligible to participate. They were required to have a baseline score of at least 30 on the Inventory of Depressive Symptoms-Clinician Rated. Exclusion criteria included but were not limited to a primary Axis I disorder other than depression, a high risk of suicide, or a psychotic or bipolar disorder.

In the crossover design, each participant received a dose of ketamine 50 mg or placebo at least 7 days apart. Ketamine was provided in five applications of 10 mg each over a 20-minute period, and patients were observed on the research unit for at least 4 hours after administration.

The primary outcome was change in depression severity 24 hours after administration, using the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary measures included the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), the Hamilton Anxiety Rating Scale (HAM-A), and the percentage of individuals in each group who met criteria for response, defined as a decrease of at least 50% in the MADRS score from baseline.


Eighteen patients completed both treatment periods, receiving either ketamine followed by placebo or the reverse. These individuals had failed an average of 4.1 ± 3.9 prior adequate antidepressant trials and had been experiencing depression symptoms for an average of 27 years.

Study authors found that depressive symptoms 24 hours after treatment administration were significantly improved with intranasal ketamine compared with placebo (p<.001). At this 24-hour stage, 8 of 18 ketamine patients met response criteria, compared with only 1 of 18 placebo patients. Response to ketamine also separated from response to placebo at 40 minutes, 240 minutes, and 48 hours, but not at 72 hours or 7 days.

The authors found that intranasal ketamine was associated with small increases on measures of psychosis and dissociation, as well as small increases in systolic blood pressure. The most commonly reported treatment-emergent adverse events among ketamine patients 4 hours after administration were feeling strange, having poor memory, and feeling weakness or fatigue.


The authors stated that this study offers the first randomized controlled evidence that intranasal ketamine is safe and effective for rapid reduction of depressive symptoms in patients with treatment-resistant depression. The percentage of treatment responders, however, was lower for intranasal ketamine than what was observed in previous studies of intravenous ketamine; this may have been a result of lower blood levels of ketamine with intranasal administration.

Because the study allowed patients to continue to use antidepressant medications during the study period, this made it impossible for the researchers to distinguish between effects of ketamine in isolation and possible benefits of ketamine with antidepressants. The study’s relatively small sample size also was cited as one of its limitations.

The study’s authors wrote, “Much more research is required to determine the optimal dose, duration, frequency, and route of administration of ketamine for depression.”

Study co-author Dennis S. Charney is named on a use patent on ketamine for the treatment of depression. Several other co-authors report research support or consulting arrangements with pharmaceutical companies.

Lapidus KAB, Levitch CF, Perez AM, et al. A randomized controlled trial of intranasal ketamine in major depressive disorder. Biol Psychiatry 2014; 76:970–976. E-mail: