Identifying Fast-Acting Treatments for Resistant Depression

Current antidepressant medications often take a few weeks to work, creating an urgent need for improved and faster-acting antidepressant treatments for patients with severe, life-threatening forms of depression.

Recognizing this need, the National Institute of Mental Health (NIMH) established the Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID) research project.

Its objective is to identify and test promising pharmacological and nonpharmacological treatments that could lift depression within a few days.1

Potential rapid-acting pharmacologic therapies

A handful of small studies suggest ketamine may produce a rapid effect on depression in many patients via the glutamate receptor N-methyl-d-aspartate (NMDA).

James Murrough, MD, and colleagues at Mount Sinai School of Medicine, enrolled 73 patients with treatment-resistant major depression and randomly assigned participants in a 2:1 ratio to receive either ketamine or midazolam.

Patients in the ketamine group had significantly greater improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (7.95 points lower; 95% CI: 3.20-12.71) and were more likely to achieve a treatment response within 24 hours (odds ratio, 2.18; 95% CI: 1.21-4.14) compared with the midazolam group.2

“It is important to note that it is still a proof of concept study. We’re still just asking the first question which is, ‘Is the rapid antidepressant effect we observed after a single injection of ketamine real,’” Murrough said.

“We think we’ve answered that question with that study, but it doesn’t speak to the potential of ketamine as a treatment. Much more research will be needed for that.”

In a second study, Rebecca Price, PhD, of the University of Pittsburgh and colleagues looked specifically at suicidal ideation among 57 patients randomly assigned to ketamine (n=36) or midazolam (n=21) at baseline and again 24 hours after infusion.

Compared with the midazolam group, patients in the ketamine group experienced a significant reduction in suicidal cognition on both the explicit suicidal cognition score (Beck Scale; 53% vs. 24%, P=0.03) and the implicit association test (IAT).2

Drawbacks to ketamine are that it must be administered through infusion, and it is short acting, with an average duration of 21 days in the Mount Sinai study.

In a third 20-patient crossover study, Dan Iosifescu, MD, also of Mount Sinai, and colleagues tested the efficacy of administering ketamine via an intranasal route.

Intranasal administration showed similar benefits as IV ketamine, but variations in absorption through nasal mucosa prompted the researchers to test with a conservative dose.[3]

“We used about half the dose based on blood levels,” Iosifescu said. “It still provided a fairly solid benefit, but shorter than a typical IV dose. These [results] are all approximate, but the bottom line is that there is good reason to believe this [intranasal route] could work.”

To address the challenge of treatment duration, Murrough said his group is currently conducting a trial to see if adding lithium to ketamine might prolong the effect.

Mechanism of action

How NMDA antagonists modulate the neurobiology of depression remains unclear in humans, but there is evidence that ketamine and other glutamatergic agents trigger downstream events.

“What is interesting is that ketamine only acts relatively briefly on NMDA receptors,” Iosifescu said. “You are only giving it for 40 minutes, but that basically triggers a cascade of processes. There is a molecule called mTOR [mammalian target of rapamycin] that seems to be critical in triggering neuroplastic effects in animal studies of standard antidepressants and that is thought be the biological basis of the healing effect.”

Alternative therapies

Other pharmacologic research is focusing on allosteric modulators of AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) that function in tandem with NMDA.

Research into 5HT4 receptor drugs that act on serotonin receptors, and thyrotropin-releasing hormone (TRH) is also ongoing.

In terms of nonpharmacologic therapies that act on the glutamate receptors, Yang et al of the University of Calgary conducted a small case-series involving six patients to assess transcranial magnetic stimulation (TMS).

They found that repetitive TMS produced a modest (11%) elevation of glutamate levels in four patients, and a 68% reduction in Hamilton Depression Rating Scale score.4 The procedures were generally well tolerated with no adverse events.

Device approaches to antidepression therapy are an exciting area of interest, according to Iosifescu. He is particularly interested in magnetic seizure therapy, which he says is similar to electroconvulsive therapy (ECT) in that it triggers a seizure, but using a magnetic field instead of electricity.

“The magnetic field allows you to be a bit more precise in where you trigger the seizure, so that you might have fewer side effects such as memory loss,” Iosifescu said.


Intravenous ketamine appears to be effective for fast-acting relief of treatment-resistant major depression, and intranasal administration could make its use available in a wider variety of settings. Additional challenges remain in extending duration and ensuring safety.

Meanwhile pharmacologic research into other NMDA receptor modulators suitable for clinical use is continuing. In parallel, research is proceeding into other nonpharmacologic approaches, such as device-based approaches.


  1. National Institute of Mental Health (NIMH). Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID).
  2. Price RB et al. “Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression.” Depress Anxiety. 2014;31:335–343.
  3. Lapudis KA et al. “A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder.” Biol Psychiatry. 2014; doi: 10.1016/j.biopsych.2014.03.026.
  4. Yang XR et al. “Glutamate Alterations Associated With Transcranial Magnetic Stimulation in Youth Depression.” J ECT. 2014; doi:10.1097/YCT.0000000000000094.Yang XR et