Ketamine: A Promising Agent for Managing Treatment-Resistant Depression

Unipolar major depressive disorder (MDD) is one of the leading causes of disability, affecting 16 million individuals in the United States,¹ and more than 300 million individuals worldwide experience depression.² Roughly one-third of patients with MDD do not respond to currently approved antidepressants, and even in those who do, these agents typically take several weeks or even months to achieve a significant effect.³

“There is a major unmet need for more effective and rapidly acting antidepressants,” commented Dan V. Iosifescu, MD, director of clinical research, at the Nathan Kline Institute and associate professor of psychiatry at New York University School of Medicine.

Ketamine has garnered research attention as a promising agent for treatment-resistant depression (TRD), using a different mechanism of action from currently available treatments. “While the ketamine story is still a work in progress, it has the potential to offer dramatic benefits to people with TRD,” Dr Iosifescu told Psychiatry Advisor.

Mechanism of Action

Ketamine is an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor agonist that has classically been used as an anesthetic. It is also prescribed off-label to treat chronic pain.³

Ketamine activates synaptic plasticity by increased brain-derived neurotrophic factor

(BDNF) translation and secretion and also is involved with glycogen synthase kinase-3 inhibition.³

“When ketamine blocks the NMDA receptor, it triggers a signal change in the AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] receptors, increasing the AMPA flow,” Dr Iosifescu explained. “This multistep mechanism is a sort of ‘one-two punch’ on two receptors that trigger a cascade of neuroplastic changes in the brain cells, and those changes eventually lead to formation of new neural membranes and new synapses.”

BDNF also plays a role in responses to classical antidepressants and to ketamine, mediating synaptic plasticity. But, unlike with standard antidepressants, plasticity occurs rapidly in as little as a few hours after ketamine administration.³

“This correlates with the clinical observation of a very rapid antidepressant effect that we are not seeing with traditional antidepressants,” Dr Iosifescu said.

Who Will Benefit From Ketamine?

Most clinical trials have used a single low dose (0.5 mg/kg) of intravenous (IV) ketamine, which yielded a 50% to 70% response rate in patients with TRD,⁴ with symptom relief as early as 2 hours following administration and lasting up to 2 weeks.⁵ The wide range of the duration of efficacy appears to be related to variability in study populations (eg, age, gender, duration of depression, and comorbidities).³ It appears that the benefits of ketamine are of shorter duration in bipolar depression than in unipolar depression.⁶

Several meta-analyses evaluating studies with heterogeneous samples found that comorbid anxiety disorder, lifetime history of antidepressant treatment, as well as duration of depression and current episode did not affect mean differences between ketamine and placebo; this is “clinically very important, as all these clinical variables have been associated with poor response to traditional antidepressants.”³ One study⁷ found IV ketamine to be efficacious in treating posttraumatic stress disorder, “which can have particularly important implications for civilians, veterans, and military personnel,” Dr Iosifescu noted. 

Some studies have pointed to a rapid antisuicidal benefit for ketamine, making it a potentially life-saving drug in chronic and acute settings.⁸

Two Lines of Research

The rapid action of ketamine has led to 2 parallel lines of research, Dr Iosifescu said. “Because it works so quickly, it is an excellent model for what should happen with a good antidepressant when there is adequate response, so studying the ketamine response can inform the development of new agents.”

A second line of research investigates ketamine on its own terms as a clinical treatment. However, there are drawbacks, he noted.

“It is true that ketamine can have a remarkable response, but for the majority of patients, the effect does not last beyond a week to 10 days, so the question is what to do next,” he said.

One potential solution is to continue administering ketamine on a regular basis. However, there are several concerns with that approach, Dr Iosifescu warned. “Giving ketamine, especially via IV administration, is relatively cumbersome,” he pointed out. More serious is that, “although we have excellent safety data for single doses and a few administrations — up to 12 or 24 — there are insufficient data regarding ongoing administration over a long period of time.”

Additionally, ketamine has been associated with white matter changes in people who have used it as a drug of abuse. Rats exposed to high doses of ketamine for several months were found to have developed significant brain white matter lesions, likely related to glutamate toxicity.

“So there is reason to believe that there is a point at which ketamine can become too much of a good thing, but we just don’t know what that threshold is,” Dr Iosifescu suggested.

Window of Opportunity

“The rapid effect of ketamine on depression and suicidality brings a promise of taking a very sick and brittle patient and enacting a window of significant improvement in which other interventions can be implemented,” Dr Iosifescu said. However, those interventions remain unclear.

Psychotherapy is one possibility, he noted, citing a trial of cognitive behavioral therapy administered concurrently with ketamine treatment.⁹ “When people are extremely depressed, they usually can’t meaningfully engage in psychotherapy, which can be too much of a psychological burden for them, so an agent that can help the depression lift rapidly can facilitate meaningful engagement in a long-term healing process of therapy,” he observed. 

Another approach might be to use traditional antidepressants or novel agents after ketamine treatment to prolong the beneficial effects of ketamine, he suggested.

Using Ketamine in Clinical Practice

The most frequently studied mode of ketamine administration is via IV. Oral, sublingual, transmucosal, intranasal, subcutaneous, and intramuscular delivery methods are also available.¹⁰ Intranasal, subcutaneous, and oral dosing methods are more convenient, although oral administration results in lower bioavailability. However, these administration methods “will require better study before they can be recommended over IV dosing.”¹⁰ Intranasal administration is reported to have similar effects to IV.³

Although IV infusions of ketamine typically last for 40 minutes, benefits have been described even with shorter or longer periods of time.¹⁰ Although it is most commonly dosed at 0.5 mg/kg, some patients may benefit from even lower doses.¹⁰

The effect of a single dose of ketamine appears to last up to 7 days for individuals with unipolar TRD and for 3 to 4 days in individuals with bipolar depression.³ Data are limited for use of more than 6 to 12 repeated sessions.³ Patients who have not responded to the first 1 or 2 infusions are unlikely to benefit from further attempts.³

It is essential for patients receiving ketamine to be carefully monitored during the infusion and for several hours afterward. Short-lasting neuropsychiatric effects can include dizziness, blurred vision, headache, nausea or vomiting, dry mouth, restlessness, and impairment in coordination and concentration. Heart rate and blood pressure can be increased, so additional monitoring of patients with prior history of cardiovascular disease is necessary.³

Caution should be exercised in patients with a history of psychosis, Dr Iosifescu advised. “Some nonpsychotic patients have dissociative experiences that are similar to psychotic perceptions.” These may, in theory, create a potential for exacerbation of psychotic symptoms in patients with a history of psychosis, but there are insufficient data on this issue.

And because ketamine is a drug of abuse, concern has been raised that patients with a history of substance abuse might seek ketamine because they desire to get high. “In my opinion, that is not a big concern because a person who really wants to get ketamine can do so more easily than by enrolling in a study or paying a psychiatrist for an outpatient procedure,” Dr Iosifescu said.

However, he warned that administration of ketamine to a patient actively abusing other substances is not advisable “because we don’t know what the potential interactions might be and whether their substance use will be helped or worsened by the treatment.”

Conclusion

Psychiatrists should be “aware of emerging alternative treatments, such as ketamine, for TRD,” Dr Iosifescu said.

Although it is not approved by the US Food and Drug Administration for the treatment of depression, the decision to use ketamine off-label is “reasonable” and based on robust research. However, clinicians and patients should remain aware that the optimal dosing and long-term effects of ketamine are still a “work in progress.”

Clinicians and patients should also be aware of potential adverse effects associated with ketamine use and the importance of conducting the ketamine administration in a setting where there is at least one individual available who is trained in advanced cardiovascular life support (ACLS) to address any potential cardiovascular complications.

“An important question will be how to use the ‘window of wellness’ to initiate other pharmacologic or nonpharmacologic interventions,” Dr Iosifescu pointed out. “The ketamine story is by no means finalized and ongoing research is focusing on addressing these questions.”

References

1. National Institute of Mental Health (NIMH). Major depression. Updated November 2017. https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Accessed January 25, 2018.
2. World Health Organization (WHO). Depression fact sheet. Updated February 2017. http://www.who.int/mediacentre/factsheets/fs369/en/. Accessed January 25, 2018.
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