Ketamine as Treatment for Depression: An Old Drug is Making a Comeback

Depression in America is not just a millennial problem.

What is ketamine? To start off, ketamine is a sister compound of phencyclidine, PCP. Ketamine is a N-methyl-d-aspartate (NMDA) blocker in the brain which interacts with the neurotransmitter glutamate. Ketamine has been used for decades by the medical community for conscious sedation and is mainly used as anesthesia for medical procedures since 1970. When administered, it relieves pain by interfering with pain transmission to the spinal cord.

Only recently has ketamine been tried for treating severe depression.

Depression is a Serious Problem in the U.S.

Depression often affects pain, appetite, motivation and is associated with disability and decreased quality of life. Major depressive disorder often goes unrecognized and undertreated. It is quite prevalent in the U.S., affecting 4.5%-9% of women and 3% men. When diagnosed and recognized, treatment includes nonpharmacologic therapy such as cognitive psychotherapy and pharmacological treatments such as antidepressants including selective serotonin reuptake inhibitors (SSRIs).

Antidepressants are helpful in ~60-70% of cases.

Responses to antidepressants can take weeks (~4-6weeks) and the chances of a later response decrease the longer patients continue to not improve. A large number of patients do not get adequate relief even after trying several different types.

Ketamine as Treatment in Resistant Depression

Ketamine found to be rapidly effective in treatment-resistant depression although effects usually do not persist. Considerable research has been done on ketamine and there is potential in ketamine’s use in short-term therapy. However, treatment remains experimental and is considered “off-label” use.

A key ethical dilemma is when to prescribe ketamine to patients since there are concerns about off-label use monitoring says Dominic Sisti, an assistant professor in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine, University of Pennsylvania, PA, USA.

I don’t think patients who have exhausted all options should have to wait, but I worry that off-label use is not being properly monitored…If patients are fully competent and informed, they should have the right to access ketamine—but we have to be sure they understand it is basically an experimental treatment. This is a vulnerable patient population.

Dominic Sisti

Rapid Improvement of Depression

Some studies have shown that after just one dose of ketamine, depression can decrease within three days. For example, Dr. Carlos Zarate Kr., M.D. has investigated ketamine and its effect on depression and suicidal thoughts and have found that his patients in the trial had marked improvement within a few days and even as little as a couple hours. However, it remains unclear whether the rapid antidepressant effect is sustained.


Ketamine Mechanism of Action on Depression

Ketamine’s mechanism of action is not completely understood for depression. And that’s what making ketamine so fascinating in the treatment of depression. A possible mechanism of action is the ability of ketamine to remodel neurons.

Current theories suggest that severe, treatment-resistant or chronic depression is not simply the result of disturbances of serotonin and norepinephrine systems but involves alterations in the resiliency and neuroplasticity of synapses and circuits. 

Carlos Zarate, M.D.

Ketamine Infusion Clinics

Although not FDA approved, treatment of depression with ketamine infusions is seen in clinics all across the United States. Most insurances won’t cover it, so you can expect treatments to be incredibly expensive. Patients can pay more than $1000 per session for ketamine treatment. In addition, infusion treatments are multiple times a week which can be impractical for those working a fulltime job.

Nasal Ketamine Spray and Ketamine Pills?

Newer methods of ketamine treatment are currently being developed. Johnson & Johnson (New Brunswick, NJ, USA) are developing a ketamine-like nasal spray which is much more practical. Crecicor (Baltimore, MD, USA) is developing a once-daily oral pill. We assume that oral ketamine and nasal ketamine spray will be much cheaper than infusions but this is an assumption since we know pharmaceutical companies are keen to mark up drug prices and do as they please.

During the infusion of ketamine given for treatment-resistant depression, patients might experience sensory disturbances, psychological symptoms (loss of awareness of surroundings, distortion of time, etc.), and increases in blood pressure and heart rate. These symptoms are time-limited and usually end shortly after the infusion of ketamine ends.

Carlos Zarate, M.D.

Special K

Long term therapy of ketamine presents some challenges due to its potential for substance abuse and side effects. On the streets, ketamine is known as “special k” or simply as “K” characterized as a party drug due to its high and dissociative effects. Ketamine dependence is an important concern as well as accidental overdoses.

Ketamine Side Effects

Ketamine side effects include bad hallucinations, disorientation, increased heart rate, elevated blood pressure. In addition, large doses of ketamine can include intense hallucinations with detachment from reality. As with psychotropic drugs, the quality of the hallucinations depends on the user’s state of mind – an unhappy state of mind can lead to unpleasant hallucinations.

Rupert McShane, based at Oxford Health NHS Foundation Trust, Oxford, UK, led the clinic in a UK National Institute for Health Research study (REDKITE) in which ketamine was given for a series of 28 cases of treatment-resistant depression.

The dissociative side-effects are clearly dose related. Some patients will get benefit from ketamine at doses which do not cause them, but there is likely to be a trade-off. Ketamine is safe enough, and there has been so much experience of it, that it is on the WHO essential drugs list. Tolerance may develop, especially if used very frequently, but this would only be problematic if ad libitum use was proposed. Routes such as intranasal, oral, intramuscular, and sublingual all have potential advantages and disadvantages in this regard. Yet whether alternative related compounds will have real safety advantages over ketamine would require formal study: it will be expensive to show that, for a dose of equivalent efficacy, their long-term safety is as good as ketamine.

Rupert McShane

A new class of antidepressants might be on the horizons and we will continue to look for promising insights as new research in the field continues.

We love to hear what you think, feel free to comment below.

Read about Ketamine and Alcohol Dependence

Interesting books to check out

Ketamine for Depression by Dr. Stephen J Hyde

It’s Not Supposed to Be This Way: Finding Unexpected Strength When Disappointments Leave You Shattered by Lysa TerKeurst

Cognitive Behavioural Therapy: 7 ways to Freedom from Anxiety, Depression, and Intrusive Thoughts (Happiness is a trainable, attainable skill!) by Lawrence Wallace

Feeling Good: The Mood Therapy by David D. Burns, M.D.


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  2. Levy B. Shedding Light on the Deep Darkness of Depression. National Institutes of Health. Published November 15, 2018. Accessed January 30, 2019.
  3. Kirby, Tony. Ketamine for depression: the highs and lows. Lancet Psychiatry. 2015; 2(9): 783-784
  4. Prommer, Eric et al. Ketamine and Depression: Is It Ready for Primetime? Journal of Pain and Symptom Management. 2018; 55(2): 645-645
  5. Zimmerman, Mark and D’Avanzato, Catherine. Depression, Major. Ferri’s Clinical Advisor. 2019; 419-421.e1

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