The Deal with Ketamine

The Bad

• Ketamine mind-altering effects have made it a popular party drug and the hallucinatory experience is commonly known as being K-holed.
• It was not until the late 1980s and the arrival of rave culture that it really took off as a recreational drug. It has also been used as a date rape drug due to it being odorless and colorless.
• Ketamine symptoms include: dream-like feeling, blurred vision, double vision, jerky muscle movements, dizziness, drowsiness, nausea, vomiting, loss of appetite, or sleep problems (insomnia) -rxlist.com

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The Good

• Ketamine is on the World Health Organization’s List of Essential Medicines as the most effective and safe medicines needed in a health system.
• It was first discovered in 1962 and was used in casualty clearing stations in the Vietnam war as an anesthetic. Currently, ketamine mainly works as an anesthetic as it puts the patient in a trance-like state so they can’t feel pain, while also acting as a sedative.
• So why is it a big deal now?? Recent clinical trials showed patients at high risk of suicide reported huge improvements in depressive symptoms within hours of taking ketamine called Esketamine (its trade name). Traditional antidepressants target the brain’s serotonin system. But tests have shown that Esketamine works differently, by blocking NMDA receptors. Rupert McShane, a consultant psychiatrist who has spearheaded UK trials, said Ketamine and similar drugs ‘offered the most exciting development in psychopharmacology for 50 years’. Preliminary evidence suggests ketamine could also be efficient at fighting disorders including PTSD, general anxiety disorder, social phobia, and OCD.

Less well known is its growing off-label use in the USA for depression, in many cases when other options have been exhausted.

David Feifel, a professor of psychiatry at the University of California, San Diego, was one of the first clinicians to use ketamine off-label to treat depression at UCDS’s Center for Advanced Treatment of Mood and Anxiety Disorders, which he recently founded. “Currently approved medications for depression all have about the same, very limited efficacy. A large percentage of patients with depression do not get an adequate level of relief from these antidepressants even when they have tried several different ones and even when other drugs known to augment their effects are added to them”, Feifel tells The Lancet Psychiatry. “The stagnation in current antidepressant medication on the one hand, and the tremendous number of treatment-resistant patients has propelled me to explore truly novel treatments like ketamine.” Compelling published study results and case reports exist of patients’ depression—in some cases deeply entrenched depression that has lasted months or even years—alleviating within hours of use of ketamine.

The Criticisms

• The drug has not been studied sufficiently (at least outside clinical trials)
• Patients may pay more than $1000 per session for treatment that must usually be repeated several times. That cost is rarely covered by the patient’s medical insurance.
• Patients who have exhausted all options shouldn’t have to wait, but off-label use is not being properly monitored “If patients are fully competent and informed, they should have the right to access ketamine—but make sure they understand it is basically an experimental treatment. This is a vulnerable patient population.”
• Another criticism is that patients who have exhausted treatment options might be willing to try anything. “This implies that patients with treatment-resistant depression (TRD) may be so desperate for relief that their ability to perform an appropriate calculation of the risks and benefits of trying ketamine is impaired. This insinuation infuriates many TRD patients in my experience”, says Feifel. “The other assumption is an implicit one that somehow using ketamine for depression is highly risky or fraught with many side effects. Both are simply wrong.”

Why Ketamine?

It has a different mechanism of action to standard antidepressants, which affect signaling by monoamine neurotransmitters such as serotonin, noradrenaline, or dopamine. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the aminoacid neurotransmitter glutamate. The resultant chemical changes in the brain caused by ketamine are not yet fully understood but could involve ketamine-induced gene expression and signaling cascades that act long after the drug has been eliminated from the body.

Meanwhile, critics say that the adverse effects of the drug, including the emergence reactions (hallucinations, dreams, and out-of-body experiences) sought after by recreational users, need further study before long-term use of ketamine can be approved for depression. Feifel states that he has patients who have been receiving ketamine treatments every 2–4 weeks for long periods, some for around 3 years, and has not yet seen any safety issues arise.

Pharmaceutical companies are entering this exciting arena by attempting to develop new drugs based on ketamine without similar side-effects. Naurex, situated in Evanston, IL, USA, recently reported results from a phase 2 study of its drug GLYX-13, which reduced depression in around half of the 400 patients in the study without any psychotic side-effects. The drug is given by injection once every 1–2 weeks and should enter phase 3 trials later in 2015. Other pharmaceutical companies are developing drugs with other modes of administration. Johnson & Johnson (New Brunswick, NJ, USA) are developing a nasal spray containing a ketamine derivative, Crecicor (Baltimore, MD, USA) is developing a once-daily oral pill, and Naurex is also developing an oral version of GLYX-13.

However, Feifel dismisses the notion that the dissociative so-called trip induced by ketamine is actually an important negative side-effect. “I have not had a single patient discontinue treatment due to the dissociative psychedelic experience”, he explains. “Although I have had a couple of patients have unpleasant ‘trips’, it’s exceedingly rare, usually dose-related, and very transitory due to ketamine’s rapid metabolism,” Feifel says that, more often than not, patients find the trip to be positive, or even spiritual, and believe it is an important component of the antidepressant effect they experience afterward. “There is no doubt the dissociative effect represents a logistical issue, requiring monitoring—and this should be addressed in any approval given for ketamine”, he adds.

In the UK, ketamine has been used in two clinical trials for treating depression. Rupert McShane is the lead consultant for the local electroconvulsive therapy (ECT) service based at Oxford Health NHS Foundation Trust, Oxford, UK. His clinic took part in a UK National Institute for Health Research study (REDKITE) in which ketamine was administered for TRD in a series of 28 cases. These patients were largely referred by secondary care psychiatrists, but some contacted McShane’s team following advertising or after reading about the study on the internet. Some patients had been actively looking for somewhere where they could receive ketamine treatment.

“Our team used one of the beds in the recovery bay of the ECT suite to administer ketamine during sessions where other patients—not those receiving ketamine infusions—were receiving ECT”, explains McShane. “This had the advantage of having a team present which is familiar with treating resistant depression, and also an anesthetist. Despite evidence of the efficacy of ECT, many patients are unwilling to try it. Thus, ketamine or similar compounds may have a role in those who would otherwise have had ECT.”

McShane adds that his team is “exploring what options there may be for providing a ketamine service for people with treatment-resistant depression”. He explains that intravenous infusions seemed to clearly establish whether someone was a responder or not. “Our experience was that a second infusion was necessary in order to be able to decide whether someone was a responder, but if they have not responded by then, then they will not respond to further infusions at the same dose”, explains McShane. “Its effect on those people who respond is dramatic. However, it is hardly surprising that a single dose does not usually have an enduring effect—one would not expect that of a single dose of any antidepressant.” He adds, however, that “a few people seem to have much more prolonged responses—for several months. So far, the only way we know of to create a sustained effect in someone who has a brief response is to give it repeatedly, and also through co-prescription of conventional antidepressants which may also prolong the effect. I cannot see a future in which we will not be harnessing the use of ketamine in some way.”

In terms of the safety profile of ketamine, McShane believes that adverse effects of long-term ketamine use on the bladder, which have been reported in people who misuse it recreationally, are strongly dose and frequency related, and have not occurred in the context of medical use.

“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”, he explains. 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.”

Sisti cautions that any clinicians giving ketamine for depression should be fully trained in ketamine administration. “Many are but some may not be”, he says. “Clinics should be outfitted with appropriate emergency equipment, and staff trained on its use. The FDA should set up a voluntary reporting system to track outcomes or adverse events so that some data can be gathered in the field on the safety and efficacy of ketamine for depression.”

Feifel says that it is not for him, but for his patients to decide where the balance of risks and benefits lies in trying ketamine to treat their depression. “I live in a different world from my patients and each one of them, in turn, lives in a different world from each other”, he explains. “We each place a different value on things, have different priorities, have differing notions of what makes life worthwhile but most importantly, unlike many of the people who come to see me, I am not experiencing the perpetual misery that makes every waking moment a struggle not to end my life. So it is much easier for me to place more weight on the unlikely negative possibilities of treatment than the more likely potential benefits —this is the trap pundits who decry this off-label use are falling into. One could make a compelling argument that it’s unethical to withhold ketamine treatments from someone who has chronic, severe treatment-resistant depression. But I know this from the patients who tell me they would not be in this world right now if it were not for the ketamine.”

Feifel concludes that it is straightforward to talk to TRD patients about ketamine. “I tell them all the relevant information. The efficacy rates, time to onset of benefits, duration limitations, alternatives, lack of insurance coverage, and other information. My job is to make sure they understand the parameters of the treatment, not to decide whether they should do it.”

-The Lancet

Learn more about Ketamine:

• Esketamine nasal spray sold as Spravato became the first treatment for depression with a new mechanism of action approved by the Food and Drug Administration (FDA) since Prozac (fluoxetine hydrochloride) by APA
• How ketamine can change the brain to fight depression by Medical News Today
• Ketamine effects are not sustaining and ways to make it better by Inverse
• Ketamine for major depression: New tool, new questions by Harvard Blog (5/22/19)
• Ketamine Reverses Neural Changes Underlying Depression-Related Behaviors in Mice by NIMH
• Lamar Odom says ketamine helped him overcome his anxiety, depression and empathy issues by Daily Mail
• New Hope for Treatment-Resistant Depression: Guessing Right on Ketamine by NIMH (8/13)
• What to know about Ketamine Effectfs by WebMD