What if the cure is worse than the disease…

Imagine that you are in the throes of a severe depressive episode. Your energy and enthusiasm seem to have abandoned you. Life has lost its meaning. You struggle to even get up in the morning and can’t face your work. Lately, you’ve taken to staying at home hoping that the cloud will lift, but your fear is that you are stuck in this pit of hopelessness. Thoughts of ending your life begin to flit across your mind. You’ve been taking an antidepressant, but like others that you tried during previous episodes, it doesn’t seem to be doing much to reduce your symptoms.

In desperation, you decide to go to your doctor. She listens with concern. While you’ve been down before, she’s never seen you at this depth. She suggests a consult with a psychiatrist. Because you are so desperate, and your symptoms are dangerously severe, the psychiatrist recommends taking an assertive approach. You learn from him that because of your poor response to antidepressant medications, switching to yet another is unlikely to help. Even if it does, your risk of relapse is high. He offers you an alternative called ketamine and explains that while its effectiveness as an anesthetic is well documented, recently it has shown promise as a fast acting treatment for resistant forms of depression. You are desperate, but something twigs in your memory. Didn’t you try something with a similar name when you were young and reckless? Your friends called it “Special K”, and it gave you a weird high complete with hallucinations. Who would have thought that years later your shrink would be offering you a prescription for a drug that most people know from raves.

What should you do?

The scenario is a real one and is playing out increasingly across North America. While ketamine’s sole approved use is as part of the cocktail used to put you under for surgery, it is seeing increasing “off label” use as a medication used to treat depression. The term “off label” means that a drug is being used for a purpose that has not been approved by the FDA, the agency that monitors and regulates prescription drug use in the United States. FDA approval requires a stringent process to ensure that a given drug is effective and safe. In the case of ketamine, there has been a flurry of studies in recent years whose results have caught the attention of clinicians. In some cases, intravenous administration of ketamine has appeared to reduce symptoms of even severe, treatment resistant depression within several hours. The effect can be profound and exceed that of several weeks treatment with an antidepressant medication. It also has the potential to knock out suicidal thoughts, which is the holy grail of depression treatment. Almost all the arguments used to reduce concerns about antidepressant side effects refer to the danger of suicide if depression goes untreated. No wonder that the former director of the NIH suggested ketamine treatment “might be the most important breakthrough in antidepressant treatment in decades”  1.

Before we get too excited about this “wonder drug”, I should point out that FDA has not just been caught in a backlog of clinical trials in its refusal to certify ketamine use for treating depression. There are some very real concerns that much of the evidence gathered so far in favor of its use is inconclusive. Recently Melvyn Zhang and his colleagues published an open access article debating the sort of off-label use of ketamine that is becoming so popular in clinics that are popping up across the US 2. Zhang et al. point out that the mood elevation associated with ketamine is hardly news, and is associated with most psychedelic drugs, including amphetamines. Its effects are also fairly short-lived. In fact, most of the studies looking at ketamine only considered its benefits over a period of days or at most a few weeks. Treatment resistant depression is a long-term

Treatment resistant depression is a long-term curse, sometimes persisting for years at a time and returning over and over through a person’s life span. Ketamine has also not been compared to other antidepressants, most of which have positive effects that have been repeatedly validated. When it has been compared to other drugs, these are usually other agents like Midazolam that are neither antidepressants nor recommended by guidelines for the treatment of depressive disorders. Here in Canada where I practice, a thorough review of the evidence by the Canadian Agency for Drugs in Health concluded that the benefits of ketamine have only been demonstrated for a period of 24 hours after its administration, and we still do not know which patients are more likely to respond even over this very short period of time3. Over the long run, what evidence we have is not encouraging. In their review of recent research, Katalinic et al. found that by day 40 after treatment 90% of patients receiving ketamine treatment for depression had experienced relapse 4.

Ketamine’s value as a relatively safe anesthetic agent is undisputed, however its ability to promote an altered state of consciousness has boosted demand among recreational users, where it has become a popular drug at raves and clubs. Thanks to its anesthetic effect at higher doses, along with common side effects like confusion and amnesia, it has also gained notoriety as a date rape drug. In places like Hong Kong, it is the most prevalent drug on the streets. The serious health problems that go with its recreational use, like amnesia, poor impulse control, dependence, and addiction, not to mention death from overdose have resulted in its categorization in the US under the controlled substances act. In other words, like its infamous cousin PCP, ketamine is considered to be a dangerous street drug and efforts to control its spread include large fines and/or imprisonment.

Ketamine for major depressive disorder.

Recently, the FDA awarded breakthrough therapy designation for the development of intranasal ketamine as a treatment for major depressive disorder. Not surprisingly, snorting is a popular way to ingest recreational drugs along with injection. We are about to see a proliferation of prescriptions for this drug, and potentially a corresponding increase in the problems associated with its use. Already emergency room visits due to its side effects and overdose risks have been skyrocketing.  Yet the promise of fast, short-term relief for depressive symptoms is proving to be too strong to resist. For desperate people with depression who are offered a prescription for this drug, the choice will probably appear simple. They just want to feel better now and won’t be too concerned about ketamine’s “off label” status, side effects, or risks to society at large.

As for the compassionate health providers who are often left feeling frustrated and helpless in their efforts to help people with treatment resistant depression, the promise of quick results will likely outweigh concerns about the lack of evidence, its psychosis inducing properties, dangerous side effects (30% of users experience a spike in blood pressure that poses a cardiac risk factor), or the fact that all the authors of a recent “consensus statement” on its use report multiple relationships with pharmaceutical companies 5. Consequently, my prediction is that ketamine prescriptions among clinicians will continue to increase. With pharmaceutical companies lending their weight to researching

With pharmaceutical companies lending their weight to researching promoting new forms of this medication, such as the intranasal spray, we will see not only an explosion in prescription sales but in the diversion of this drug and its availability on the street. This will bring with it a corresponding jump in the number of emergency room visits, addiction problems, and overdose deaths. It will also fuel the proliferation of problems like date rape. Like other controlled substances such as oxycontin, which revolutionized pain treatment while simultaneously setting off an epidemic of opiate drug abuse and addiction in our communities, ketamine will bring a lot of pain with its promises.