Wednesday, March 05, 2014

Warning about Ketamine in the American Journal of Psychiatry


The dissociative anesthetic and ravey club drug ketamine has been hailed as a possible “miracle” cure for depression. In contrast to the delayed action of standard antidepressants such as SSRIs, the uplifting effects of Special K are noticeable within an hour. “Experimental Medication Kicks Depression in Hours Instead of Weeks,” says the National Institute of Mental Health. NIMH has been bullish on ketamine for years now. Prominent researchers Duman and Aghajanian called it the “the most important discovery in half a century” in a recent Science review.

But in 2010, I pondered whether this use of ketamine was entirely positive:
Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

Ketamine can also cause memory impairments, and abuse of the drug can result in severe bladder damage. There's even a model of schizophrenia based on antagonism of glutamate NMDA receptors, ketamine's main mechanism of action.

Now, in the latest issue of the American Journal of Psychiatry, Dr. Alan F. Schatzberg of Stanford University School of Medicine has a commentary entitled, A Word to the Wise About Ketamine. He first acknowledges the excitement about acute ketamine for refractory depression, then raises several cautionary notes and warns:
“This unbridled enthusiasm needs to be tempered by a more rational and guarded perspective.”

He notes that the drug is administered off-label in free-standing private psychiatry clinics without regulation by the FDA. Some leading proponents have advocated for strictly inpatient use, but that cat is already out of the bag.

Another potential issue is abuse liability.  The antidepressant effects of ketamine are short-lived (less than a week), which means that repeated infusions are required. The published literature suggests a relatively safe profile over two weeks in a hospital setting, but patients at commercial clinics are unlikely to be monitored as closely.

The commentary also suggests that “We Need To Know More About the Mechanism of Action of the Mood-Elevating Effects” but that is true of all drugs with antidepressant properties.


The Slippery Ketamine Slope

In response to the question, “Should Clinicians Prescribe Ketamine for Patients With Refractory Depression?” Dr. Schatzberg answers:
Without more data on what ketamine can do clinically, except to produce brief euphoriant effects after acute administration, and knowing it can be a drug of abuse, it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression. ... The recent ketamine studies are exciting, and they open up important avenues for investigation that should be supported; however, until we know more, clinicians should be wary about embarking on a slippery ketamine slope.

However, in the midst of all this naysaying, it's important to note that Dr. Schatzberg has extensive ties to the pharmaceutical and biotech industries. He receives consulting fees from 19 different companies and has equity in 16 different companies, including one for which he is a co-founder. Ketamine of course is not under patent and is cheap to purchase. Perhaps not coincidentally, he does not receive fees from AstraZeneca, which (until recently) was developing a “low-trapping” NMDA antagonist that does not cause the hallucinogenic effects of ketamine (AZD6765, aka lanicemine).

In the past, I have suggested that short-term use for immediate relief of life-threatening symptoms (i.e. suicidal ideation) or end-of-life depression seem to be the best indications. Neuroskeptic has argued for the use of an active placebo condition (i.e, a non-dissociative comparison drug) in clinical trials, which has happened only rarely (Murrough et al., 2013), and for better assessment of dissociative behavioral effects.

At this point, the long-term ramifications of ketamine use for treatment-resistent depression remain to be seen...

In a future post I'll investigate the potential side effects in more detail.


Declaration

I have no financial conflicts to declare. But if some company wants to employ a critic for some bizarre reason, I'll take this under advisement.


Further Reading

Ketamine for Depression: Yay or Neigh?

Chronic Ketamine for Depression: An Unethical Case Study?

While I Was Away... (more on ketamine for depression)

Update on Ketamine in Palliative Care Settings


Reference

Schatzberg AF (2014). A word to the wise about ketamine. The American journal of psychiatry, 171 (3), 262-4 PMID: 24585328





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10 Comments:

At March 05, 2014 3:07 AM, Anonymous Anonymous said...

Somebody found a way of making a lot of money out of it. That's when you get unbridled enthusiasm of this type despite the known risks.

 
At March 05, 2014 6:33 AM, Blogger August said...

From my perspective, the depression springs from all the novel (from an evolutionary perspective) things in our lives, which gives rise epigenetic changes that lead to depression. From this standpoint, all the drugs look dangerous. If you want a drug intervention a course of steriods (yes, like what bodybuilders do, but hopefully more sophisticated) looks like the most sensible approach. They tend to make people feel good and any resulting muscle mass represents positive change for the better. The non-drug approaches- diet, light regulation, sleep, exercise are most important though, and is what ultimately works. The steroids would just provide a strong kick in the right direction. I know there are cases of depression/suicide when some of these bodybuilders come off of steroids, but with proper oversight this could be avoided with far more efficacy than is happening now with the currently accepted drug regime. One can easily wonder if the current drugs aren't actually causing more suicide than they are preventing.

 
At March 05, 2014 8:03 AM, Blogger Neuroskeptic said...

Good post.

I'm not sure the "it's a drug of abuse" argument holds much weight, because many other drugs have higher abuse potential (opioids, amphetamines, benzos) yet are widely used in psychiatry and in medicine more generally.

I find it hard to see how injecting someone with one dose of ketamine is more concerning than giving them an whole pack of dextroamphetamine to take home with them yet that happens routinely in ADHD clinics.

No, what worries me is that we don't know whether it has a direct pharmacological antidepressant effect or an indirect, 'active placebo'/psychedelic psychotherapy-type effect.

If the latter, it is still interesting, but this would suggest that drug-discoverers trying to make a non-psychoactive analogue of ketamine are going in totally the wrong direction.

 
At March 06, 2014 11:48 AM, Blogger The Neurocritic said...

Neuroskeptic - Thanks. Schatzberg's "drug of abuse" argument holds water only IF you think people will seek illegal ketamine outside their (hopefully limited) therapeutic injections. I don't think one (or a limited number) of injections is problematic, either. But I'm skeptical that ketamine is a viable option for long-term maintenance treatment. And I do wonder if those "ketamine4depression" clinics try to push long-term, chronic administration.

And there's this - Chronic Ketamine for Depression: An Unethical Case Study?

Regarding the "psychedelic therapy" effect, Pascal Wallisch pointed out a paper showing that the dissociative side effects of ketamine actually do predict the drugs's efficacy as an antidepressant (Luckenbaugh et al., 2014). AZ dropped development of their non-dissociative analogue... it failed for both safety and efficacy.

August - I don't think anabolic steroids are a wise choice for depression... Here's one study that associated usage with hypomania.

Anonymous - You're right, treatment at private clinics is unlikely to be cheap...

 
At March 06, 2014 12:17 PM, Anonymous Anonymous said...

I am wondering whether other NMDA antagonists, like memantine, are good for depression?

 
At March 06, 2014 12:45 PM, Blogger The Neurocritic said...

That's a very good question. Schatzberg cited an article which said that, "Despite interesting preclinical data, results in major depression are not encouraging." This paper was by Sani et al. (2012), The Role of Memantine in the Treatment of Psychiatric Disorders Other Than the Dementias.

 
At March 09, 2014 9:45 AM, Blogger Bernard Carroll said...


To get a firmer handle on ketamine’s apparent antidepressant activity, I think more focused Phase II studies would help. We might do well to adopt the 1980s strategy of testing the drug in small numbers of clear-cut, prototypical cases instead of in inevitably larger numbers of cases with generic major depression. Stuart Checkley at the Maudsley in London proposed this approach years ago. I would be interested to see how the drug works in definitely recurrent melancholic, DST-positive, short REM latency patients on the one hand, compared to definitely nonmelancholic cases who lack abnormal biomarkers. It also needs to be assayed in a sample of bipolar I depressed patients. In my book, that is an acid test.

As for Dr. Schatzberg, you did well to raise a flag about his independence. When he cautions that “This unbridled enthusiasm needs to be tempered by a more rational and guarded perspective,” he should acknowledge his own dismal performance. He is on record as making unwarranted claims for his own company’s drug Corlux (mifepristone) to treat psychotic depression. The quality of those trials was pitiful. You can read about that here and in subsequent posts on Health Care Renewal: http://tinyurl.com/njd4kwd

 
At March 11, 2014 6:54 AM, Blogger August said...

That study was a survey of people using steroids on their own, not a trial of a professionally formulated protocol. I am not necessarily for this approach being taken, but I am saying this approach would have better results than the current pharmaceutical intervention.
Even a simple goal of 10% increase in lean muscle mass pushes the entire biochemical profile away from the conditions under which depression is chronic.
Long term lifestyle changes have to occur in order to keep those benefits, and the same lifestyle changes can get the patient healthy without any drug intervention.
Anyway, I suppose the key here is for the psychiatric world to figure out a 10% increase in muscle mass correlates with less depression. Currently, they act like there is no connection to the body or the environment.

 
At March 20, 2014 10:08 AM, Anonymous Anonymous said...

As a person with a years long depression I feel almost offended when I read such obviously ill motivated statements by the likes of Schatzberg. I tried about 6 different types of antidepressants over the years, and none of them came even near to the effectiveness of ketamine, nor the low side effect profile. I treated myself, since there was no legal alternative on offer, and I feel like I finally got my life back. I'm absolutely enraged that the antidepressant effects of k have been known for almost 10 years - even i heard about it 5 years ago - without (almost) nobody doing research in this direction. My conclusion is that there is simply no money in A 50 year old compound, and that our system for doing pharm research is completely sick and counter productive. And Forget about this blinding bullshit: at the doses used there are no hallucinations or anything that's remotely like a psychedelic. You don't need control groups for effect sizes like this. Ketamine is safe at these levels, and far less addictive than people claim. Depression killed 2 of my best friends in the last 4 years, and people like Schatzberg are scum.

 
At March 20, 2014 10:42 AM, Anonymous Anonymous said...

Just one addition to my post above, about the damage that long term abuse creates: ketamine addicts usually take amounts upwards of 5 grams a day, while depression treatment usually affords something like 50mg for one session. It's almost silly to expect similar damage for ad-treatments, especially because ketamine is such a well known and safe drug when used at clinical doses.

 

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