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