Neuroscience
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:
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:
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:
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
- On The Long Way Down: The Neurophenomenology Of Ketamine
Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”? For years,...
- Update On Ketamine In Palliative Care Settings
Many recent headlines have heralded a new use for the old veterinary anesthetic ketamine, which can provide rapid-onset (albeit short-lived) relief for some patients with treatment-resistant depression (aan het Rot et al., 2012). This finding has been...
- While I Was Away...
While I was (mostly) away from the internet, I missed over a week of online excitement. These items are old news by now, but in case you've forgotten... (1) NPR Morning Edition had a piece on acutely administered ketamine for the treatment of depression:...
- Jama On 60s Psychedelic Drug Culture
An amusing semi-anthropological study was published in JAMA by Ludwig and Levine in 1965. It was based on extensive interviews with 27 "postnarcotic drug addict inpatients" who were treated at a hospital in Lexington, Kentucky. The specific drugs of...
- Ketamine For Depression: Yay Or Neigh?
Venn diagram of psychoactive drugs [click for larger image] NOTE: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic...
Neuroscience
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
- On The Long Way Down: The Neurophenomenology Of Ketamine
Is ketamine a destructive club drug that damages the brain and bladder? With psychosis-like effects widely used as a model of schizophrenia? Or is ketamine an exciting new antidepressant, the “most important discovery in half a century”? For years,...
- Update On Ketamine In Palliative Care Settings
Many recent headlines have heralded a new use for the old veterinary anesthetic ketamine, which can provide rapid-onset (albeit short-lived) relief for some patients with treatment-resistant depression (aan het Rot et al., 2012). This finding has been...
- While I Was Away...
While I was (mostly) away from the internet, I missed over a week of online excitement. These items are old news by now, but in case you've forgotten... (1) NPR Morning Edition had a piece on acutely administered ketamine for the treatment of depression:...
- Jama On 60s Psychedelic Drug Culture
An amusing semi-anthropological study was published in JAMA by Ludwig and Levine in 1965. It was based on extensive interviews with 27 "postnarcotic drug addict inpatients" who were treated at a hospital in Lexington, Kentucky. The specific drugs of...
- Ketamine For Depression: Yay Or Neigh?
Venn diagram of psychoactive drugs [click for larger image] NOTE: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic...