Ketamine to the Rescue?

© albund |Stockfresh.com

© albund |Stockfresh.com

Enthusiasm for using ketamine to treat depression has been growing. The interest in the fast action effects of ketamine for treatment-resistant depression began with the publication of a study by Zarate et al. in 2006 that found “Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection.” Since then, dozens of studies have been done and thousands of people have been treated for depression off label with ketamine. Now the American Psychiatric Association has a ketamine task force and is seriously considering an endorsement of ketamine for treatment-resistant depression.

An NPR story featured psychiatrist David Feifel’s work in treating depression with ketamine. Feifel began treating people with low dose ketamine in 2010. After reading the papers on ketamine, he said he was electrified. People were getting better in hours. “It became clear to me that the future of psychiatry was going to include ketamine, or derivatives of ketamine, or the mechanism of action in some way.”

He said it was hard for him to take the “wait and see” approach suggested by other psychiatrists when people are desperate for help. It didn’t make sense to him. Sara Solovitch, writing for The Washington Post, said some experts are calling it the most significant advance in mental health treatment in fifty years.

Ketamine has been around since the 1960s. It is regularly used as an ER anesthetic because it can rapidly stop pain without affecting vital functions like breathing. It’s often the go-to painkiller for children who come to the ER, say with a broken bone. It’s used in veterinary medicine and is an important tool in burn centers. It’s also been used as date-rape drug, because of some of the self-same properties that make it an attractive ER anesthetic. It will quickly numb and render someone immobile.

A single dose of ketamine costs under $2. The drug is easily available in any pharmacy; and doctors are free to prescribe it for off-label use. But ketamine treatment for depression is expensive. Dr. Feifel charges $500 for an injection and $1,000 for an intravenous infusion. The high cost is attributed by practioners to the medical monitoring and IV equipment required during an infusion.

It isn’t an approved depression treatment, so the costs are out-of-pocket, placing it out-of-reach for many people. But clinics are going up everywhere. A directory found 19 different centers in the US as of the beginning of February, in 2016. Dr. Feifel is afraid something will happen to a depressed patient at one of these unregulated clinics that could set back efforts to make the drug more widely available.

Sara Solovich reported there a growing number of academic medical centers that are offering ketamine treatments off-label for severe depression. These medical centers include: Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic. A San Francisco psychiatrist, Alison McInnes, thinks this is the next big thing in psychiatry. Psychiatry has “run out of gas” in trying to help depressed patients. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

Dr. McInnes reported a 60% success rate for people with treatment-resistant depression who try ketamine. Dr. McInnes is also a member of the APA’s ketamine task force. She expects the APA to support ketamine treatment in 2016.

Ryan, Marta and Koek did a literature review on ketamine as a treatment for depression in a 2014 issue of the International Journal of Transpersonal Studies,Ketamine and Depression: A Review.”  They acknowledged that the largest challenge with ketamine was extending its benefit for the longer term. Repeated infusions of ketamine showed some promise, but it is far from clear what the optimum dose, frequency and number of infusions should be. “It also worth noting that some patients do not benefit from ketamine, despite multiple treatments.”

Ready for the drawbacks? “Even low-dose ketamine infusion can cause intense hallucinations.” Patients experience a kind of lucid dreaming or dissociative state where they lose track of time and have out-of-body experiences. Many people enjoy it; but others don’t. The treatment effects are often temporary. Dr. Feifel reported one patient whose depression remission would begin to fade within twenty-four hours. With others, the remission can be longer; even weeks. The fleeting remission effect means that many patients return for booster infusions. A business executive from Seattle flies back-and-forth to New York for bimonthly infusions. Sometimes his remission periods will last six months.

Gerald Sanacora, the director of the Yale Depression Research Program, said ketamine infusion is an extremely important treatment. His concern is that people may begin using it as a first-line treatment—before CBT (cognitive behavioral therapy) or antidepressants like Prozac. “Maybe someday it will be a first-line treatment. But we’re not there yet.”

It’s a medication that can have big changes in heart rate and blood pressure. There are so many unknowns, I’m not sure it should be used more widely till we understand its long-term benefits and risks.

There isn’t a registry yet for tracking ketamine patients treated for depression. So the number of people treated, the frequency of those treatments, the dosage levels, follow up care—and importantly—adverse effects from ketamine treatment aren’t known. Carlos Zarate, the NIMH’s chief of neurobiology and treatment of mood disorders, said: “We clearly need more standardization in its use.”  In his opinion, it should still be sued in a research setting or a highly specialized clinic.

There also seems to be a turf war or sorts brewing. Ketamine was once almost exclusively a drug known to anesthesiologists. Psychiatrists are now saying that with the use of ketamine for depression growing, it should be left for psychiatrists to prescribe. David Feifel said:

The bottom line is you’re treating depression. . . . And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients. Many of them have bipolar disorder and are in danger of becoming manic. My question [to anesthesiologists] is: “Do you feel comfortable that you can pick up mania?”

Six of the providers in the above-linked directory are specialists in anesthesiology. Six are psychiatric specialists. The rest are a mixture of specialists in emergency medicine, neurology, internal medicine and even family medicine. Enrique Abreu, A Portland Oregon anesthesiologist who began treating depressed patients with ketamine in 2012, said: “Most anesthesiologists don’t do mental health, and there’s no way a psychiatrist feels comfortable putting an IV in someone’s arm.”

Ketamine in larger doses than are being used in the above discussed depression research is a club drug known as “Special K,” “K,” of Ket.” It is a Schedule III Controlled Substance, meaning it is classified as having an addictive potential. Current depression research has not indicated dependence as an adverse effect, likely because of the low doses currently being used. When used with other sedating drugs like alcohol, the potential of slowing or shutting down the central nervous system are increased. And it is possible to overdose on ketamine. While some clinicians like Drs. Feifel and McInnes would like to see ketamine treatment revolutionize the psychiatric treatment of depression, caution in waiting for the results of further research seems advisable.

Unfortunately, I don’t think that will happen. Psychiatric treatment of depression is in crisis. Even the articles and researchers cited here seemed to acknowledge this. Dr. McInnes said psychiatry has “run out of gas” in trying to help depressed patients. Dr. Fiefel said he found it hard to “wait and see” what further research found regarding ketamine, when so many people were desperate for help.

Pharmaceutical companies stopped doing research into new antidepressants. The chemical imbalance theory of depression is now referred to as more of an urban myth than a true description. Pharma and psychiatry need an antidepressant savior and it seems they hope it will be ketamine.


No Laughing Matter

© Ievgen Soloviov | Dreamstime.com

© Ievgen Soloviov | Dreamstime.com

In his famous work, The Varieties of Religious Experience, William James discussed what he said was the ability of nitrous oxide (laughing gas) to produce “mystical consciousness” to an extraordinary degree. “Depth beyond depth of truth seems to be reveled to the inhaler.” But the revelation fades as the gas wears off. What is left seems like nonsense to the awakened mind. But the sense of “a profound meaning” persists. James said he knew more than one person who was persuaded that a genuine metaphysical revelation could come in a nitrous oxide trance. Now, laughing gas is being researched as a treat for depression.

James said he had personally tried nitrous oxide, and even wrote of his experience in print. He said one impression from these experiments stayed with him—that our waking consciousness was but one of several other potential form of consciousness. “No account of the universe in its totality can be final which leave these other forms of consciousness quite disregarded.”  Looking back on his own experiences, he saw them converge towards a kind of insight that he felt had metaphysical significance.

His essay was “Subjective Effects of Nitrous Oxide,” and it appeared in the 1882 volume 7 issue of Mind. It can be found in a few places online. I’ve linked it on the website Erowid, which will also have other references we’ll examine. In his essay, James said that the keynote of nitrous-oxide intoxication was an intense sense of metaphysical illumination that occurred as the altered state of consciousness was wearing off.

The mind sees all logical relations of being with an apparant subtlety and instantaniety to which its normal consciousness offers no parallel; only as sobriety returns, the feeling of insight fades, and one is left staring vacantly at a few disjointed words and phrases, as one stares at a cadaverous-looking snow peak from which sunset glow has just fled, or at a black cinder left by an extinguished brand.

What James saw as the most coherent and articulate of his bursts of insight was this: “There are no differences but differences of degree between different degrees of difference and no difference.” James said there was an initial rapture of emotion in “beholding a process that was infinite” that turned to horror as the individual realized they were caught in an inevitable fate, “with whose magnitude every finite effort is incommensurable and in the light of which whatever happens is indifferent.”

As James himself said in the essay, just as every person’s encounter will vary, the individual’s personal experience with nitrous oxide will vary from time to time. However, he still thought that there still was a common thread running through all those who were intoxicated with nitrous oxide, namely an “intense metaphysical experience.”

A group of researchers, Nagel et al., reported on a pilot study done to assess the potential of nitrous oxide as a rapidly acting treatment for treatment resistant depression (TRD). The theory was based upon the influence of nitrous oxide on the NMDA receptor, which has been “implicated” in the neurobiology of depression. Other NMDA receptor antagonists, such as ketamine, have been shown “to provide a rapid and sustained antidepressant effect” when used at low doses. Given the similar mechanisms of action, the researchers hypothesized that nitrous oxide may also have rapid antidepressant effects on treatment resistant depression. So they designed a study to assess the immediate (2 hours) and sustained (24 hours) antidepressant effects of nitrous oxide in TRD patients.

Patients received either an admixture of up to a maximum of 50% nitrous oxide and 50% oxygen (as the active ingredient) or 50% nitrogen/50% oxygen (as the placebo) for one hour. Outcomes were assessed for each participant at baseline, 2 hours after treatment and 24 hours after treatment. The results indicated a significant improvement in depressive symptoms at 2 and 24 hours. There was also a sustained improvement with some participants for 1 week. Yet there were several limitations noted by the researchers of this study.

The full 60-minute nitrous oxide treatment was only completed by 15 of the 20 patients. The placebo treatment was completed by 20 individuals. The side effects for the treatment group were noted to be mild or moderate (nausea, anxiety, vomiting) and immediately reversible. This suggested an acceptable risk/benefit ratio of nitrous oxide for TRD to the researchers.

Their discussion suggested several limitations of the study. The small sample size meant that the results should be interpreted with caution until the results were replicated in larger populations. They also noted that the euphoric effects of nitrous oxide are hard to mask, so the blinding attempted in the study may not have been adequate. Despite knowing this, the researchers did not try to assess whether or not the participants were aware of their group assignment, “and this limits our conclusions.”

They also pointed out that there could have been a masking effect of depressive symptoms, meaning that: “the depressive symptoms were not really altered, but rather ‘covered up’ by other effects.” They noted where symptom masking has been evident with rapidly acting psychostimulants like cocaine and methylphenidate, “which promote a transient alteration in mood but not a true antidepressant effect.” Their preliminary study concluded there was evidence that nitrous oxide may have rapid and marked antidepressant effects in patients with TRD. They called for further studies that would attempt to determine optimal antidepressant dosing strategies and the risk/benefit of nitrous oxide in a larger and more diverse population of individuals with TRD.

Psychiatrist Sandra Steingard expressed reservations with the promotion of nitrous oxide as a rapid acting treatment for depression. She commented that while she never personally tried nitrous oxide herself, she knew others who did and expected that her mood would undoubtedly have been elevated as theirs was. Her suggestion was the observed “treatment’ effects of nitrous oxide were actually drug effects that would occur with any individual who used it. She proceeded to voice several questions on the use of nitrous oxide, ketamine or stimulants to treat depression. She thought there was a huge potential for harm; possibly greater than the drugs psychiatrist currently prescribed for depression.

What are the long term side effects? How hard is it to stop them?  How do we deal with the corrupting influence of the profit driven forces so powerful in medicine?  Most of these drugs are still studied over weeks and then prescribed for years. With drugs like stimulants, ketamine and nitrous oxide, I have a particular worry because these drugs are known to cause psychosis. Colleagues of mine have told me that they do not see people who become psychotic on stimulants. If they don’t, they are not looking. I am not comfortable assuming when an 18 year old develops psychotic symptoms after several years of treatment with an antidepressant that these two things are not related or that the psychosis was inevitable because the person had a diathesis to Bipolar Disorder. Stimulants are used to create animal models of psychosis because we have known for decades that stimulants can cause a person to become psychotic.

Erowid is the website for an organization that seeks to “provide accurate, specific, and responsible information about how psychoactives are used in the United States and around the world.” So you will find pro and con information on the use and effects of psychoactive substances there. Here are a few of the catalogued articles on problems from nitrous oxide use and abuse: “Asphyxia deaths from the recreational use of nitrous oxide;” “Suicide by nitrous oxide poisoning;” B 12-related medical problems from nitrous oxide: “Nitrous oxide myleopathy in an abuser of whipped cream bulbs [whippets] (nitrous oxide is used in whipped cream cans), “Myleneuropathy after prolonged exposure to nitrous oxide,” and this case report from outside of Erowid of a woman who developed myleopathy.

Below is a quote from a 1991 article on “Health hazards and nitrous oxide” in medical settings. Here is a link to a case report of an individual who suffered paranoid delusions after abusing whippets.

Although N2O was for many years believed to have no toxicity other than that associated with its anesthetic action, bone marrow depression in patients administered N2O for extended periods of time and neurological abnormalities in health care workers who inhaled N2O recreationally have disproved this notion.

Simply put, regardless of the short-term reversals of a depressed mood state, it does not seem that there will be any long-term benefits from the therapeutic use of nitrous oxide (N2O). And there seems to be plenty of concerns with its use. Treating depression with laughing gas is no laughing matter.