Can the anesthetic find an off-label footing in psychiatric applications?
The role of ketamine in the treatment of patients suffering with unremitted symptoms of depression became clearer with the recent release of A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders by a task force of the American Psychiatric Association (APA), and a separate publication in the Unit- ed Kingdom on ethical arguments for providing the treatment.
With growing interest in the agent coinciding with increasing research into its effects, MD Magazine® asked Steven P. Levine, MD, psychiatrist, and founder of Ketamine Treatment Centers, to comment on the status and prospects for the currently off-label treatment. The following is excerpted from that conversation.
MD Magazine®: Most of the information on ketamine effects and dosing comes from studies on its use as an anesthetic. Are the data sufficient to guide its use for psychiatric applications?
Steven P. Levine, MD: There have been multiple studies at this point on the psychiatric applications of ketamine, mostly focusing on depression, with a handful of other indications.
The studies are not as large as most of the FDA-approved antidepressants. Most of them have had phase 3 trials with hundreds and sometimes thousands of patients. But there is an accumulation of a lot of small studies, and when these have been subjected to meta-analyses, you still have an amazingly large effect size.
That’s something that really jumps out about the research on ketamine, as opposed to something like an SSRI [selective serotonin reuptake inhibitor]. We’ve seen effect sizes in the degree to which the medicine beats placebo that are pretty impressive. That’s why even when you aggregate these small studies—which typically waters down the statistics—they still de- liver quite a large effect size. So, overall there certainly are some arguments to be made about the size of the studies, the design of some of the studies, and where we are in development relative to its usage becoming widespread.
I think a lot of that speaks to the need. If you look at studies like the STAR*D (Sequenced Treatment Alternatives to Relieve Depression Trial), it really showed us what happens when people get the best possible care. If they get the best possible care and they move carefully through an algorithm with standard treatment, only a third of them have a response with the first attempt. Even when they go through the entire algorithm, only two-thirds remit.
A third of 6% or 7% of the US population is a lot of people who have a lethal illness who don’t get treated and for whom the standard treatments take way too long to work.
Is there also a need for studies on the repeated dosing of ketamine, which is sometimes administered 2 to 3 times a week for several weeks to prolong its therapeutic effect on depression symptoms?
There’s a good amount of anecdotal data at this point. We’ve had people for more than 5 years, and we’re about to present a retrospective chart analysis of 740 patients we have in our newer database, over the last year and a half, where we show no long- term adverse events.
In addition, we’re also getting a collaboration underway with a lot of people to put together an international patient registry, and this is what everybody has been asking for, this is what’s needed. It’s going to very quickly create a database with many patients that are way beyond what is typically included in phase 3 trials.
It will, hopefully, put a lot of the concern to rest because you will be able to look at the effects of this medicine in a large population and track adverse events over a long period of time. This will be much better than a practice saying, “my patients are doing well,” and will provide the results to support that.
I know that the need for a registry is something that was talked about in the consensus statement, and it's coming.
The consensus statement also indicates the importance of appropriately selecting patients for the treatment. With regards to treatment-refractory depression, does the patient selection process ensure that there have been sufficient trials with conventional treatment, with adequate antidepressant dose and duration?
It’s true that the number-one reason why someone may not respond to an antidepressant trial is because they haven’t taken it at an adequate dose for a long enough time. So, some people who are labeled “treatment resistant” may not actually be so, because they haven’t had a fair trial.
That being said, over time—at least as far as patient selection at the Ketamine Treatment Centers—it’s evolved. At first, I would not treat someone who had not tried, not only SSRIs [selective serotonin reuptake inhibitors] and other newer antidepressants, but also older classes of medicines like the TCAs [tricyclic antide-pressants] and the MAOIs [monoamine oxidase inhibitors].
Now, since that time, we’ve given thousands of infusions and treated well over a thousand patients. We’re not alone in this anymore, and many major academic centers now offer this, as well as other private practices. We’ve seen that outcomes are good and the safety is terrific, and this works much more rapidly than other options.
We no longer require people to be as treatment refractory. If somebody has tried 5, 6, 7 medicines but maybe a couple of them haven’t been adequate trials, we may still think it's reasonable at that point to try ketamine.
What about a threshold for symptom severity in deciding whether to treat with ketamine?
We’re certainly not treating people with mild depression. We’re only treating people with at least moderate to severe depression.
There’s certainly, across the country and around the world, go- ing to be some variability in how people do their pretreatment patient selection. But one thing that’s happening right now is we’re forming a professional body called the American Society of Ket- amine Physicians, and the founding board will include some of the most experienced and respected people in practice around the United States.
One of the intentions of the body is to lead and set some ex- ample of what we think are safe patient selection practices, and provide minimum safety requirements and guidelines.
As this dissociative anesthetic has provoked psychotic symptoms, would safety concerns preclude administering the treatment to patients with a history of psychosis?
Part of the history with ketamine is that it has been studied in psychotic disorders, in schizophrenia, and there was actually some hope that it might help with what are called “negative symptoms” of schizophrenia—which often times can be more disabling than the “positive symptoms.”
The positive symptoms are the ones we typically associate with schizophrenia because they’re more obvious: hallucinations, delusions, people talking to themselves. The negative symptoms are things like social withdrawal, flattening of affect. People slide down the socioeconomic rungs because they’re not able to really participate in life.
Now, what those studies showed was that ketamine transiently worsened the positive symptoms and did not improve negative symptoms. So, there was no reason to pursue that. Recently, Gerry Sanacora at Yale [Gerard Sanacora, MD, PhD, director, Yale Depression Research Program] published a case study of treating people with an active psychosis, where their depression was successfully treated without there being adverse effects.
Nevertheless, I think a good rule of thumb at this point, and one that we follow, is to not treat people with primary psychotic disorders, like schizophrenia, or with active psychosis at the juncture of the current mood disorder.
Do you have concerns about the potential for abuse, with ketamine having a history of diversion for recreational use?
The setting and intentions are important. Our patients are not coming in with the intention of having a party or getting high. If they were, there are much easier, cheaper ways of going about it.
Certainly, the United Kingdom and many parts of Asia have been seeing ketamine abuse problems, so we should not take this lightly. It’s one of the reasons why I feel strongly that, at least at this point, ketamine should not be given in any form to be taken at home. It should be used in a controlled medical setting. In those settings and conditions, the risk of abuse is really nil because they don’t have access to it outside and they’re getting it relatively infrequently.
With the short duration of ketamine effect, as dramatic as it can be, what kind of follow-up are you providing or referring your patients to receive?
A lot of articles have talked about the “rapidly acting, dramatic, but short-lived effects of ketamine.” It’s unfair because most of those have been reporting on, or mostly looking at single-infusion studies. We don’t have options in psychiatry that you can have 1 treatment and you’re cured.
If we take the longest studies, the best evidence reported is that electroconvulsive therapy is the most effective treatment for treatment-resistant depression. With that, there are multiple treatments on a maintenance basis or the patient will relapse. That’s the case for any therapy.
In the case of ketamine, to go back to the retrospective study we are conducting with a 740-patient cohort, the aver- age time between maintenance treatments was 4.13 weeks. That’s basically once a month. It’s good, but it’s not our intention to keep a patient on ketamine treatment forever. It should be a tool, a rapidly acting jump start to a sustained recovery.
It’s one of the drums that we beat loudly: that ketamine treatment is time-limited, and rapidly acting, to allow the patient to be able to assimilate a body of knowledge and set of skills from programs like CBT [cognitive behavioral therapy] or DBT [dialectical behavior therapy]. They go together with ketamine, which may enhance new learning, like peanut butter and chocolate.
We are strongly encouraging treatments like that, along with treatments for insomnia, because it’s very likely that if people have ongoing insomnia, they won’t have significant recovery. For that, our recommendation is for CBT-I [CBT for insomnia].
Any additional thoughts?
It’s important to realize that we’re really at a critical point with this medicine now. To this point, there really hasn’t been much official discussion or discussion from the academic community outside of the research setting.
This is now being used in the world as a clinical tool, and so I think it’s going to be important that the academic community responds, like the APA task force has done in issuing the Consensus Statement, to acknowledge that this is being done.
We need to think about, not necessarily whether it should be—because the barn doors are already open—but what is now the best way that we can gather good information about the treatment that can shape the safest and most effective use. ■