The “Surgical Signature” of Future Antidepressant Treatments

EDITORS NOTE: This is the first blog in a series exploring how our methods for treating depression are on the edge of undergoing important changes and improvements. 

The world can change so quickly. Four or 5 years ago, I felt pretty certain that we had hit insurmountable roadblocks to the identification of really new antidepressants that might work better than what we had and with fewer downsides. My discouragement over this state of affairs was heightened by the fact that data were pouring in confirming that pharmacological interventions for depression were less effective for many patients than we had believed them to be in the halcyon days of the 1990s.

My sense that there was nothing left to discover that would improve our ability to treat depression reminds me of the famous statement by the scientist Lord Kelvin in 1900 that there was nothing left new to discover in physics. Of course, within 5 years Einstein released relativity theory and not long after came quantum mechanics.

I am happy to report that my prior pessimism about treating depression looks at least as embarrassing as the great Lord Kelvin’s pronouncement about physics. Even 4 or 5 years ago, the future of depression treatment was coming toward us, but it was far enough off to look uncertain. Now, the future is almost here, close enough at least for us to begin getting a sense of what the general outlines will be.

And by saying that the future is here, I mean the next 10 years, not treatment in 2050. There are people working on depression treatment for 2050 or 2100, and it appears to me that these modalities may well involve a combination of genetic manipulations and human—computer interfaces. These interventions would sound like science fiction now, but I am pretty sure they will come if the world continues more or less on its current course for the next 100 years.

Perhaps we can start with what the future treatment that is happening now won’t be. It won’t be a miracle cure for all depressed patients. And most importantly it won’t be one thing. We have no evidence that a medication or intervention will be discovered that will make depression go away. That’s the bad news.

So what will the future of depression treatment over the next 10 years be?

For me, one of the most interesting qualities of the next wave treatments is that many of them will not be chronic interventions. We have taken it as gospel for so long that depression is a chronic condition that requires chronic medication management (similar to diabetes or hypertension) that it will come as a shock to many in our field that new treatments may be more “surgical” in nature. By “surgical,” I mean that the intervention is delivered once and the condition is either resolved or resolved/improved for a significant period of time afterwards without the need of continuous exposure to the intervention. And as with surgery, the impact on the underlying condition is rapid.

So rapid and sustained responses to a single treatment seem to be hallmarks of at least some of the most promising interventions of the near future. Take ketamine. Most of us would agree that it is currently at the forefront of pharmacologic interventions for major depression (and related conditions like bipolar depression and posttraumatic stress disorder). Its rapidity of action has been widely trumpeted and has now been confirmed by meta-analyses that compare ketamine to a variety of placebo conditions.

What has not been said strongly enough is that the ketamine data also suggest that a single treatment may have long-lasting antidepressant effects in at least some individuals. For example, a recent meta-analysis finds that although the efficacy of a single infusion of ketamine fades compared to placebo over the subsequent 2 weeks, it still shows a large effect size advantage (Romeo et al, 2015). In one of the larger studies conducted to date, almost 30% of patients with treatment resistant depression had remained relapse free up to 4 weeks following a single infusion of ketamine (Ibrahim et al, 2015). More recently, a single infusion of ketamine at the onset of treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram was found to produce both a more rapid antidepressant response and a significantly larger response 4 weeks later when compared to escitalopram plus an initial infusion of placebo.

These findings do not mean that people might not have better responses to multiple ketamine treatments, only that we now have a treatment with the “surgical” signature of rapid and sustained relief of the underlying condition following a single intervention.

One might be tempted to suspect that this “surgical signature” is unique to ketamine were it not for the fact that other novel treatments on the horizon share this trait. Work by Wayne Drevets and colleagues at the National Institute of Mental Health suggests that a single infusion of the muscarinic cholinergic antagonist scopolamine produced a robust antidepressant effect that was apparent within 3 days and that persisted for at least 2 weeks (Drevets et al., 2013). Whether the effect would have persisted longer is not clear, because the studies conducted to date have used a cross-over design.

More recently, a small pilot study has shown that a single exposure to nitrous oxide, which like ketamine has effects on the glutamate NMDA receptor, produced rapid antidepressant effects that remained significant a week following the single treatment (Nagele et al, 2015).

So we have published data from a number of randomized studies suggesting that the next wave of treatments will be characterized by rapid effects that persist following a single treatment. This would be convincing in and of itself, but there are additional novel treatments on the horizon that may show the same response patterns. Our research group has been studying the impact of whole body hyperthermia (WBH) on major depression. In these studies, we give patients a single WBH treatment that lasts about 2 hours and then follow their symptoms for several weeks afterwards. We have published an initial open study suggesting that a single WBH treatment produces a rapid antidepressant effect that persists for at least a week (Hanusch et al, 2013). More recently, we have finished a larger randomized study of WBH that should be published in the next calendar year. And finally, studies published over the last decade indicate that when administered under rigorous therapeutic protocols, a single exposure to psychedelic compounds (ie, ayahuasca and psilocybin) may induce rapid and long-lasting emotional/behavioral effects that are relevant to the treatment of major depression

Of course, you might point out that the idea that antidepressants might have a “surgical signature” is hardly new, given what we’ve known for almost a century about the efficacy and response pattern seen with electroconvulsive therapy (ECT). To which I would say, “Yes, exactly”.

In fact, the observation that antidepressants with a “surgical signature” are not new points to another feature common to many of the new treatments for depression that are on the near horizon: many of these treatments will build upon what might be called “ancient practices and associations.” And so, in that way they will not be new at all—unless we buy into the dictum that “everything old is new again”.

This will be the topic for the next installment of this blog. 

REFERENCES

1. Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review. Biol Psychiatry. 2013;73(12):1156-1163.

2. Hanusch KU, Janssen CH, Billheimer D, Jenkins I, Spurgeon E, Lowry CA, Raison CL. Whole-body hyperthermia for the treatment of major depression: associations with thermoregulatory cooling. Am J Psychiatry. 2013;170(7):802-804.

3. Ibrahim L, Diazgranados N, Franco-Chaves J, et al. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology. 2012;37(6):1526-1533.

4.MacLean KA, Johnson MW, Griffiths RR. Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol. 2011;25(11):1453-1461.

5. Nagele P, Duma A, Kopec M, et al. . Nitrous oxide for treatment-resistant major depression: a proof-of-concept trial. Biol Psychiatry. 2015;78(1):10-18.

6. Osório Fde L, Sanches RF, Macedo LR, et al. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Rev Bras Psiquiatr. 2015;37(1):13-20

7. Romeo B, Choucha W, Fossati P, Rotge JY. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Res. 2015;1230(2):682-628.

Charles L. Raison, MD, is Mike and Mary Sue Endowed Chair in Mind, Body, and Family Well-being Professor; School of Human Ecology Professor, Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin, Madison. He is also the behavioral health expert for CNN.com, and he is a Psych Congress Steering Committee member.

The views expressed on this blog are solely those of the blog post author and do not necessarily reflect the views of Psych Congress Network or other Psych Congress Network authors.