Patrick D. Hahn

The Baltimore Sun

This month, the FDA approved Janssen’s new drug Spravato, or esketamine in nasal spray form, for “treatment-resistant” depression. A Washington Post headline declared it the “biggest advance for depression in years.”

A quick explanation is in order here. Many drugs come in two molecular forms, called optical isomers, which are mirror-images of each other. Often, only one of the two isomers is active. Esketamine is one of the two isomers of the club drug ketamine, known colloquially as “Special K.” Separating this isomer and dispensing it in pure form enables Janssen to patent a drug that has already been available for decades, and to market it at premium prices.

All this raises some questions.

A large and growing body of evidence indicates that most of the benefits of these drugs called “antidepressants” are due to the placebo effect. When we say a person is “resistant” to “treatments” that may be barely distinguishable from sugar pills, have we really said anything at all? Nevertheless, let’s take a look at the evidence that led the FDA to approve Spravato.

Normally, before a drug can be approved, the FDA requires the manufacturer to submit the results of two trials showing that the drug performed significantly better than placebo. That sounds pretty good, until you realize that there can be any number of trials that do not show a significant effect. That’s like you and I betting on the outcome of a coin toss, with this stipulation: I get to toss the coin as many times I wish until it comes up the way I want it to.

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Another point to keep in mind is that when a scientist talks about a “significant” difference, all that means is the difference is unlikely to have arisen by chance. The difference can be tiny, as long as the probability of it arising by chance is below some arbitrarily selected level – usually 5 percent.

In the case of Spravato, a single four-week placebo-controlled trial showed a 4-point improvement on the 60-point Montgomery-sberg Rating Scale for Depression. While this met the criteria for statistical significance, a 4-point difference is likely too paltry to be noticeable in a face-to-face assessment of global functioning by a trained clinician.

The results of the two other placebo-controlled trials of Spravato were negative. The only way to satisfy the FDA requirement for two positive trials was to count the results of a relapse study, which essentially showed that patients who did well on the drug, did well on the drug.

The recommended course of treatment for this drug, which is to be administered only in a doctor’s office, is twice-weekly for one month, followed by weekly or biweekly treatments thereafter. It comes with a price tag of $4,720 to $6,785 for the first month of treatment and $2,360 to $3,450 per month thereafter, which means the cost of a year’s treatment could be as high as $44,735. This is the same stuff (admittedly in purer form) that you can buy in a nightclub bathroom for a good deal less.

Disturbingly, there were three suicides in the trials, all in the treatment arm. This finding becomes even more ominous in light of the fact that actively suicidal patients were excluded from these trials.

By the way, Janssen is no stranger to controversy. On Nov. 4, 2013, the United States Department of Justice announced that Janssen’s parent corporation, Johnson and Johnson, agreed to pay $2.2 billion to settle claims of illegal marketing of its products, including allegations that Janssen had illegally marketed the antipsychotic drug Risperdal for children.

Three years ago, a jury awarded a young boy $70 million after Risperdal caused him to grow breasts. What will the long-term effects be of Janssen’s latest miracle drug? We don’t know, but if this is the “biggest advance for depression in years,” maybe it is time to consider the possibility that this is not the sort of problem amenable to chemical solutions.

— Patrick D. Hahn is an affiliate professor of biology at Loyola University Maryland and a freelance writer.