Ketamine’s promise as an antidepressant is being undermined by its lack of profit

Esketamine has been approved for depression and suicidal ideation.
Esketamine has been approved for depression and suicidal ideation.
Image: AP/ Ariel Schalit
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Esketamine, the first new method to treat depression in 25 years, is gaining credibility. Last year, Janssen Pharmaceutical’s ketamine-based drug was approved by the US Food and Drug Administration (FDA) to treat patients with treatment-resistant depression. And on Aug. 3, the FDA followed up with a second approval, allowing doctors to prescribe the tranquilizing drug to patients experiencing suicidal ideation.

But though there’s growing evidence that Janssen’s drug can help those with depression, some psychiatrists question why ketamine, its better-known and cheaper cousin, isn’t being similarly developed.

Ketamine has long been approved in the US as an anaesthetic. That means that though it’s not approved to treat depression, patients can legally use it for this purpose if their doctor provides them with a prescription for so-called “off-label” use. And they do: Medical ketamine clinics have been treating patients in the United States since 2014, and there are now dozens of such clinics across the country.

Evidence to support this practice has been building since 2006, and the benefits are increasingly recognized by mainstream medical centers. “Regular ketamine is safe, available in multiple different formulations, has demonstrated efficacy in multiple small-scale studies for treatment-resistant depression, and is available for a fraction of the cost of esketamine because it’s been off patent for decades,” says Michael Alpert, a psychiatrist at Harvard Medical School.

Why isn’t ketamine an approved depression treatment, then? It comes down to profits. Ketamine’s patent expired in 2002, meaning that further studies into the drug would not bring any financial returns to the companies funding them.

Instead, corporations could benefit from adapting the drug to create a patentable compound. “Since Johnson & Johnson was unable to patent it, they simply isolated one of the components of regular ketamine, esketamine,” says Alpert.

Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, filed a patent for esketamine in 2013, and subsequently funded research on the drug. Their two published studies, which supported the drug’s FDA approval, display the unique attributes of ketamine-like drugs: Both found that depression symptoms reduced just 24 hours after receiving the first dose, and more than 40% of patients went into remission over the course of four weeks. This means esketamine can be used in an emergency situation, for example if someone is admitted to hospital with suicidal thoughts.

But those studies, while promising, are complicated by the placebo they used to compare to esketamine treatment. All participants received the standard of care for depression, including psychiatric hospitalization for five days, new or adjusted SSRI antidepressants, and regular clinic visits. Of those who received esketamine, 40% in both studies went into remission. But patients given placebo also did well: 34% went remission in one study, and 27% in the other.

Gerald Sanacora, psychiatrist at Yale University and co-author of the study, says this demonstrates the benefits of esketamine: “It is very telling that the esketamine treatment seemed to add an additional 10-14% on to these very favorable remission rates,” he says.

Others disagree. “To me this fact suggests that overall esketamine isn’t that great as an antidepressant, even if there is a small percentage of people who receive it for whom it does work,” says J. Wesley Boyd, a psychiatrist and professor at the Center for Bioethics at Harvard Medical School.

So far, the studies show that esketamine works well in combination with regular, effective care, meaning it’s difficult to parse the impact of esketamine versus the hospitalization and regular clinical visits. And they don’t answer the critical question of whether an existing generic drug would work just as well.

Alpert argues that all esketamine studies should compare the drug to ketamine, which is far cheaper and so more widely available. That would allow researchers to determine whether ketamine should be formally approved to treat depression.

It’s not just a question of managing patients’ costs, but their health outcomes. Following the approval of esketamine, some healthcare systems pressured patients to switch from ketamine to esketamine. But changing treatments can carry risks, says Alpert. If a patient is receiving good care and support from a ketamine clinic, then switching treatment plans could exacerbate symptoms of depression and suicidal ideation.

Several veterans suffered worsening depression after VA San Diego Healthcare System, which provides health care to veterans in southern California, abruptly prevented all patients from taking ketamine via IV and pushed them to take esketamine at a different clinic, according to an investigation published earlier this year by inewsource.

Though esketamine is currently approved as depression treatment while ketamine is not, the existing research on ketamine suggests the latter is effective in treating depression. Eventually, Boyd hopes ketamine will also be approved for this use, though no private company has yet stepped up to fund the necessary research and FDA application. Until then, esketamine is likely to remain controversial.