Esketamine, the first new method to treat depression in 25 years, is
gaining credibility. Last year, Janssen Pharmaceutical’s ketaminebased
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

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

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

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

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.

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