Is Esketamine Safe and Effective for Treating Depression?

What you need to know

Esketamine’s effectiveness in treating depression is uncertain, with only one out of six short-term trials showing a statistically significant improvement over placebo.
The approval process for esketamine has been criticized for lowering the usual standards required for new drugs.
There are concerns about esketamine’s safety, including potential bladder problems and the risk of suicidal thoughts or behaviors.
The distinction between withdrawal symptoms and relapse of depression is unclear in esketamine studies, which may affect the interpretation of its long-term effectiveness.

Understanding Esketamine and Its Approval Process

Esketamine is a nasal spray derived from ketamine, a drug primarily used as an anesthetic. It has been proposed as a treatment for depression, particularly for people who haven’t responded well to other antidepressants. However, the journey of esketamine from clinical trials to approval has raised several questions and concerns among researchers and healthcare professionals.

Clinical Trials: A Closer Look

The effectiveness of a new drug is typically established through clinical trials. For esketamine, six short-term trials (each lasting 4 weeks) were conducted. Surprisingly, only one of these trials showed a statistically significant difference between esketamine (combined with an antidepressant) and a placebo nasal spray (also combined with an antidepressant).

Even in this single “positive” trial, the improvement in depression scores was modest. The difference between the esketamine and placebo groups was 4 points on a depression rating scale. This difference is smaller than what the drug’s manufacturer, Janssen, had initially estimated would be needed to show a meaningful effect (they had predicted a 6.5-point difference).

It’s also worth noting that the placebo group in this study showed a large improvement (15.8 points), possibly due to the extra attention and care participants received during the trial. This large placebo effect makes it harder to determine how much of the improvement was due to esketamine itself.

The FDA Approval Process: Lowering the Bar?

Typically, the Food and Drug Administration (FDA) requires two short-term studies showing a drug’s effectiveness before approving it. However, in the case of esketamine, this standard appears to have been relaxed.

Initially, the FDA agreed that one of the two required positive studies could be a “withdrawal study” (where the drug is stopped to see if symptoms return), as long as the other study showed “statistically very persuasive results.” Later, this requirement was further relaxed to allow “any short-term study” as the second piece of evidence.

This departure from the usual standards has led many experts, including the authors of this paper, to question whether the evidence for esketamine’s effectiveness is truly sufficient.

Safety Concerns: A Balanced View

While the potential benefits of a new treatment are important, we must also carefully consider its risks. Several safety concerns have been raised about esketamine:

Suicidal Thoughts and Behaviors

In the long-term safety study of esketamine, about one in seven patients developed new suicidal thoughts during treatment. This is particularly concerning because the study excluded people who were actively suicidal at the start.

It’s important to note that people with severe depression may already be at higher risk of suicide, making it challenging to determine if esketamine increases this risk. However, the emergence of suicidal thoughts in people who weren’t actively suicidal before treatment is a red flag that warrants further investigation.

Bladder Problems

Ketamine, the parent compound of esketamine, is known to potentially cause bladder problems with long-term use. In the long-term safety study of esketamine, about 17% of patients (136 out of 802) showed symptoms that resembled these ketamine-related bladder issues.

While many of these symptoms were reported as mild and temporary, a significant portion (33%) were not minor, and nearly a quarter of cases hadn’t resolved by the end of the study. The FDA has noted that serious bladder conditions may have been missed or misidentified in these studies.

Withdrawal Effects

Ketamine can cause tolerance, dependence, and withdrawal symptoms. The doses of esketamine used in the studies were similar to recreational doses of ketamine, raising concerns about potential withdrawal effects.

In the long-term safety study, several symptoms were reported when people stopped using esketamine. These included loss of appetite, anxiety, depression, insomnia, fatigue, and difficulty concentrating. Many of these symptoms overlap with depression symptoms, making it challenging to distinguish between withdrawal effects and a return of depression.

The Challenge of Interpreting Long-Term Effects

One of the key challenges in evaluating esketamine’s effectiveness is distinguishing between three possible scenarios when a person’s depression symptoms worsen after stopping the drug:

Withdrawal effects: Temporary symptoms caused by the body adjusting to the absence of the drug.
Relapse: A genuine return of depression symptoms.
Drug-induced changes: Long-lasting changes in brain function caused by the drug that persist after it’s stopped.

The main study used to support esketamine’s long-term effectiveness was a “discontinuation” trial. In this type of study, people who respond well to the drug initially are randomly assigned to either continue the drug or switch to a placebo. The problem is that if they get worse after switching to placebo, it’s not clear if this is due to withdrawal effects or a true relapse of depression.

This uncertainty is crucial because treatment-resistant depression (the condition esketamine is approved to treat) typically requires long-term treatment. If we can’t be sure about the drug’s long-term effects or the nature of symptoms that occur when it’s stopped, it’s difficult to make informed decisions about its use.

The “High” and Its Implications

Ketamine, like some other anesthetics, can cause a pleasurable “high” in some users. It also tends to reduce depression scores within hours of use. This rapid effect is often cited as one of esketamine’s advantages.

However, this raises an important question: How can we distinguish between a drug-induced mood lift and a true antidepressant effect? Some argue that the persistence of the effect marks it as a genuine antidepressant action. But as we’ve seen, the evidence for esketamine’s lasting effect is not robust.

This “high” also complicates the interpretation of clinical trial results. If participants can tell whether they’re receiving the active drug or a placebo based on whether they feel a mood lift, it could bias their reported outcomes.

Conclusions

The evidence for esketamine’s effectiveness in treating depression is limited, with most short-term trials failing to show a significant benefit over placebo.
There are significant concerns about esketamine’s safety, including the risk of bladder problems and the potential for suicidal thoughts or behaviors.
The distinction between withdrawal effects and relapse when stopping esketamine is unclear, making it difficult to interpret its long-term effectiveness.
More research is needed to fully understand the benefits and risks of esketamine, particularly in long-term use for treatment-resistant depression.

While esketamine may offer hope for some people with difficult-to-treat depression, the current evidence suggests that its benefits and risks need to be carefully weighed. Patients and healthcare providers should have open discussions about the uncertainties surrounding this treatment. As with any medical decision, it’s important to consider all available options and make informed choices based on the best available evidence.