What's All the Fuss About Special K?

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The United States Food and Drug Administration (FDA) recently approved esketamine for patients struggling with treatment resistant depression. This approval comes just days after scientists revealed they have potentially cured a second person infected with the human immunodeficiency virus (HIV), a revolutionary discovery that could also offer hope for millions around the world. It has undoubtedly been a huge week for medicine.

Esketamine is a chemical constituent of ketamine, a drug used traditionally as a mild anesthetic that is thought to produce dissociative effects, a sense of calm, as well as feelings of euphoria. Esketamine, marketed under the brand Spravato by the Janssen Pharmaceutical Companies of Johnson & Johnson, will be offered to patients who have failed standard of care treatments for depression. Evidence also supports that estekamine could rapidly reverse suicidal thoughts within a matter of hours (Canuso, 2018).

This is great news not only for mental health, but for public health in general. But how is esketamine different from other approved treatments for depression? The Prozac revolution of the late 80s and early 90s saw a popularization of the notion that depression is in large part influenced by a chemical imbalance in the brain. Integrative psychiatry approaches that this view is an oversimplification and that a number of factors aside from brain chemistry are implicated in depression. However, most antidepressants utilized today, which do help many patients, focus on targeting monoamines, chemicals in the brain like serotonin, dopamine, and norepinephrine that are thought to influence our feelings and our mood.

Monoamines are found naturally in the brain and the antidepressant effect offered by many of the drugs we prescribe are produced by a host of routine life experiences: dopamine, for instance is released from the nucleus accumbens and is a part of our natural reward system. The monoamine hypothesis offers that people with major depressive disorder may notice an improvement in depressive symptoms when these specific neurotransmitters are targeted.

Esketamine, however, focuses on a different pathway. Imaging studies have suggested that chronic stress (as often seen in depression) may lead to a loss in density of critical areas of the brain implicated in mood regulation. Esketamine is thought to rapidly reverse this dilemma by allowing the brain to compensate so that these important chemicals involved in mood can function and communicate with other brain regions more efficiently. When looking at ketamine, instead of focusing on monoamines, neurotransmitters glutamate and GABA are front and center. The idea is that ketamine can indirectly increase GABA (implicated in relaxation) and lower glutamate by blocking a receptor in the brain called NMDA. What does all of this mean? Well, evidence supports that esketamine could produce a rapid reversal of depressive symptoms within hours and hopefully last days to weeks with repeated dosing.

While all of this is encouraging, esketamine's FDA approval is not without controversy. Several studies, including one published recently in the American Journal of Psychiatry, suggested that any positive effect gained from esketamine was short-lived and essentially wore off by day 25 (Canuso, 2018). An observed reduction in suicidal thoughts, however, was sustained 4 hours after dosing, which is important considering the time between suicidal ideation and attempt is usually short as Canuso and colleagues point out (Canuso, 2018).

Before we all jump on the ketamine bandwagon, it is important to realize that the drug does not come without risks. Acute hypertension, hallucinations, and abuse potential are very real concerns. To mitigate these risks, the FDA has recommended that patients remain in their physician’s office for two hours after receiving treatment and that they abstain from driving the day they receive esketamine. Furthermore, Spravato is not to be taken at home to mitigate potential for abuse. Ketamine is commonly abused at raves where is it known on the streets as Special K.

What's the bottom line?

It is widely acknowledged that antidepressants take about 4-6 weeks before they work, which is an awfully long time to wait considering how devastating depression can be. As an integrative psychiatrist, I believe that simply prescribing an antidepressant and doing nothing else is not offering patients the best possible option for sustained recovery. Targeting community engagement, mind-body therapies (like yoga and meditation), and focusing on nutritional interventions are approaches we can discuss with our patients. However, some patients do present with significant functional impairment and depression that is so severe that more aggressive interventions may be warranted. Electroconvlusive therapy (ECT) and transcranial magnetic stimulation (TMS) are options for these patients for a more rapid response, however, the effects are not nearly as rapid as what is being reported with ketamine. So, ketamine could offer a possible and temporary bridge for struggling patients while more long-term treatments are pursued. Also, considering the potential for esketamine to rapidly reverse suicidal thoughts, it could possibly reduce the number of inpatient psychiatric hospitalizations for patients who present to the emergency room with imminent safety concerns.

The truth is that even though the FDA has approved esketamine, there is still a lot we do not know and we still have a lot to learn about the drug’s safety and effectiveness. Time will tell if this new treatment will be utilized broadly. However, I am encouraged that we are looking into new ways to help patients who are suffering. This is good news for us all.