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Ketamine: Old Drug, New Tricks

An NMDA antagonist treads where no psychiatric drug has before.

Source: Lesterman/Shutterstock

Ketamine has been used as an anesthetic for 50 years, and for decades the clinicians prescribing it have noticed sudden, appreciable anti-suicide and antidepressant effects in their patients. Case reports of desperate suicidal depression relieved within half an hour were discussed in the waning years of the 20th century, but actual research papers with small trials have only started trickling in within the last two decades.

Even after all this time, the research done thus far has not led to ketamine being mainstream FDA-approved as standard therapy for depression or suicidal ideation. For one thing, the kind of ketamine used in the US for most of the last 50 years is an IV drip requiring nursing and vital sign monitoring. In my neck of the woods, IV ketamine treatment is $3,000 (not covered by insurance or Medicare), usually completed in six treatments over two weeks. Not exactly within reach for many of my patients with resistant depression (who tend to decline in socioeconomic status over time).

In the case studies, folks’ depression rather notoriously rebounded back from ketamine therapy and then became resistant, though that didn’t happen to everyone. But how could we study how effective ketamine is? It’s generic, so there’s no pharmaceutical company with the millions to blow on state-of-the-art, beautiful randomized controlled trials to bring before the FDA. The patient population for ketamine is also a difficult one. Suicidal folks and depressed people with illness resistant to standard therapy or meds are more likely to give a drug company an expensive and public failure rather than profit, no matter that this is a population desperately in need of new ideas and new thinking. However, new formulations and the slow grind of publicly funded studies means new life for this elderly drug.

Before we talk about how ketamine works, let’s talk about how mental illness arises in terms of the actual pathology in the brain. (Note: This will necessarily be an oversimplification.) In short, most mental illness develops at the intersection of too much emotional or physical stress and genetic vulnerability leading to limitations in efficient brain functioning. This happens when brain becomes overwhelmed with excitatory signals: too much stress, too much activation of the fight-or-flight nervous system leading to specific over-activation of certain brain areas (like the left prefrontal cortex, the hippocampus, or the amygdala) without compensatory time or resources for recovery and repair.

The emotional and physical stressors could be, for example, a death in the family, extended work stress, viral illness that affects the brain, medications that affect the brain, or traumatic brain injury. The genetic vulnerability could be an increased inefficiency in being able to make specific neurotransmitters or brain fertilizers that help in recovery and repair, or an increased genetic ability to send excitatory ions through cell membranes, or many more complex issues we haven’t yet figured out.

Under this theory, almost any intervention could decrease symptoms of mental illness if it increases general neuron recovery and repair—or the efficiency of neurotransmitter use in the recovery and repair pathway—or reduces neurotoxic activation of the excitatory pathway (or “excitotoxicity"). Interventions such as regular exercise, meditation, psychotherapy, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, lithium, magnesium, anti-seizure meds and many other treatment paradigms can be at least partially effective to decrease symptoms. Keep in mind, sometimes the disease is a tank, and the spear in your arsenal (regular exercise, for example) is never going to be enough to take out that tank. Sometimes you need anti-tank missiles (such as low dose antipsychotics for severe resistant depression).

Ketamine is, among many other things, an NMDA receptor antagonist (though even this characterization is complicated). This means that ketamine blocks the action at the NMDA receptor, normally turned on by the major excitatory neurotransmitter in the nervous system, glutamate. NMDA receptor over-activation is ground zero for excitotoxiticy, kind of like a gas pedal that is stuck in the downward position. So far, though, not a single FDA-approved psychiatric medication in general practice specifically unsticks that gas pedal. But ketamine does. (So will, to a much lesser extent, magnesium* and the supplement NAC, which decreases glutamate concentrations). This gas pedal unsticking is how ketamine can seemingly do the impossible: take a dangerously suicidal patient and make them feel much, much better in less than an hour.

Wikimedia Commons
Source: Wikimedia Commons

In 2016, a new formulation of ketamine, esketamine, was granted FDA “breakthrough therapy” designation for major depressive disorder with imminent risk of suicide. It’s a nasal spray used in Europe for anesthesia, but never used in the US before. It has three to four times the affinity for the NMDA receptor as ketamine and fewer intolerable side effects (such as hallucinations, dissociation, and dangerous fluctuations of vital signs). A phase two study of esketamine was published in April 2018, a randomized controlled trial of suicidal depressed patients. They agreed to be monitored on an inpatient unit for five days after the first administration of the medicine, followed by twice-a-week administration for four weeks in addition to standard antidepressant treatment. To empathize how ill the population in this study was, three (placebo) patients out of 68 made suicide attempts during the follow up period, and half needed additional suicide precautions during their inpatient stay (usually decreased time between nursing checks which is, at the low end, every 15 minutes on a standard inpatient unit). Esketamine results separated from those of placebo treatment by four hours and at 24 hours, with rapid relief from suicidal thoughts and depressive symptoms, but there seemed to be no difference with esketamine and placebo at 25 days.

This study seems to support the old case study observations, that ketamine can be amazingly helpful short term, but is not really a long-term intervention. But it’s hard to tell, and we need more data. No one really knows why there’s such a rapid ketamine poop-out, but from a clinical perspective, who cares? A fast intervention that decreases suicidal ideation could save lives while our other, proof-tested, slower interventions take their time to work. This could also shorten inpatient hospital stays for depression, freeing up precious resources and getting people back to their families, work, and communities. While the use in observed settings such as inpatient units and emergency rooms is likely to accelerate, we need way more-real world data before we start prescribing nasal spray in outpatient treatment, especially for dangerously suicidal patients.

Ketamine studies have also opened the doors for other NMDA receptor antagonist interventions. Some drugs in development include new formulations of dextromethorphan and rapastinel. Given that psychiatric drugs have been endless renditions of the same tricyclic antidepressants, SSRIs, dopamine blockers, and dopamine partial agonists for decades, we could use a new approach.

And remember, there are plenty of ways to unstick that gas pedal early in the game, with proper self care and healthy living. Modern life, in America at least, doesn’t much incentivize vacation or sleep, both of which help that recovery and repair cycle. As a psychiatrist I’ll use whatever evidence-based intervention I can at any stage to treat the patient where he or she is to make them start getting better in the moment. As a health writer I can suggest eating a (mostly) home-cooked whole foods diet, avoiding a lot of alcohol and smoking, and getting enough physical movement, rest, and recharging time. In the brain, it’s all about reducing that excitotoxicity. In life, it’s all about a clear head, good energy, and serenity.

*Magnesium is also felt to work, in some respects, by antagonizing NMDA receptors

Copyright Emily Deans MD