More Than Just A Trip: Why Does Ketamine Work For Depression When Nothing Else Does?

Illustration: Elena Scotti (Photos: Getty Images)

Even though depression is a common and debilitating mental illness, the last groundbreaking medication released for it was Prozac, approved in 1987. Throughout the last 20 years, though, research scientists have discovered that ketamine, a common anesthetic and, at times, a recreational drug, is a rapid and effective medication for treatment-resistant depression. As we’re learning deeper about why, we turn specifically to its dissociative effects for clues.

“In my experience, patients who have high positive regard for the hallucinogenic—mystical and transcendental—experience also tend to have better antidepressant response to ketamine infusion,” Mark Niciu, assistant professor of psychiatry at the University of Iowa and one of the main authors of a 2015 study that found a correlation between ketamine and dissociation, told Gizmodo. Ketamine’s effectiveness, Niciu claimed, can depend on the patient’s mindset. There are several factors to continue investigating, which may yield treatment for a large population of patients for whom nothing has worked so far.

In 2000, Robert Berman and his colleagues at Yale ran a small study testing the effectiveness of ketamine in patients with treatment-resistant depression. They discovered that the ketamine significantly reduced their patients’ depressive symptoms, according to a widely accepted questionnaire, the Hamilton Depression Rating Scale. Until this study, ketamine was known in a few different ways. It is an anesthetic and non-opioid painkiller that was released in the late 1960s and is often used in emergency rooms. The more adventurous among us might know ketamine as Special K, a rave drug often snorted that causes euphoria, hyper energy, hallucinations, and dissociation—an experience where the user is unaware of time, their body, or surroundings.

Because of its reputation as a club drug, ketamine carries a large stigma, even though its recreational use involves much higher doses than what’s used to treat depression. Larger amounts of ketamine can result in more unpleasant side effects, such as muscle spasms, dizziness, loss of balance, slurred speech, and nausea, along with hallucinations or dissociation.

Despite the lower doses used to treat depression, patients still experience dissociation, though the low dose leads to a more pleasant outcome for the patient. Some researchers have theorised that dissociation actually improves its effectiveness as an antidepressant. During ketamine-induced dissociation, patients feel disconnected from what’s going on around them. They also might have ethereal visions, feel warm and comforted, and might even claim to have seen relatives who have passed. Some doctors believe that these spiritual experiences help patients gain a new perspective.

Depression is a mental illness that is largely misunderstood. Those who suffer from depression experience a myriad of symptoms, many of which can be contradictory, such as apathy and restlessness, sleeping too much or too little, loss of appetite or overeating, anxiety, hopelessness, irritability, sadness, and trouble concentrating. Research scientists have discovered that depression is actually more of a combination of mental health disorders, and it is the umbrella label for them.

Currently, the gold standard treatment for depression is usually some form of psychotherapy and medications, including selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft, serotonin norepinephrine reuptake inhibitors (SNRIs), such as Cymbalta or Pristiq, or norepinephrine dopamine reuptake inhibitors (NDRIs), such as Wellbutrin. According to the National Institute of Mental Health, in a 2017 U.S. survey, 11 million Americans suffered from depression with severe impairment, and of those, one-third suffered from treatment-resistant depression.

Once all options of medication and therapy are exhausted, those with treatment-resistant depression have only a few options, including electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS). During ECT, doctors induce a small seizure in their anaesthetised patient in order to reset neurophysiologic and neurochemical processes in the brain. In rTMS, a magnetic coil is placed near the patient’s forehead and is designed to stimulate the regions of the brain that control mood. Though both of these treatments can be effective, they also have potential side effects. ECT can result in headaches, nausea and disorientation in the short term and memory loss and impaired cognition long-term. In rTMS, patients can experience headaches, scalp pain, and spasms in the facial muscles.

Most ketamine treatments occur in a specialised ketamine clinic. There are hundreds of these clinics throughout the United States. In order to prepare for the infusion, a nurse will establish an IV, as well as monitors to track heart, blood pressure, pulse oximetry, and respiratory rate. The doctor will administer a low dose, usually around 0.5 mg/kg. The ketamine treatment should be peaceful. Often, patients wear an eye mask and listen to relaxing music. A nurse is in the room throughout the treatment, especially since heart rate and blood pressure tend to increase as the ketamine takes effect. The treatment itself lasts approximately 40 minutes, and the patient is monitored for another 20 to 40 minutes after the infusion.

Many patients experience relief immediately, compared to traditional antidepressants, which can take several weeks or even several months to work. According to Sam Ko, a doctor who owns Reset Ketamine, a ketamine clinic in Palm Springs, California, not everyone experiences dissociation or an ethereal experience, but those who do typically have a positive encounter.

In the 2015 study from the National Institute of Mental Health, David Luckenbaugh and his associates ran a clinical trial that tested the correlation between a patient’s experience of dissociation and its antidepressant impact, if any. Researchers administered a low-dose, 40-minute IV infusion of ketamine to 108 treatment-resistant subjects with either depression or bipolar disorder, all of whom at the time had moderate or severe depression.

Traditionally, ketamine doctors give their patients a series of IV infusions, but to simplify results, Luckenbaugh and his team administered just one round of ketamine. Researchers also measured the subjects’ blood pressure and pulse throughout the infusion as a control measure, and to compare with patients’ dissociation. Their increased blood pressure and pulse did not correspond with an improved depression score. Using the Clinician Administered Dissociative States Scale and the Hamilton Depression Rating Scale, researchers discovered that after 40 minutes of treatment, patients reported a statistically significant correlation between a higher level of dissociation and improved symptoms of depression.

Because ketamine works so quickly and so distinctively, and has such different side effects than traditional antidepressants, ketamine research has led scientists to gain more insight into the root of depression in the brain. They generally acknowledge that they still have much to learn in explaining how and why ketamine works, but almost certainly they know that ketamine works in the glutamate system. In previous autopsies of people who have died by suicide, doctors found that they had higher levels of glutamate in their brains. N-methyl-D-asparate receptors, or NMDA, are in the glutamate system, and when glutamate levels in the brain get too high, the NMDA receptors are overstimulated, leading to depression, as well as several other disorders of the nervous system, such as Alzheimer’s and Parkinson’s disease.

Ketamine is considered an NMDA antagonist, which means it blocks glutamate, lowering the levels of glutamate and reducing depressive symptoms. Researchers are trying to figure out how exactly ketamine works, but in witnessing its effectiveness, research psychiatrists are learning a completely different way to treat resistant mood disorders such as depression. Niciu, one of the authors of the dissociation study, told Gizmodo that ketamine also improves symptoms of bipolar disorder, PTSD, obsessive compulsive disorder, social anxiety disorders, and addiction.

A brain of a person with depression often has weakened or broken synapses which contribute to their symptoms. These synapses are junctions between two nerve cells, and, when healthy and active, they contribute to good mental health. When someone is depressed, it causes chronic stress, and these synapses become less active. Scientists continue to find that ketamine actually strengthens the faulty synapses and can build new ones. Todd Gould is an associate professor of psychiatry at the University of Maryland School of Medicine, and he clarified how ketamine heals certain parts of the brain: “I’d use the term strengthening synapses. You can create new synapses as well. Stress and depression weaken synapses, and then ketamine strengthens those synapses.” The glutamate system is also responsible for the dissociative response, as it affects sections of the brain that provide learning and memory, emotion, and perception of pain. Their interconnectedness in the glutamate system could explain how dissociation could reduce a patient’s symptoms of depression.

While some researchers believe there is a link between dissociation and ketamine’s antidepressant impact, many others dispute this finding. In a 2011 study led by researchers at Yale University’s School of Medicine, the psychiatrists conducted proton imaging of subjects’ brains before, during and after ketamine treatments. Throughout the infusion, subjects filled out various rating scale forms to measure their level of depression, anxiety, and dissociation. Subjects only indicated dissociation 20 minutes after the IV infusion.

These researchers concluded that there was no correlation, since subjects still had antidepressant benefits, even after the disconnectedness subsided. Even those who did not feel detached benefited from ketamine’s antidepressant impact. Brandon Kitay, an assistant professor of psychiatry at Yale, told Gizmodo, “The fact that you have less of a dissociative experience, let’s say, over time, and can still have just as much efficacy, again speaks to me that it probably is not required for results.”

One aspect of ketamine treatment that can only be anecdotally measured is a patient’s transformation after treatment. Researchers at Boston Children’s Hospital and the Texas Tech Health Sciences Centre conducted a study in November 2019 that examined the impact of ketamine and dissociation in military combat veterans with PTSD, and they had surprising results. Doctors gave 30 veterans a series of six one-hour IV infusions. The specific goal of each infusion was to induce dissociation. For this study, researchers predicted that the dissociation under ketamine would offer the veterans a life-changing, transformative experience. Most veterans reported a remarkable change, where they had reduced symptoms of PTSD and established a reset of their negative thoughts and behaviours.

While neuroscientists continue to examine how ketamine works in the brain, front-line doctors often witness immeasurable results from ketamine, especially when patients experience dissociation. Ko describes the level of dissociation as more of a gradient than a yes or no answer. With each infusion, he tries to find the “sweet spot” where patients feel detached but are able to explain and remember the experience. Ko strongly believes that ketamine can be a catalyst for personal improvement. “So this includes things like, hey, I’m going to start going for a walk or I’m going to change my diet. I’m going to start engaging in more social activities.”

Ketamine can even be life-changing in the worst of cases, such as for people struggling with suicidal ideations. Researchers have speculated that the NMDA receptor is also tied up with suicidal thoughts and ketamine’s ability to block glutamate can significantly lessen the severity of these intrusive thoughts. The debate on the relationship between dissociation and antidepressant effects will continue, but the debate in itself has led to further research on how ketamine works so fully and so rapidly.

Even so, the current administration of ketamine precludes many sufferers from benefiting. Pure ketamine is still not approved by the FDA for depression, although a ketamine-like drug, called esketamine, has recently been approved and is available in certain markets. An IV infusion of ketamine requires close monitoring, and a patient must be available sometimes for a few hours per treatment. Many of the researchers in the field hope for more studies on medications that are glutamate blockers, which would serve as a more viable alternative to ketamine.

The inclusion or exclusion of the dissociative side effects in these future trials will all depend on ongoing research. One thing is for sure—future research will further expose how ketamine works, and as these discoveries are examined, new and less invasive medications could come to market and potentially improve the symptoms of those suffering from treatment-resistant depression. The difference could be life-altering.

If you or someone you know is having a crisis, please call Lifeline, Australia's national crisis support and suicide prevention hotline, on 13 11 14.

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