Depression as Disease & the Case for Ketamine
While I am not one who regularly makes public statements, recent events — including the deaths of Kate Spade and Anthony Bourdain and a CDC report showing significant increases in suicide nationwide — compel me to do so. I also write with some apprehension, as data have shown that media attention to celebrity suicide can actually increase suicide rates in the following months. But this is just too important to ignore:
We have a national epidemic of suicide and of undiagnosed mental health conditions, and neither of those is going to change until we fundamentally change how we view and treat mental illness.
First, we must accept that depression is a disease of the brain and body. It’s not a weakness of mind, character, or faith. While researchers are identifying some of the genes implicated in mental illness, we still know so little about how the brain works compared to other organs, that our understanding of depression is primitive at best. It is a disease whose etiology and pathogenesis is not within our current grasp. In 2016, Surgeon General Vivek Murthy released a report that unequivocally stated that addiction is a chronic brain disease, not a moral failing, and his successor Jerome Adams continues that fight in light of our nation’s opioid epidemic. I call upon Dr. Adams, the Department of Health and Human Services, and the CDC to do the same for depression.
Second, we must realize that depression is not just sadness or feeling down; rather, it is a terminal illness — no different than Alzheimer’s, congestive heart failure, or cancer — but it doesn’t have to be. Just as immunotherapeutics are ushering in a new era of cancer care, so too are new treatments emerging for depression and, specifically, suicidality. Until recent years, there have been two medications used in the treatment of suicidal thoughts: lithium and clozapine, the former for bipolar disorder and the latter for treatment-resistant schizophrenia. Both of these medications must be monitored extremely closely for safety (eg, clozapine can cause both life-threatening neutropenia and constipation — yes, constipation so severe that it can be fatal) requiring frequent doctor’s visits and blood tests, and their side effect profiles are such that most patients are reluctant to even try them. Because of these concerns, these medications are likely underutilized in our treatment of mental illness.
In recent years, a new choice is gaining popularity with both doctors and patients. Ketamine, an anesthetic agent, used at low doses has emerged as a rapid and often life-changing treatment for depression, anxiety, and suicidality. Small studies (and substantial clinical experience) have shown that ketamine treatments improve mood and anxiety after a short initiation phase of treatment, and some studies have suggested that even a single ketamine dose can resolve acute suicidality. Ketamine blocks NMDA receptors, where the chemical glutamate acts as a modulator of neurostimulation. However, this change alone does not account for why ketamine works for depression and suicidal thoughts. So how does it work? The short answer is that we don’t really know. Most likely, these glutamic changes cause a downstream chain of events involving AMPAR (another glutamate receptor), voltage-dependent calcium channels, and the release of brain-derived neurotrophic factor. [Update July 7: A more recent study suggests that ketamine aids in activating messenger G-proteins by pushing them off of lipid rafts in cell membranes.] Like much of the brain, the details are still unclear, but it works, and for some people it could be the difference between life and death.
Ketamine can be given via a variety of routes of administration: oral, sublingual, nasal, intramuscular (IM), and intravenous (IV), and the route chosen can significantly affect its bioavailability, or how much of the drug actually makes it into the bloodstream and thus can take its indented effect. By definition, the bioavailability of IV treatment is 100%. Ketamine’s oral and sublingual bioavailabilities are as low as 16 and 30%, respectively, and that of intranasal ketamine can be extremely variable, ranging from 8 to 50% depending on the study. But there is more to ketamine’s effectiveness than just how much ends up in your blood, as evidenced by IM injections (90% bioavailable) and fast IV pushes of the medication (not to mention those abusing high doses of ketamine recreationally). In these cases of rapid administration, patients may experience significant dissociative and hallucinogenic effects but not necessarily the desired lasting antidepressive effect. While yet another unknown, there is something about the slow, intravenous infusion of ketamine that leads to the best treatment of depression, and thus low-dose infusions lasting about 40 minutes each are the gold standard in ketamine treatment.
Ketamine is generally well-tolerated and has a long track record of use in much higher doses for anesthesia. In fact, it is the anesthetic of choice in many ER’s, developing countries, and field hospitals because it lacks the significant respiratory suppression of other common anesthetics; as such, the World Health Organization has made it part of its Essential Medicines List for decades. However, like every medication, ketamine does have risks, including tachycardia and hypertension, and thus is not an option for all patients. [Update August 29: A recent Stanford study suggests that the mu-opioid receptor is likely involved in ketamine’s antidepressant effect — perhaps further highlighting its addictive potential.] Studies looking at the chronic recreational abuse of ketamine have identified bladder dysfunction and memory deficits in these abusers, but it is unknown if this translates to the repeated, low-dose use in the treatment of depression. While the long-term side effects are unclear, those potential unknowns must be weighed against the very real morbidity and mortality of depression and suicide.
Ketamine treatments must become more available for patients, and insurance coverage can play a significant role in this. I practice in an area where many patients can afford the facility and staffing costs associated with IV ketamine infusions without the use of their insurance, but that is not the case for all Americans. Health insurance companies need to include coverage for IV ketamine to do their part in providing this treatment to patients who need it to save their lives, just as they provide coverage for stents, surgery, and chemotherapy. At least one pharmaceutical company is pursuing FDA approval (and subsequent insurance coverage) for an intranasal ketamine formulation, but intravenous coverage is essential.
It is within our reach to make an impact in the nearly 45,000 American lives lost each year to suicide. The only question that remains is if we as a society will take this disease seriously enough to do so.
M Rameen Ghorieshi, MD, MPH is a psychiatrist, addiction medicine specialist, Adjunct Clinical Assistant Professor at the Stanford University School of Medicine, and the founder of Ketamine.MD, a clinical and advocacy organization for the advancement of novel treatments for mental illness.
