Depression is the number one cause of disability in the U.S. and, according to the World Health Organization (WHO), is ranked fourth in the world in terms of “disease burden.” Current practice standards for depression consist of the use of one or more medications from the five classes of antidepressants, with serotonin reuptake inhibitors (SSRIs) being the most common. Yet nearly half of these patients discontinue their treatment prematurely. The delayed onset of relief, lack of efficacy, adverse reactions, fear of becoming dependent, and the inability of clinicians to encourage or enforce adherence are the reasons most cited in the literature for discontinuation. As a result, the outcome for untreated or undertreated depression is dismal. The mortality rate for these people is over 15%.

Ketamine – Hope or Hype?

The surprising results of a several small clinical trials demonstrating the efficacy of low dose (sub-anesthetic) infused ketamine for depressed and suicidal persons has ushered in the most significant advance in antidepressant therapeutics in decades. These studies have demonstrated that low, sub-anesthetic doses of infused ketamine can produce total remission of depressive symptoms among treatment-resistant patients and acutely suicidal patients in less than 24 hours. The other important finding was significant alleviation of chronic pain, which frequently co-occurs with depression.

As a result, more clinicians are using ketamine for their patients who have not responded to traditional therapeutic modalities. However, the limitations of small studies using a convenience sampling of depressed and suicidal patients has predictably invoked healthy skepticism among scientists and clinicians. To address these concerns Cohen, et al (2017) employed a novel, Inverse-Frequency Analysis of eight million reports from the FDA’s Adverse Effect Reporting System.

The researchers found that the incidence of depression symptoms in patients who took ketamine for pain dropped by 50% (with an error margin less than 2%) compared to the patients who took any other drug or drug combination for pain. In addition, those patients who took ketamine for depression reported decreased pain and remediation of common opioid side effects, such as constipation and insomnia, when compared to patients who received other pain medications. The analysis also showed that other off-label drugs, when used for treating depression (Botox, Minocycline and Diclofenac), were also effective in symptom reduction. As I have previously noted, the 50-year-old catecholamine hypothesis may in fact be a secondary system of depression. The robust acute results from the limited data on ketamine suggest we are getting closer to the neurobiological mechanism and control of mood states.

Why Does This Matter?

Depression and chronic pain are among the most debilitating conditions facing our aging population. Nearly 50 million American adults have chronic or severe pain, and over 16 million adults experience a major depressive episode each year. (National Institutes of Health, 2015). The good news is: we now have a new target for antidepressant drug development. Research at Yale and elsewhere is focused on understanding how ketamine interacts and modulates NMDA receptors, its pharmacokinetics, its chirality and the effect of its active metabolites. The fact that we have stumbled upon an old party drug/effective in anesthesia, that, when properly dosed and delivered offer symptom reduction for severely depressed patients, is good news. It may turn out that ketamine derivatives are superior to any previous antidepressant medications. Further safety and efficacy studies are necessary and part of the FDA process. And…as an added bonus, when opioids failed to offer significant relief worth the risk for non-malignant pain, ketamine and similar drugs may offer hope here as well. But, we should remember that ketamine is the number one club drug of abuse in many countries in Asia and the toxic and other effects report a cautionary tale. Still, once approved by the FDA with clearly defined risks and benefits, ketamine may become the biggest medical breakthrough in decades.