Hard Talk

Depression: a changing concept in the age of ketamine


What does it mean to define an amalgamation of symptoms as a “psychiatric disorder?” Are psychiatric disorders an extreme variation of normative human behavior? Is human behavior simply an output phenotype of some neurologic chemical processes that become disordered in mental illness? Can depression be localized in the brain and subsequently turned on or off? If depression were to be localized in the brain, would it be an excess of a neurotransmitter, the depletion of a receptor, a malfunctioning neuron, an overactive connectome, poorly processed genetic material, or something as yet undefined? Those questions always have been present in our minds and influenced our understanding of patients, but a recent development in psychiatry raises questions about one of the few things we were historically confident about.

Dr. Nicolas Badre

Dr. Nicolas Badre

A part of our foundational understanding of depression was that it is not sadness, per se. One can be sad for any amount of time. It is not uncommon to feel sad for any variety of reasons, such as watching an adorable 60-second commercial for dog food.1 Those fleeting moments of sadness can even be empowering; they remind us about the things we care about and would be sad to miss.

Sadness in oneself can demonstrate the experience of empathic sadness for others. On the contrary, depression appears to have little apparent purpose, and instead results in a maladaptive way of coping that is all-consuming and often very damaging. Depression is not a mood but a state of being, something that is not defined by how one feels but who one is or has become because of the disorder. So it comes as somewhat of a surprise when we heard that ketamine could alleviate depression in minutes.2,3 As described by a ketamine expert, symptoms are relieved in “no less than an hour.”4 The surprise is not so much that a treatment would work but that improvement could be defined in such a short time frame.

Psychiatry has debated the definition of depression for its entire existence. There are many ways to tackle the concept of depression. A lot of the debate has been about the causes of depression. One example of the continued evolution of our understanding of depression is our prior categorization of depression as “exogenous” or “endogenous.”5 Exogenous depression was described as happening in the context of social stressors and as best treated with therapy. Endogenous depression was a supposedly truer form of depression as a disorder and was more biologically based. Patients suffering from endogenous depression were thought to have chemical abnormalities in the brain that could be alleviated by tricyclic antidepressants and subsequently SSRIs. Like many prior debates about depression, this one appears to be little discussed nowadays. A review of the use of the term “endogenous depression” in books shows an onset in the 1930s, a peak in the 1980s, and a rapid decline since.6

More recently, psychiatrists have defined depression using the DSM-5 criteria. Depression is thought to be the presence of at least five out of nine symptoms listed in the manual for a period of 2 weeks that cause significant distress or impairment.7 The DSM attempts to address criticism by providing information on its limitations and best use, and encourages clinical interpretation of symptoms. The DSM does not portray itself as a gold standard but rather as a tool for treatment planning and effective communication between peers. Furthermore, the National Institute on Mental Health is promoting an alternative understanding of depression using its own Research Domain Criteria, which attempt to provide a more objective understanding of the disorder based on biological rather than subjective correlates.

Dr. David Lehman, associate professor of psychiatry, University of California, San Diego

Dr. David Lehman

The growing literature on ketamine partly hinges on the belief that depression is something that can be redefined and changed at any moment. Many trials ask patients whether their depression remains in remission in the subsequent hours, days, and weeks following administration of the drug. However, one wonders if that is even possible. If a patient’s depression is alleviated in an hour, was it really clinical depression? Is it truly in remission? Contrary to our previous understanding, is depression, in reality, a switch that can be turned off by an infusion of an N-methyl-D-aspartate (NMDA)–receptor antagonist? Without minimizing the suffering of patients seeking ketamine or the relief provided to patients who benefit from the treatment, we simply are pointing out that the definition of depression did not account for this reported phenomenon of relatively instantaneous relief. The seemingly miraculous effects of ketamine suggest a new paradigm where any intervention – whether chemical, social, or psychological – could turn off the devastating effects of depression in an instant.


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