This piece is part of in-Training Mental Health Week.
Within the next three years, ketamine, the popular club drug referred to as “Special K,” may replace the current generation of antidepressant drugs. By substantially reducing the latency of antidepressant effect, the use of ketamine as an antidepressant may hold promise and is in fact in Phase 3 trials for FDA approval. But, how does ketamine work to alleviate depressive symptoms, and how does this approach fit with our current understanding of depression? Do we currently understand depression?
While many scientists contend that depression is a brain disease due to a neurochemical imbalance, there are others that argue that depression may be rooted in problems with neural plasticity. Yet, some believe that depression and elation are a matter of choice. Regardless of where depression comes from, the reality is that in addition to the challenges faced by depressed patients and their families, the economic cost of depression in America evaluated through suicide, absenteeism from work, and direct treatment costs is 210.5 billion dollars annually. Treatments consist mostly of psychotherapy and antidepressant drugs, which possess low efficacy rates, challenging our current understanding of depression. The origins of depression, as well as the effectiveness of our current pharmacological approach is highly contested by physicians and scientists alike, and our current pharmacological approaches work in only up to 50 percent of patients, even after a treatment switch.
According to a lecture given by Professor of Psychology Joshua Gulley at the University of Illinois at Urbana-Champaign in April 2015, there are currently three major hypotheses about the origin of depression. The first is the monoamine depletion hypothesis, which is supported by the effectiveness of the current first-line antidepressant, selective serotonin reuptake inhibitors (SSRIs). This theory suggests that reduced production or function of any one or more of the brain’s monoamines (serotonin, dopamine, and norepinephrine) could underlie depressive symptoms. It is supported by the evidence that antidepressant drugs elevate monoamine levels, especially serotonin.
The second major hypothesis of depression is the glucocorticoid hypothesis, which relates hypothalamus-pituitary-adrenal axis dysfunction to the onset of depressive symptoms. It is believed that patients have an overactive hormonal response to stress due to problems with negative feedback regulation, and subsequently, elevated cortisol levels which could be aversive.
Lastly, the third hypothesis is the neurotrophic hypothesis, which suggests that neurotrophic factors, proteins that promote cell survival and growth, may be in low levels. Specifically, brain-derived neurotrophic factor (BDNF) is believed to have a major role in depression.
The above hypotheses operate under the assumption that depression is a brain disease, caused by an imbalance of neurochemicals that antidepressant drugs are designed to alleviate or manage. But, even this notion is highly debated, as there have been a number of recent meta-analytic studies questioning the clinical usefulness of antidepressants.
In fact, on the basis of these results, a prominent scientist in the field, Irving Kirsch, PhD, wrote a novel elaborating on the involvement of the FDA on the “conspiracy” of antidepressants. His book, titled “The Emperor’s New Drugs: Exploding the Antidepressant Myth,” asserts the claim that alternative therapies, such as exercise and psychotherapy, may in fact be a better treatment choice for depression, and has triggered significant media attention and support. Kirsch discusses data that suggests that relief from depressive symptoms in placebo-controlled antidepressant studies originate from a powerful placebo effect, rather than a significant active mechanism of the drug. The studies he conducted and cites illustrate only a 25 percent improvement with antidepressant drugs over placebo, regardless of the drug used, furthering the speculation on the actual efficacy of these drugs.
However, the hypothesis that Dr. Kirsch presents to challenge the “depression as a brain disease” idea contains assumptions that may be problematic. Dr. Kirsch contends that because some patients experience relief from symptoms after switching from one SSRI to another, there must be a powerful placebo effect underlying the patient’s remission, because the mechanism of action of the drug must be identical between SSRIs. In fact, different SSRIs have different off-target low-affinity effects, and do not necessarily cause the same perturbation in the brain. Furthermore, Dr. Kirsch’s book also discusses how drugs like the SSRIs that affect serotonergic tone, and drugs like bupropion that affect norepinephrine and dopamine levels have different mechanisms of action, but the same efficacy rate over placebo. He cites this as evidence that the monoamine depletion hypothesis is incorrect because these drugs affect different systems but still produce the same low efficacy rate; however, this finding could in fact support this hypothesis. While the direct effect of these drugs is on different systems, the monoaminergic regions of the brain are highly interconnected and have profound effects on one another. It is possible that these drugs produce similar or related effects on the brain that are not entirely independent, as the book suggests.
While Dr. Kirsch and others hold the claim that antidepressant drugs are not working, and that depression may not be a brain disease, there are other experimentalists who offer other explanations to the low SSRI efficacy rate. Dr. Pierre Blier, MD, PhD, offers a theory that involves considering the monoamine-producing regions of the brain (the dorsal raphe nucleus, the ventral tegmental area, and the locus coeruleus) as a network of interacting regions that adapt to antidepressant drugs by regulating their receptor sensitivities. His group suggests that the elevation of brain serotonin levels in response to SSRIs may be inhibiting the other monoaminergic regions, and depleting dopamine and norepinephrine levels as a result. This down-regulation of the other two monoaminergic regions may be involved in the lack of antidepressant efficacy, as elevated serotonin with depleted dopamine and norepinephrine levels may not bring relief in the majority of those who use SSRIs.
It has been shown that initial depression severity does not play a significant role in determining how well a patient will respond to SSRIs, and it is unclear what causes some to be responsive to their effects and not others. However, it has been reported that depression afflicts 16.6 percent of Americans at some point in their lifetimes, and can increase the risk of acute myocardial infarction three-fold compared to the general community. It is a problem that we do not have an adequate solution to treating depression, perhaps because of a lack of understanding of its origins. While neurochemical hypotheses were discussed in detail here, there are many other hypotheses about depression, including a role of neuro-inflammation. Perhaps research into ketamine’s effect on depressed patients will provide some insight. Still, there is no doubt that mental illness, especially depression, carries a stigma that is difficult to challenge without an adequate understanding of where it comes from. As a disease that lacks robust diagnostic criteria due to the heterogeneity of patient symptoms and responsiveness to interventions, depression requires further research into its derivation in order to ultimately produce more effective and timely interventions.
Bridging the Gap focuses on the relationship between basic research and medicine to develop an appreciation for the science that underlies the foundations of modern medicine