In Search of a Better Treatment for Depression

In depression this faith in deliverance, in ultimate restoration, is absent. The pain is unrelenting, and what makes the condition intolerable is the foreknowledge that no remedy will come—not in a day, an hour, a month, or a minute. If there is mild relief, one knows that it is only temporary; more pain will follow. It is hopelessness even more than pain that crushes the soul
— William Styron, Darkness Visible: A Memoir of Madness

There are over 300 million people living with depression in the world, and depression is ranked by the WHO as the single largest contributor to global disability [1]. The total estimated number of people living with depression increased by 18.4% between 2005 and 2015 [1].

Despite these alarming statistics, our biological understanding of depression and our ability to treat it remains woefully inadequate. 50% of patients do not respond to current first-line antidepressant treatments and 30% of patients do not respond to any treatment [2,3]. Even for the subset of patients who do respond to antidepressants, the first-line antidepressants require four to eight weeks to start taking an effect. This time delay is inadequate for many patients and leaves much to be desired. The last major breakthrough in the treatment of depression was the introduction of Prozac in 1987— over three decades ago! There is a grave need for new treatments that might help an acutely depressed or suicidal patient.

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Recently, a new drug represents a potential solution to this need—ketamine. Ketamine is classically used at high doses as a general anesthetic, but it is also used recreationally at lower doses to create a dissociative effect. Ketamine’s antidepressive effects were discovered serendipitously, and notably it starts working immediately. A single administration of ketamine elicits antidepressant effects both in humans and animal models in as little as half an hour.[4] In an effort to capitalize on this discovery, Johnson & Johnson pushed esketamine (a ketamine derived nasal-spray) through clinical trials to treat depression. On March 5, 2019, the FDA approved esketamine. Esketamine is a dirty drug—it has addictive and hallucinatory side-effects.[5] Yet, despite the excitement of a major breakthrough in depression treatment, we still have very little sense for how ketamine acts on the brain to mitigate depression.

Dr. Hailan Hu and her colleagues try to shed light on this missing mechanism in their recent paper in Nature. The authors examine a part of the brain known as the lateral habenula which has been associated with negative emotion. Specifically, the lateral habenula inhibits the brain’s reward centers. This makes the lateral habenula a great candidate to be involved in depression. The authors make the claim that ketamine’s rapid antidepressant effects are due to the drug’s ability to block neuronal activity in the lateral habenula.

They tested their hypothesis via several elegant experiments. First, they asked if the antidepressive effects of ketamine were mediated by the lateral habenula alone. In order to demonstrate this the authors used congenitally learned helpless (cLH) rats which model several aspects of depression—they give up swimming quickly in a forced swim test and they ignore rewards during a sucrose preference test. The authors delivered ketamine to only the lateral habenula on both sides of the brain in cLH rats via a small cannula (rather than delivering it to the entire brain, as in an injection). They found that this localized delivery of the drug was sufficient to reduce depressive signs in rats.

To further the hypothesis the authors examined the lateral habenula in a separate mouse model of depression. These mice, known as chronic restraint stress mice, show classical signs of depression after being placed into 50ml conical tubes for 14 days. The authors discovered that the lateral habenula was significantly more active in these mouse models of depression than in regular wild type mice. This was due to an increase in ‘bursting’ activity in that brain structure. Notability, when these mice were given ketamine, the depression-associated bursting in the lateral habenula was significantly reduced. In order to probe at this mechanism on the molecular level, the authors then proceeded to examine the how ketamine specifically affected bursting. In their experiments the authors found that bursting required two ion-channels known as NMDA receptors and low-voltage-sensitive T-type calcium channels (T-VSCCs). Ketamine is a NMDA receptor blocker and thus is able to inhibit the lateral habenula bursting associated with depression.

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Crucially, to support their idea that bursting the lateral habenula was responsible for depression, Yang et. al, use a sophisticated genetic technique to build a neuronal switch, allowing them to turn neuronal activity on in this area. They found that if they flipped the genetic switch and made the lateral habenula more active then mice would become more depressed. Notability, when they pre-treated the mice with ketamine, flipping the switch in the lateral habenula had no noticeable effect on depressive behaviors.

Overall, the authors’ work demonstrates an elegant mechanism by which overactivity in the lateral habenula excessively inhibits reward centers in depressed animals. Ketamine induces its rapid antidepressant effect by inhibiting overactivity in the lateral habenula. This new basic science understanding of a mechanistic pathway associated with depression raises hopes that not only will ketamine-derived drugs help large patient populations with treatment resistant depression, but also raises hopes for development ketamine-like drugs that do not have the negative addictive and hallucinatory side-effects of esketamine.



References

1. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization; 2017.
2. Garcia-Toro, Mauro et al. “Treatment patterns in major depressive disorder after an inadequate response to first-line antidepressant treatment” BMC psychiatry vol. 12 143. 18 Sep. 2012, doi:10.1186/1471- 244X-12-143
3. Al-Harbi, Khalid Saad. “Treatment-resistant depression: therapeutic trends, challenges, and future directions” Patient preference and adherence vol. 6 (2012): 369-88.
4. Yang, Yan et al. “Ketamine Blocks Bursting in the Lateral Habenula to Rapidly Relieve Depression.” Nature 554.7692 (2018): 317–322.
5. "FDA Approves New Nasal Spray Medication For Treatment-Resistant Depression; Available Only At A Certified Doctor’s Office Or Clinic". fda.gov, 5 March 2019, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm.