Novel Drug Therapies Could Tackle Treatment-Resistant Depression


Depression affects more than 264 million people of all ages globally. The World Health Organization ranks depression as one of the most debilitating diseases to society. It is the leading cause of disability worldwide and the psychiatric diagnosis most commonly associated with suicide, which accounts for nearly 800,000 deaths globally each year. Individuals suffering from depression may face an inability to manage life’s demands and maintain social connections, affecting all aspects of their experiences, from school and employment to relationships and overall quality of life.

When it comes to treatment, approximately one third of those suffering from depression do not respond to two or more antidepressants and are considered treatment-resistant. Treatment-resistant depression is a chronic condition that places an increased emotional, functional and economic burden on the individual, their loved ones and society. It is also associated with greater morbidity, higher health care costs and various comorbid conditions.

While a number of antidepressants exist, they all work through changing the levels of brain-signaling molecules called monoaminergic neurotransmitters. New drug development for depression had stalled for a number of years, and many pharmaceutical companies have withdrawn from neuroscience entirely. But recent scientific advances have led to the development of novel antidepressants working via completely different mechanisms.

The brain is the most advanced, adaptive information processing system in existence—in large part because of its tremendous plasticity. Scientists have been building upon these neuroscience advances to develop completely novel, rapid-acting antidepressants. In this regard, considerable evidence has demonstrated that the regulation of two receptors—AMPA and NMDA—on many neurons that respond to the neurotransmitter glutamate control changes in the tiny junctions, or synapses, between neurons. Think of this synaptic plasticity as the mechanism by which the strength of information flow in these tiny gaps among brain cells is manipulated. Based on this research, scientists have demonstrated that blocking NMDA receptors on inhibitory neurons, thereby facilitating a burst of glutamate release, can exert rapid antidepressant effects in treatment-resistant depression. Indeed, this discovery led to the U.S. Food and Drug Administration and European Medicines Agency to approve esketamine, an NMDA antagonist for treatment-resistant depression, in 2019. (Esketamine is related chemically to ketamine, the anesthetic and psychedelic.) Agency approvals open up the possibility of developing the next generation of treatments in this class. Although at the very low doses used for treatment, esketamine is quite selective, it does target all NMDA receptors. It may be that some NMDA receptors are more responsible for its therapeutic antidepressant effects, whereas others may be more responsible for some side effects. Thus, the next generation of certain drugs that are NMDA antagonists may maintain efficacy while reducing some side effects.

Also in 2019 the FDA approved intravenous allopregnanolone as a first-in-class medication for the treatment of postpartum depression. Allopregnanolone is a neuroactive steroid, structurally similar to progesterone, that acts on GABA receptors and is believed to improve symptoms of depression and anxiety by amplifying GABAergic signaling throughout the brain. Zuranolone, an oral formulation of allopregnanolone, is currently being trialed more widely for treatment-resistant depression.

Psychedelics, such as psilocybin, also have a role to play. In a landmark exploratory trial published in the New England Journal of Medicine earlier this year, psilocybin was compared with the widely used antidepressant escitalopram. Although not powered to detect a difference between the drugs, a number of positive findings—levels of response and remission of symptoms—were more common in psilocybin-treated individuals. This has sparked renewed interest in psychedelic therapies as another avenue of drug discovery. Other novel approaches are also in the drug development pipeline, and each of them could add important new medications to treat this debilitating condition. The Orexin system regulates neuronal limbic circuits implicated in depression, and trials of Orexin 2 receptor antagonists are well underway. There is emerging evidence that neuroimmune factors may play a role, not only in neurodegenerative disorders but also in depression. Microglia are the resident immune cells in the brain, and efforts investigating P2x7 antagonists (which regulate microglial function) are underway. Finally scientists are exploring innovative ways to increase the levels of the body’s own cannabinoids (rather than administering cannabis or other external sources of cannabinoids ) as novel antidepressants.

Despite advances, unmet needs still exist in the mental health space, including ones related to tailoring specific treatments to specific patients, adequately treating the cognitive symptoms of schizophrenia, ensuring durable relapse prevention and persistence of efficacy for most conditions, and achieving better functional (not just symptomatic) outcomes.

It is these gaps in treatment that spur industry, academia and governments to continue research in depression with discovery and development of new and more effective treatments for people who still continue to experience symptoms and do not fully recover with existing treatments.

This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of Scientific American.


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