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Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future: Page 4 of 5

Antidepressants, Part 2: Kinetics, Dynamics, Mechanisms of Action, and the Future: Page 4 of 5

John J. Miller, MDJohn J. Miller, MD
Suggested variables included in an analysis before making a treatment decisionTable 1 – Suggested variables to be included in an analysis before mak...
Important pharmacokinetic properties to consider about any medicationsTable 2 – Important pharmacokinetic properties to consider about any m...
Important pharmacodynamic properties to consider about any medicationTable 3 – Important pharmacodynamicproperties to consider about any me...
The various elements of the serotonin systemTable 4 – The various elements of the serotonin system

A comprehensive review summarized much of the science related to the impact of epigenetic changes on depression, and how these epigenetic modifications appear to be reversed with current antidepressant treatments. This ongoing research provides a glimpse into the evolving understanding of the relationship between epigenetics and depression.2 Epigenetic modifications that affect levels of brain-derived neurotrophic factor (BDNF) and the glucocorticoid receptor have been most studied. When the brains of individuals who had a history of childhood abuse and committed suicide were examined, variations in the degree of methylation of the promoter sequence of the glucocorticoid receptor were discovered. Several studies demonstrated a decrease in DNA methylation (which would increase gene transcription) associated with an increase in BDNF in individuals treated with various antidepressants.2

An important paradigm shift occurred when drug development moved from a focus on blocking serotonin reuptake pumps to targeting specific serotonin receptors. Arguably, blocking a serotonin reuptake pump is a very crude way to modulate the serotonin system. The result is a global increase in synaptic serotonin, which results in the agonism of all 7 serotonin receptor families and their associated subreceptors.

Post-synaptic serotonin receptors can execute their message on many different neuronal types. Post-synaptic serotonin receptor modulation may ultimately result in changes in concentration of a different neurotransmitter in a different part of the brain. Downstream effects of serotonin receptor activity may increase or decrease synaptic levels of serotonin, dopamine, norepinephrine, acetylcholine, glutamate, and GABA. In addition, serotonin receptors can regulate prolactin, oxytocin, cortisol, and substance P, just to name a few.

When you extrapolate the complexity of the serotonin system to all neurotransmitters that may affect depression, an infinite possibility of drug targets exists. This is very good news for the future of drug development to treat depression—thus far, we have only scraped the surface of potential mechanisms of action.

Looking to the future: opioids, magic mushrooms, and Special K

Research on novel antidepressant molecules that function outside of the monoamine hypothesis of depression has been somewhat of a roller coaster over the past 3 decades. Initially promising drug classes such as neuropeptide Y modulators, substance P analogs, corticotropin-releasing hormone (AKA factor) receptor antagonists, and metabotropic glutamate receptor agonists (especially subtypes 2 and 3) ultimately failed as treatment options. One continued frustration and clinical limitation of our current antidepressants that follow the monoamine mechanism is that it can take from 2 to 8 weeks to achieve an adequate antidepressant effect. It appears that a common denominator of the delayed antidepressant response correlates with increasing levels of BDNF as the depression lifts. This increase in BDNF is associated with increased synaptogenesis in the brain’s hippocampus—a crucial gateway connecting memories and emotions—which may often be atrophied in cases of chronic depression and chronic stress. When the depression has resolved, the hippocampus increases in size.

The recent excitement about ketamine is that it has been shown to have immediate antidepressant effects, which correlate with increasing brain levels of BDNF.3 Ketamine is a racemic mixture of S-ketamine (esketamine) and R-ketamine (arketamine), and both molecules are antagonists at the glutamate NMDA ion channel. Esketamine is 3 to 4 times more potent than arketamine. Arketamine appears to have a greater antidepressant effect than esketamine. Ketamine continues to be aggressively studied as a possible “next-generation” antidepressant, and the racemate esketamine delivered intranasally is likely to be the first formulation to apply for FDA approval.

Both esketamine and arketamine are metabolized to hydroxynorketamine, which activates the glutamate AMPA ion channel. Increasing AMPA glutamate ionotropic receptors may produce an antidepressant effect, and with no dissociative adverse effects and no abuse potential. This metabolite has no activity on the NMDA glutamate ion channel and may be responsible for the increase in BDNF.4 The discovery in 2016 that hydroxynorketamine has antidepressant efficacy in mice (likely related to increased BDNF), without the abuse potential or dissociative adverse effects of ketamine, may provide a new avenue for drug development.

The clinical use of ketamine for the treatment of refractory depression is still considered experimental, and much remains to be learned about optimal dosing, delivery mechanisms, short- and long-term adverse effects, and duration and frequency of treatment.

Another class of drugs with a resurgence of interest for the treatment of refractory depression is the hallucinogens. Psilocybin, LSD, and mescaline are all serotonin analogs that have significant agonism at the 5HT-2A receptor. Most of the recent studies in refractory depression have involved psilocybin.


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