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

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

John J. Miller, MDJohn J. Miller, MD
Figure
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

In one study, patients with treatment-resistant depression received 2 oral doses of psilocybin (10 mg and 25 mg in a supportive setting, 7 days apart). One week after they received the second dose, 67% of patients had an improvement in symptoms, and 58% maintained this response at 3 months.5 Although the data on psilocybin are in the early stages, and the current studies are open label, the findings are very intriguing.

The buprenorphine-samidorphan combination results in kappa-opioid antagonism. Buprenorphine is an antagonist/partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor (this is the putative antidepressant action of the combination drug). Samidorphan is an antagonist at the mu-opioid receptor, with tighter binding affinity than buprenorphine; hence, it prevents the mu-opioid analgesic effect of buprenorphine.

Rapastinel is being studied as an augmentation agent for treatment-resistant major depression. It received FDA fast-track status on March 3, 2014, and has a novel mechanism of action by selectively binding as an antagonist/partial agonist at an allosteric site on the glycine binding region of the NMDA glutamate receptor. Rapastinel is administered intravenously and is a rapidly acting drug that demonstrates antidepressant as well as cognitive-enhancing properties likely related to its activity as an antagonist/and partial agonist of the glycine binding site on the NMDA glutamate ion channel.

There has been increased interest in the role of inflammation in causing depression, exacerbating depression, and/or contributing to non-response in patients with treatment-resistant depression. Raison and colleagues6 looked at infliximab, a monoclonal antibody that inhibits the inflammatory cytokine tumor necrosis factor, in a cohort of 60 outpatients whose depression was moderately resistant to antidepressants. The subgroup of patients with elevated baseline levels of inflammatory biomarkers, including tumor necrosis factor and high-sensitivity C-reactive protein, demonstrated some improvement in their depressive symptoms compared with patients whose baseline levels of inflammatory biomarkers were not elevated.6

Conclusion: looking forward to the next 100 years

MDD is a common and often disabling mental illness that has plagued humanity since the existence of historical records. The past 100 years has been a time of impressive advances in medicine, neuropsychiatry, pharmacology, and our understanding of the circuitry of the brain.

The birth of the monoamine hypothesis of depression in the early 1960s revolutionized our understanding of, and ability to treat, depression. However, full remission from a major depressive episode is hard to achieve, and even obtaining a 50% response in patients with depressive symptoms can be challenging.

All of our FDA-approved antidepressants have mechanisms of action that are grounded in the monoamine hypothesis. Over the past several decades, there have been exciting breakthroughs of novel mechanisms of action—all too often followed by disappointment after extensive basic science research and early-phase clinical trials. However, we must always look to the future with optimism. We never know when a new molecule discovered by serendipity or an idea coalescing in the mind of some graduate student will bear the fruit of our next paradigm-changing antidepressant.

 

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