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The Importance of Receptor Profiles of Antidepressants
Question:
“I often treat depression with antidepressants. Why is knowledge about receptors and receptor profiles of the medications I choose important? Is it really important, or is it just interesting stuff, without any clinical value?”
Good question! We clinicians are knowledge driven, but even more so, we are practically oriented. Knowledge for the sake of serving our patients even better is what we thirst after. That is where our heart is. Therefore, your question resonates loud and clear with me. What about receptors is important to us ? And even more importantly, what about receptor differences amongst medications is of importance to our patients?
In psychiatry, knowledge regarding receptors has played a fairly central role in our understanding of psychiatric illnesses, as well as the treatments we offer our patients. Medications that we offer our patients, at least in part, work on their brains as a result of them attaching to the various receptors in the patient’s brain and body, and thereafter affecting changes that are therapeutic. On the flip side, when receptors we do not wish to stimulate are inadvertently stimulated, side effects are thought to occur.
In psychotic disorders, knowledge regarding receptor profiles of antipsychotics has been well characterized. In mood disorders, we are only just beginning to fully appreciate this issue. Every known U.S. Food and Drug Administration-approved antipsychotic, in one way or another, acts on the D2 receptors. 1-4 This highlights the amazing importance of knowledge regarding receptors for both drug discovery, as well as clinical utility in everyday practice. The potency of an antipsychotic can be easily understood by knowing its potency on the D2 receptor. Similarly, side effects can be anticipated with a full knowledge regarding an antipsychotic’s entire receptor profile. Do you see my point? We can truly understand the complexities of a medication much better by understanding its affinity for various receptors, and what it does to the receptor. Is it an agonist, a partial agonist, an antagonist, etc?
Also interesting is this fact: many of the known side effects of the D2 receptor is thought to be because of “accidental” modulation of receptors we are not targeting on purpose (we can colloquially call these “nuisance” receptors). This could include weight gain, sedation, etc. that occur as a result of inadvertent receptor stimulation (in this case, histamine and mucarinergic receptors) of some medications. 5-7 You can now clearly see, using the example of D2 medications, that knowledge regarding a particular medication’s receptor profile can inform us of both therapeutic benefit as well as potential adverse side effects. This is a very good thing; it’s not perfect science, and one has to appreciate the limits of what receptors tell us. Nevertheless, increased knowledge of such issues can only aid us in offered targeted, better-tolerated medications to better fit an individual patient’s needs.
As I mentioned earlier, our knowledge base regarding antidepressants somewhat lags behind antipsychotics, but progress in this area is being rapidly made. For example, classification of antidepressants is mostly (but not always) based on their receptor profile. A medication that predominantly affects the receptors at the serotonin reuptake pump site is labeled as a selective serotonin reuptake inhibitor (SSRI), and a medication that does the same thing to both serotonin and norepinephrine receptors gets labeled as a serotonin-norepinephrine reuptake inhibitor (SNRI). This is not true for all classes of antidepressants, of course. Tricyclics are called tricyclic antidepressants (TCAs) only because of their chemical structure and not their receptor profiles. Though, we often subclassify TCAs into various categories that are defined by receptor profiles, eg, dual reuptake versus predominantly noradrenergic. Even with TCAs, our understanding of specific antidepressants relies heavily on their receptor profile. Many classes of antidepressants are labeled and identified according to their receptor profiles. Examples include norepinephrine-dopamine reuptake inhibitors (NDRIs), serotonin antagonist and reuptake inhibitors (SARIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and a newly emergent class – SSRI and 5HT1A partial agonist. 8 More antidepressants with rich and specific receptor profiles are in development. 9-12
These receptor differences among antidepressants do tell us some information about efficacy, but they are far more useful in predicting potential side effects. For example, knowing the histamine H1 binding potency or the muscarinergic M1 binding potency might educate us about the potential for weight gain or sedation. Also, certain receptors are thought to perhaps add an extra dimension of specific clinical help in efficacy, and recent attention has focused on the serotonin 5HT1A receptor partial agonism, serotonin 5HT7 antagonism, among others. 13-15 This science of predicting benefits based on a drug’s receptor profile is still quite nascent, but it is growing rapidly. I encourage you to keep your eyes on the burgeoning literature in this field. 16-17
Drug discovery is, in part, heavily based on receptor targeting. It also influences our clinical decision-making - to some degree in regards to efficacy, but to a very significant degree in predicting both short- and long-term side effects of a medication. Therefore, enhanced knowledge regarding an antidepressant’s receptor profile can be useful knowledge for any clinician.
References
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8. Citrome L. Vilazodone for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antidepressant - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. Jan 29 2012.
9. Hughes ZA, Starr KR, Langmead CJ, et al. Neurochemical evaluation of the novel 5-HT1A receptor partial agonist/serotonin reuptake inhibitor, vilazodone. Eur J Pharmacol. 2005;510(1-2):49-57.
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11. Segi-Nishida E. Exploration of new molecular mechanisms for antidepressant actions of electroconvulsive seizure. Biol Pharm Bull. 2011;34(7):939-944.
12. Young SN. Possible directions for the discovery of new antidepressant treatments. J Psychiatry Neurosci. 2011;36(1):3-5.
13. Renner U, Zeug A, Woehler A, et al. Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. J Cell Sci. Feb 22 2012.
14. Vasefi MS, Kruk JS, Liu H, Heikkila JJ, Beazely MA. Activation of 5-HT7 receptors increases neuronal platelet-derived growth factor beta receptor expression. Neurosci Lett. 2012;511(2):65-69.
15. Tokarski K, Kusek M, Hess G. 5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area. J Physiol Pharmacol. 2011;62(5):535-540.
16. Mnie-Filali O, Faure C, Lambas-Senas L, et al. Pharmacological blockade of 5-HT7 receptors as a putative fast acting antidepressant strategy. Neuropsychopharmacology. 2011;36(6):1275-1288.
17. Dickson EJ, Heredia DJ, Smith TK. Critical role of 5-HT1A, 5-HT3, and 5-HT7 receptor subtypes in the initiation, generation, and propagation of the murine colonic migrating motor complex. Am J Physiol Gastrointest Liver Physiol. 2010;299(1):G144-157.
