Stephen M. Stahl, M.D., Ph.D.
|Selective serotonin reuptake inhibitors
(SSRIs) got this name from their greater selectivity
(10-fold or more) for blocking serotonin reuptake rather
than norepinephrine reuptake.1 They also lack
the sodium channel blocking properties of the tricyclic
antidepressants, making them safe in overdose. In
addition, SSRIs have less affinity for alpha1-receptors,
muscarinic cholinergic receptors, and histamine-1
receptors compared with the tricyclic antidepressants,
leading to the greater tolerability profile of SSRIs.2
Now that the fifth SSRI, citalopram,3 is being introduced into clinical practice in the United States (following fluoxetine, sertraline, paroxetine, and fluvoxamine), it may be useful to remember that these drugs are not just clones of each other. Most of the past decade's clinical literature emphasizes the similarities among these agents, including comparable overall efficacy in depression and, in most cases, obsessive-compulsive disorder and panic disorder.1,2 After a decade of use, however, it is clear to physicians who prescribe these drugs that all SSRIs are not created equal, even though they all have the inalienable property of potent serotonin reuptake inhibition. The uniqueness of different SSRIs is most evident in the dramatic differences that individual patients can demonstrate in their clinical responses as well as side effects from one SSRI to another. These distinctions are obscured by clinical investigations that emphasize the similar mean responses that large groups of individuals have to every SSRI. Until recently, there has been no scientific hypothesis to explain why various patient subtypes might respond differently to one versus another individual agent within this therapeutic class. Since the 5 SSRIs have unique individual pharmacologic profiles of secondary binding properties (see table), it is possible that these secondary properties are responsible for the clinically detectable distinctions, especially at higher doses (for details, see references 4 through 7).
There are at least 10 such secondary properties as potent or within 1 order of magnitude of serotonin reuptake potency (see figure), and the list grows as new receptors and enzymes are better clarified. Thus, at least 1 of the 5 SSRIs has potent enough activity at the following receptors and enzymes to create potentially clinically meaningful consequences: (1) norepinephrine reuptake, (2) dopamine reuptake, (3) serotonin-2C receptors, (4) muscarinic cholinergic receptors, (5) sigma receptors, (6) nitric oxide synthase, (7) cytochrome P450 2D6, (8) cytochrome P450 3A4, (9) cytochrome P450 1A2, and (10) cytochrome P450 2Cl9. No 2 SSRIs are identical, but sorting out which pharmacologic properties explain which clinical observation is just beginning.4-7 The relevance of differences in the P450 enzymes has been much debated, often generating more heat than light. Differences in binding to various neurotransmitter receptors are now generating hypotheses to explain differences in tolerability in anxious patients, in cognitive effects, in anticholinergic effects, and many others. If the role of these ancillary pharmacologic actions can be understood, it may be possible to find individualized applications for each of the not-so-selective serotonin reuptake inhibitors. u
1. Feighner JP, Boyer WF. Selective Serotonin Reuptake Inhibitors. Chichester, England: John Wiley & Sons; 1996
2. Stahl SM. Essential Psychopharmacology. New York, NY: Cambridge University Press; 1996
3. Milne RJ, Goa KL. Citalopram: a review of its pharmacokinetic potential in depressive illness. Drugs 1991;41:450-479
4. Bolden-Watson C, Richelson E. Blockade by newly developed antidepressants of biologic amine uptake into rat brain synaptosomes. Life Sci 1993;52:1023-1029
5. Hyttel J. Comparative pharmacology of selective serotonin reuptake inhibitors. Nord J Psychiatry 1993;47(suppl 30):5-20
6. Norita N, Hashimoto K, Tomitaka S, et al. Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brains. Eur J Pharmacol 1996;307:117-119
7. Palvimake EP, Roth BL, Majasuo H, et al. Interactions of selective serotonin reuptake inhibitors with the serotonin 2C receptor. Psychopharmacology (Berl) 1996;126:234-240
Brainstorms aims to provide updates of novel concepts emerging from the neurosciences that have relevance to practitioners.
From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego.