While it’s certainly interesting to theorize about neurotransmitters and antidepressants, the recent STAR*D findings bring up a difficult topic: Does mechanism matter?

Recall that the main findings of the second step of STAR*D were that when patients were switched from Celexa to any of three antidepressants (ADs) with different mechanisms of action – Effexor (venlafaxine), Wellbutrin (bupropion), and Zoloft (sertraline) – there was no difference in response. And when they were randomly assigned to augmentation with either BuSpar or Wellbutrin, there was also no difference.

These results force us to take a second look at some long-cherished assumptions about differences among ADs.

SSRI and SNRI: Are they misnomers?
Common wisdom holds that SSRIs (selective serotonin reuptake inhibitors) and SNRIs (serotonin norepinephrine reuptake inhibitors) have different mechanisms of action. SSRIs act by blocking the serotonin reuptake pump (more technically referred to as the 5-HT transporter, or simply the 5-HTT), whereas SNRIs presumably block both 5-HTT and the norepinephrine transporter (NET). Blocking these transporters prevents the neuron from “vacuuming” up excess neurotransmitters, allowing more to remain in the synapse and stimulate postsynaptic receptors.

According to standard dogma, SNRIs (Effexor and Cymbalta) increase concentrations of both 5-HT and NE, potentially leading to some clinical advantages, although the extent of these advantages is hotly debated.

Unfortunately for this theory, it turns out that most “SSRIs” have a significant effect on NE as well, and the “SNRIs” behave much more like SSRIs than is appreciated.

The table below shows the ratios for each drug’s affinity for serotonin versus norepinephrine transporters.

All the numbers are greater than one, showing that all these medications are much more selective for 5-HT than for NE. Even Cymbalta (duloxetine), proclaimed the most “balanced” of SNRIs, is twenty times more effective at blocking serotonin reuptake than norepinephrine reuptake. The other “SNRI,” venlafaxine, hardly deserves the name, since it is 120 times more effective at increasing 5-HT than NE. The only ADs that are meaningfully balanced in 5-HT and NE reuptake are the tricyclics, suggesting that they are the ones that should really be labeled “SNRIs” (J Clin Psychiatry 2003;64 (suppl 13):5-12). Given these reuptake profiles, it seems more logical to call all these medications “SRIs,” or serotonin reuptake inhibitors, reflecting their primary mode of action (acknowledgments to my colleague John J. Miller, M.D., Medical Director, Center for Health and Well-Being, Exeter, New Hampshire, for help in working out these concepts.)

Of course, if your goal is to increase levels of all three monoamines (serotonin, norepinephrine, and dopamine), you should be prescribing MAOIs (monoamine oxidase inhibitors). MAOIs are not reuptake blockers at all; they increase neurotransmitter levels by inhibiting MAO, an enzyme that breaks down all three monoamines. Thus, MAOIs increase the levels of all three neurotransmitters thought crucial in depression, which may be why they are the only antidepressants generally agreed to have an efficacy advantage over others. (See APA’s latest practice guideline for major depression for references, available free at http://www.psych.org/psych_pract/treatg/pg/Depression2e.book.cfm.)

Serotonin receptors: What do we know?
Regardless of how we choose to categorize them, antidepressants do a good job of increasing levels of monoamines in the synapses. This raises questions about what these much-vaunted chemicals do that helps our patients’ moods.

The most exciting recent research has focused on 5-HT. There are currently about fifteen 5-HT receptors known. They are classified into seven main families (5-HT1 to 5-HT7) and broken down further into subtypes, each denoted by letters (5-HT2A, 5-HT2B, etc.)

These 5-HT receptors are located in different parts of the body – some in the brain and the spinal cord, but many more in the gut. In fact, more than 90% of all 5-HT receptors are found in the GI tract. Serotonin stimulates gut motility (we all know that SRIs can cause diarrhea), and the latest medication approved for irritable bowel syndrome, Zelnorm (tegaserod), treats constipation by stimulating the 5-HT4 receptor. Researchers are great at discovering, naming, and locating 5-HT receptors (see a schematic of receptor locations at http://www.pubmedcentral.gov/articlerender.fcgi?artid=1201318&rendertype=figure&id=f1). Unfortunately, they’ve been much less successful at figuring out how stimulating them might lead to an antidepressant response.

We do know that most of them do whatever it is they do via G proteins, those monstrous molecules that coil seven times across neuron cell membranes and change in shape when 5-HT receptors are stimulated. This change in shape leads to downstream chemical events involving ATP and phosphorylation. These “second messengers” then lead to the activation of certain genes and the production of various proteins.

One of the most intriguing findings of the STAR*D research helps us to understand the clinical relevance of one type of 5-HT receptor, 5-HT2A. Researchers sifted through the genes of about 2000 patients who had been given Celexa for depression, in an effort to see if there were any genetic markers predictive of antidepressant response. They found that patients who had a specific variant of the 5-HT2A receptor gene (the “AA” variant) were 16% more likely to respond to Celexa than patients with the “GG” variant. While this finding doesn’t tell us anything about how stimulating 5-HT2A relieves depression, it does suggest that this receptor subtype is involved in the antidepressant action of SSRIs.

The table below lists some other receptor subtypes that are relevant to antidepressants, along with information that might be useful in clinical practice.

TCPR Verdict:
Antidepressant mechanisms: It’s still mostly theoretical