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Antidepressants: Does Mechanism Matter?
Published on The Carlat Psychiatry Report
(http://thecarlatreport.com)
Antidepressants: Does Mechanism Matter?
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While it’s certainly interesting to theorize about neurotransmitters and antidepressants, the recent
STAR*D findings bring up a difficult topic: Does mechanism matter?
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.
Relative Potencies of Antidepressants for Blocking Reuptake
of 5-HT vs. NE
Medication 5HT potency:
NE potency (Ratios)
Duloxetine 20
Venlafaxine 120*
Clomipramine 130
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Antidepressants: Does Mechanism Matter?
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Fluoxetine 290
Paroxetine 320
Fluvoxamine 560
Sertraline 1400
Citalopram 3600
Figures are 1/Ki, where Ki is the inhibition constant.
Adapted from J Clin Psychiatry 2003;64 (suppl 13):5-12.
*Applies to doses up to 200 mg QD; at higher doses, relative NE potency increases.
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;rendertype=figure&id=f1). Unfortunately, they’ve been much less successful at
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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.
Some Neurotransmitter Receptors Relevant for Antidepressants
Receptor
What it does when
stimulated Clinical relevance
5-HT1A Presynaptic autoreceptor; it
inhibits 5-HT release via
negative feedback loop. Also is
present postsynaptically.
May contribute to delayed AD
response; pindolol is a 1A
antagonist, and may speed up
SRI onset; buspirone is 1A
partial agonist, stimulating or
inhibiting 5-HT release as
needed
5-HT2A
and 2C
Many actions throughout
brain, especially the cortex
Stimulation may cause side
effects of agitation, apathy,
sexual dysfunction; Remeron’s
AD effect may be due to
blocking both of these
receptors; Serzone
(nefazodone) blocks 2A, so no
sexual dysfunction
5-HT3 Causes nausea SRI side effect
5-HT4 Causes diarrhea SRI side effect
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Antidepressants: Does Mechanism Matter?
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Alpha-2 Stimulated by NE; acts to inhibit
release of both 5-HT and NE
Remeron blocks
alpha-2receptors, promoting
5-HT and NE release and
leading to AD effect
TCPR Verdict: Antidepressant mechanisms: It’s still mostly theoretical
Antidepressants
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