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Antidepressants: Does Mechanism Matter? Published on The Carlat Psychiatry Report (http://thecarlatreport.com) Antidepressants: Does Mechanism Matter? Not Featured 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 copyright ゥ 2009 Clearview Publishing, LLC The Carlat Psychiatry Report, All Rights Reserved Page 1 of 4

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Page 1: Antidepressants: Does Mechanism Matter?...Antidepressants: Does Mechanism Matter? Published on The Carlat Psychiatry Report () Fluoxetine 290 Paroxetine 320 Fluvoxamine 560

Antidepressants: Does Mechanism Matter?

Published on The Carlat Psychiatry Report

(http://thecarlatreport.com)

Antidepressants: Does Mechanism Matter?

Not Featured

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

copyright © 2009 Clearview Publishing, LLC

The Carlat Psychiatry Report, All Rights Reserved

Page 1 of 4

Page 2: Antidepressants: Does Mechanism Matter?...Antidepressants: Does Mechanism Matter? Published on The Carlat Psychiatry Report () Fluoxetine 290 Paroxetine 320 Fluvoxamine 560

Antidepressants: Does Mechanism Matter?

Published on The Carlat Psychiatry Report

(http://thecarlatreport.com)

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

copyright © 2009 Clearview Publishing, LLC

The Carlat Psychiatry Report, All Rights Reserved

Page 2 of 4

Page 3: Antidepressants: Does Mechanism Matter?...Antidepressants: Does Mechanism Matter? Published on The Carlat Psychiatry Report () Fluoxetine 290 Paroxetine 320 Fluvoxamine 560

Antidepressants: Does Mechanism Matter?

Published on The Carlat Psychiatry Report

(http://thecarlatreport.com)

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

     

copyright © 2009 Clearview Publishing, LLC

The Carlat Psychiatry Report, All Rights Reserved

Page 3 of 4

Page 4: Antidepressants: Does Mechanism Matter?...Antidepressants: Does Mechanism Matter? Published on The Carlat Psychiatry Report () Fluoxetine 290 Paroxetine 320 Fluvoxamine 560

Antidepressants: Does Mechanism Matter?

Published on The Carlat Psychiatry Report

(http://thecarlatreport.com)

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

Source URL: http://thecarlatreport.com/article/antidepressants-does-mechanism-matter

copyright © 2009 Clearview Publishing, LLC

The Carlat Psychiatry Report, All Rights Reserved

Page 4 of 4