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Friday, 11 November 2011

Medications: How are SSRI Antidepressants Supposed to Work?

(This is part of a series of posts on the basics of psychopharmacology that I’m posting so that I can refer people back to it. Here is the first in the series.)

The SSRI antidepressants include medications such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

SSRI stands for Selective Serotonin Reuptake Inhibitor, which summarizes how the drugs are supposed to work. Let’s consider these terms:

Selective. Unlike some of the older antidepressants (such as the tricyclics like amitriptyline and clomipramine), SSRIs are intended to act on a single neurotransmitter system. They are, thus, selective in the system they act upon.

Serotonin. The specific neurotransmitter affected by SSRIs is serotonin.

Reuptake. Reuptake (discussed at greater length here) is essentially a recycling process. The sending neuron dumps neurotransmitter into the gap between it and the receiving neuron, then opens its own ports and takes some of the transmitter back for use next time. If there is a problem with the pathway, however (not enough neurotransmitter, for example, or too few receptors), reuptake runs the risk of preventing signal transmission.

Inhibitor. The action of an SSRI is to inhibit the reuptake process. It closes the gates to the reabsorption, or reuptake, of serotonin by the sending neuron. As a result, more serotonin is left in the gap, increasing the likelihood that enough will get across to the receiving neuron’s receptors that it will fire.

So an SSRI should make serotonin systems work better by keeping released transmitter in the gap, rather than prematurely depleting it through reuptake.

Note what an SSRI does NOT do, contrary to what some people might believe:

  • It doesn’t create more serotonin in the brain.
  • It doesn’t correct any flaw in the system.
  • It doesn’t produce more serotonin receptors.
  • It doesn't "rebalance" the neurotransmitters.
  • It does not treat the cause of the depression, whatever that might be.

The last point is important. No one believes that the root cause of depression is excessive reuptake in serotonin systems. A reuptake inhibitor might help, just as a brace might help a person with a bad knee to get around, but it does not correct any known cause of depression.

What is an SNRI?

An SNRI is a Serotonin and Norepinephrine Reuptake Inhibitor. In other words, it is thought to work much the same as the SSRIs. But rather than being selective, it does the same thing on both serotonin and norepinephrine systems.

The SNRIs include venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta), and others. Pristiq is a remarkably similar drug to Effexor, and was introduced to the market in 2008, shortly before the patent (hence profitability) of Effexor ran out. This may have been coincidental. Or not.

A variant of the monoamine hypothesis suggests that some depressed people may have a problem in serotonin-based systems, some might have more of an issue with norepinephrine-based systems, and some might have problems in both.

This notion has some appeal, because depression looks very different in different people. Some people are agitated, others look very slow-moving. Some sleep all the time, others have insomnia. Some can’t stop eating, others have no appetite. Maybe the differences have to do with different chemical problems in the brain.

The test of this idea is probably obvious. If an SSRI treats only one subgroup of depressed people, and an SNRI treats two subgroups, then SNRIs should be more effective overall.

Yes, but the data in depression treatment tends not to match the theories. There is relatively little evidence for the superiority of SNRIs over SSRIs. Response rates are about the same.

Coming up:  Let's consider some of the ideas indicated by the monoamine hypothesis.

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