How Antidepressants Work

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How Antidepressants Work

From Nancy Schimelpfening,

All Brains Are Not the Same

 

Very often I am asked to recommend a good antidepressant. My answer, other

than the obvious, " Please see your doctor for medical advice " , is this: " the

one that works for you " !

Each class of antidepressant works on your brain chemistry in a different

way. Dr. Abbott Lee Granoff, an expert in the field of panic disorder and

depression, says the following: " There are currently 23 antidepressants on

the market. (Guide Note: This figure has increased since Dr. Granoff was

interviewed for this article.) Each increases certain neurotransmitters in

the brain and each can do this in slightly different parts of the brain. "

So, while one person may get relief from having their serotonin boosted,

another may need a drug that affects both serotonin and norepinephrine.

Still another person may need an entirely different sort of medication, such

an anticonvulsant or a mood stabilizer like lithium. Further, a person who

does well on a medication such as Zoloft may not do as well on Prozac, even

though both belong to the same class.2 Each person will be very different in

their medication needs.

Just like the wide variety of brains, there are a wide variety of

antidepressants. Broadly speaking, these fall into the following classes:

monoamine oxidase inhibitors (MAOIs), tricyclics (TCAs) and selective

serotonin reuptake inhibitors (SSRIs). There are also several newer

medications that are unique in their mechanism of action.

 

MAOIs and Tricyclics

Monoamine Oxidase Inhibitors

 

The monoamine oxidase inhibitors (MAOIs) were some of the first

antidepressant medications developed. The neurotransmitters responsible for

mood, primarily norepinephrine and serotonin, are also known as monoamines.

Monoamine oxidase is an enzyme which breaks these substances down. Monoamine

oxidase inhibitors, as the name implies, inhibits this enzyme, thus allowing

a greater supply of these chemicals to remain available.

MAOIs have fallen out of favor as first-line antidepressants because they

offer several disadvantages to patients compared to newer medications.

Potentially fatal drug-drug interactions can occur with MAOIs when combined

with a variety of drugs which are serotonin agonists (the " serotonin

syndrome " ) or norepinephrine agonists.3 People on these medications must

also follow strict dietary restrictions of foods rich in tyramine4 to avoid

potential hypertensive (high blood pressure) crisis.

A major adverse effect that occurs on MAOIs alone is hypotension (low blood

pressure), which can present as fatigue and may mimic worsening of the

underlying depressive syndrome. For this reason, the blood pressure should

always be monitored when using these antidepressants.5

 

Tricyclics

Tricyclics, also known as heterocyclics, came into broad use in the 1950's.

These drugs inhibit the nerve cell's ability to reuptake serotonin and

norepinephrine, thus allowing a greater amount of these two substances to be

available for use by nerve cells.

In addition to acting on norepinephrine and serotonin, tricyclics exhibit

similar effects on histamine and acetylcholine. This is responsible for the

troublesome side-effects we usually associate with these medications, such

as dry mouth, blurry vision, weight gain and sedation.6

With tricyclics, a patient's medical history must be closely considered.

These medications may cause orthostatic hypotension (dizziness upon standing

rapid heartbeat, sometimes with palpitations; and may aggravate preexisting

heart conditions. Patients with a history of seizures or head injury must

also be cautious as these drugs may cause seizure.

 

SSRIs and Newer Mechanisms

Selective Serotonin Reuptake Inhibitors

 

Claims of decreased side-effects and increased safety relative to the older

medications have made this class of antidepressant very popular in recent

years. Drugs belonging to this class include fluoxetine (Prozac), citalopram

(Celexa) escitalopram (Lexapro), fluvoxamine (Luvox), sertraline (Zoloft)

and paroxetine (Paxil). SSRI stands for Selective Serotonin Reuptake

Inhibitor. These medications work, as the name implies, by blocking the

presynaptic serotonin transporter receptor.8 This drug differs from the

tricyclics in that its action is specific to serotonin only. Its effect on

norepinephrine is indirect, through the fact that falling serotonin

" permits " norepinephrine to fall so preserving serotonin preserves

norepinephrine.9 SSRIs, through their specificity, have the advantage of not

affecting histamine and acetylcholine.

The implication is that although they are not without side-effects, they do

not create the same bothersome side-effects as the tricyclics.

 

Newer Mechanisms

Five newer medications which do not fit into the above categories are:

bupropion (Wellbutrin), nefazodone (Serzone), trazodone (Desyrel),

venlafaxine (Effexor), and mirtazapine (Remeron). The mechanism of

bupropion's antidepressant activity is poorly understood, but it is thought

to be mediated through noradrenergic or dopaminergic pathways or both.10

This medication lacks the sexual side-effects so common to the SSRIs and is

popular for patients who exhibit a lack of energy, psychomotor slowness and

excessive sleep. Nefazodone and its precursor trazodone both inhibit

neuronal reuptake of serotonin and, to a lesser extent, norepinephrine. They

also block postsynaptic 5-HT2 receptors. Nefazodone has weak affinity for

cholingeric and a1- adrenergic receptors and, therefore, is associated with

less sedation and orthostasis than trazodone.11

 

More About Newer Mechanisms

Venlafaxine is a compound that is structurally unrelated to other

antidepressants.12 Like the TCAs, venlafaxine inhibits the neuronal uptake

of both serotonin and norepinepherine. Venlafaxine has dose-dependent,

sequential effects on the uptake pumps for serotonin and then

norepinephrine.. At 75 mg/day, venlafaxine is predominantly a serotonin

reuptake inhibitor (SRI) like the SSRIs. At 375 mg/day, it produces

comparable norepinephrine uptake inhibition to an NSRI such as

desipramine.13

 

Mirtazapine is the most recently released of these four and is the first

a2-antagonist marketed as an antidepressant.14 Mirtazapine's unique

mechanism of action does not involve enzyme inhibition or blockade of

neurotransmitter reuptake. Mirtazapine increases the release of

norepinepherine from central noradrenergic neurons by blocking the

presynaptic inhibitory alpha-2 autoreceptors.

 

 

It spares the alpha-1 postsynaptic receptor and therefore results in net

increase noradrenergic transmission. As a second presynaptic receptor

blocking function, mirtazapine blocks the inhibitory alpha-2 heteroreceptors

located on serotonergic neurons, resulting in increase release of serotonin.

Postsynaptically, mirtazapine has low affinity for the 5-HT1A receptor, thus

allowing serotonin released into the synapse to bind to and stimulate this

receptor. However, it blocks postsynaptic 5-HT2 and 5-HT3 receptors.

Stimulation of the 5-HT2 receptor is thought to be responsible for the

serotonergic side effects of insomnia, agitation, and sexual dysfunction

seen with the SSRI's and 5-HT3 receptor stimulation is thought to mediate

nausea seen with these agents.15, 16, 17 Therefore, mirtazapine's receptor

blocking profile prevents the side-effects seen with nonselective activation

of serotonin receptors which occurs with pure reuptake blockers.