SSRI + mirtazapine = ideal combo ?

[GABAlover]

My pscyhiatrist advised me that the reason antidepressants stop working for some people after a period of time, myself included, is cause by the bodies downregulation of 5HT and noradrenaline. The body is trying to return to it's normal (depressed) state.

He stated that the combination of an SSRI and mirtazapine was ideal, as mirtazapine is an antagonist at A2 adrenergic heteroreceptors and autoreceptors on the presynaptic neuron. This, in theory, will halt the downregulation of 5HT and NA.

I had reservations about taking two antidepressant agents at once, but after experiencing severe depression recently and suicidal thoughts, decided that I didn't have much to lose. I am currently taking 50mg sertraline (ZOLOFT) and 15mg mirtazapine (AVANZA, REMERON) every day. Not huge doses, I know. He maintains that an increase in the sertraline alone would probably not be very beneficial, given my history of downregulation.

Anyone have any thoughts or concerns about this combination ?

 

[BilZ0r]

My pscyhiatrist advised me that the reason antidepressants stop working for some people after a period of time, myself included, is cause by the bodies downregulation of 5HT and noradrenaline. The body is trying to return to it's normal (depressed) state.

Your psychiatrist advised you wrong.

How the would alpha2 receptor antagonists, stop 5-HT receptor downregulation?

Your psychiatrist is obviously quite immaganative, might be good for getting easy prescriptions, but I wouldn't listen to his advice on this like this.

 

[GABAlover]

"Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic a2 adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity."

-RXlist

With respect, I would be much more likely to heed your advice if you stated what you believe is lacking in this theory. The way he explained it to me made perfect sense. He states that he has had much success with this combination.

 

[BilZ0r]

"Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic a2 adrenergic inhibitory autoreceptors and hetero-receptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity."

My pscyhiatrist advised me that the reason antidepressants stop working for some people after a period of time, myself included, is cause by the bodies downregulation of 5HT and noradrenaline. The body is trying to return to it's normal (depressed) state.

He stated that the combination of an SSRI and mirtazapine was ideal, as mirtazapine is an antagonist at A2 adrenergic heteroreceptors and autoreceptors on the presynaptic neuron. This, in theory, will halt the downregulation of 5HT and NA.

Those two statements are completely unrelated.

alpha2 is an inhibitory presynaptic receptor. Blocking it disinhibits presynaptic terminals. and hence facilitates neurotransmitter release.

The original theory in how SSRIs worked is that they CAUSED serotonin receptor downregulation, and that is what caused the antidepressant action. No one has since disproved that.

 

[dhar174]

Actually, there are several points that you are missing. One is that Mirtazapine is also a strong inhibitor of serotonin 5ht2a/2c receptors. It has been proven time and time again that inhibiting or down-regulating 5ht2 receptors increases release of serotonin (at 5ht1a synapses), nor-epinephrine, and dopamine in various parts of the brain, mainly because 5ht2 neurons inhibit the release of these neurotransmitters.

Now heres the best part: Strangely enough, 5ht2 receptors down-regulate in response to BOTH excitation and inhibition. This is a good thing, and is the common denominator for the effects of SSRIs and mirtazapine. The antagonism of alpha-2, which results in the release of both serotonin at 5ht1a receptors and and NE at adrenergic synapses (due to it being, as you pointed out, an inhibitory pre-synaptic autoreceptor on both 5ht1a and adrenergic receptors), is just an added plus.

Theres your explanation, you are both correct. Downregulation of 5ht2 is good and precipitated by excess activation (by SSRIs for example) AND by inhibition by 5ht2 antagonists (mirtazapine being the best example, others including Agomelatine, Mianserin, Hydroxyzine, Retanserin, Kitanserin, as well as many atypical anti-psychotics.

The serotonin receptor you dont want downregulating is 5ht1a, except, of course, the ones that function as auto-receptors (this may also be a mechanism of anti-depressant action of ssris, the downregulation of 5ht1a autoreceptors, resulting in increased 5ht transmission at those sites)

I would be happy to provide references to any of this if you would like.

 

[MeDieViL]

^^ 5HT2A increases dopamine, it doesnt inhibit it, its true that antipsychotics increase cortical dopamine but thats rather associted with indirect 5HT1A agonism.