Mirtazapine Halves The Neural Stress Response, Lowers Norepinephrine

[DaveFoster]

Ray has mentioned that it takes around 2 weeks for the enzymatic machinery to adapt to a new stimulus in healthy individuals, and this appears with the brain's conditioning to drugs imipramine and mirtazapine. Mirtazapine also has serotonergic and noradrenergic effects in the brain, and it can provoke aggression, but at least in the prefrontal cortex, it seems to lower noradrenaline.

Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving... - PubMed - NCBI

"The effect of repeated administration of imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, was studied on the stress-induced increase in the extracellular concentration of norepinephrine in the prefrontal cortex of freely moving rats. Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs."

 

[jyb]

I used to take it many years ago. In the long term my overall stress response was increased not decreased. I would recommend using those rat studies with a pinch of salt.

 

[DaveFoster]

I used to take it many years ago. In the long term my overall stress response was increased not decreased. I would recommend using those rat studies with a pinch of salt.

Thanks for sharing jyb; what dose did you take and for how long?

 

[jyb]

Thanks for sharing jyb; what dose did you take and for how long?

Years, low dose (<10 or 15mg) and normal dose. To me the closest drug is clearly cyproheptadine - similar effects (good and bad).

 

[haidut]

Ray has mentioned that it takes around 2 weeks for the enzymatic machinery to adapt to a new stimulus in healthy individuals, and this appears with the brain's conditioning to drugs imipramine and mirtazapine. Mirtazapine also has serotonergic and noradrenergic effects in the brain, and it can provoke aggression, but at least in the prefrontal cortex, it seems to lower noradrenaline.

Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving... - PubMed - NCBI

"The effect of repeated administration of imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, was studied on the stress-induced increase in the extracellular concentration of norepinephrine in the prefrontal cortex of freely moving rats. Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs."

That's interesting. As far as I remember, mirtazapine is directly marketed as norepinephrine-boosting anti-depressant due to its agonist of 5-HT1. Maybe it is dose dependent?

 

[DaveFoster]

That's interesting. As far as I remember, mirtazapine is directly marketed as norepinephrine-boosting anti-depressant due to its agonist of 5-HT1. Maybe it is dose dependent?

The NErgic effect is definitely pronounced in higher doses, but it (along with the DRI effect) becomes noticeable at around the 1.5 mg mark. (Most would say higher, but I'm very sensitive to the feeling.) At lower doses, as in up to 1 mg or so, it's majorly sedating with the H1 and anxiolytic 5-HT2 antagonism.

The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. - PubMed - NCBI

"Mirtazapine is a new antidepressant with a unique mode of action: it preferentially blocks the noradrenergic alpha2-auto- and heteroreceptors held responsible for controlling noradrenaline and serotonin release. In addition, mirtazapine has a low affinity for serotonin (5-HT)1A receptors but potently blocks 5-HT2 and 5-HT3 receptors. It increases serotonergic cell-firing in the dorsal raphe and 5-HT release in the hippocampus as measured by microdialysis. These effects are explained by noradrenergic enhancement of 5-HT cell-firing and blockade of noradrenaline-mediated inhibition of hippocampal 5-HT release. Because mirtazapine blocks 5-HT2 and 5-HT3 receptors, only 5-HT1-mediated transmission is enhanced. The noradrenergic activation and the consequent indirect enhancement of serotonergic transmission most probably underlie the marked therapeutic activity of mirtazapine. The blockade of 5-HT2 and 5-HT3 receptors prevents development of the side effects associated with non-selective 5-HT activation and may contribute to the anxiolytic and sleep-improving properties of this new compound. Therefore mirtazapine can be described as a noradrenergic and specific serotonergic antidepressant (NaSSA)."

 

[DaveFoster]

That's interesting. As far as I remember, mirtazapine is directly marketed as norepinephrine-boosting anti-depressant due to its agonist of 5-HT1. Maybe it is dose dependent?

It seems that mirtazapine might be a superior option compared to mianserin, as the latter more readily affects norepinephrine (as I believe I've mentioned in the Ultimate Anti-Histamine thread.)

A comparison of the physicochemical and biological properties of mirtazapine and mianserin. - PubMed - NCBI

Although the chemical structures of the antidepressants mirtazapine and mianserin are closely related there are considerable differences in their biological properties. To find an explanation of this, various physicochemical properties of mirtazapine and mianserin were measured or calculated. Isosteric replacement of CH in mianserin by N in mirtazapine has profound effects on physicochemical properties. The charge distributions as indicated by NMR and calculated by semi-empirical quantum mechanics differ, not only for the changed aromatic A-ring (as expected), but also in other regions of the molecule. The N5 atom in particular, which is conjugated to the changed aromatic ring, is less negatively charged in mirtazapine than in mianserin. Consequently the oxidation potential of mirtazapine is significantly higher than that of mianserin. Another result of this difference in charge distribution is that the (calculated) dipole-moment vectors of the compounds are oriented roughly perpendicular to each other. The dipole moment of mirtazapine is, moreover, three times larger than that of mianserin; mirtazapine is, therefore, more polar than mianserin and this is reflected in a lower retention index. Finally, the basicity of mirtazapine, expressed as the pKa value, is slightly but significantly lower than that of mianserin. The observed differences between the physicochemical properties of mirtazapine and mianserin result in different interactions of these two antidepressants with macromolecules, such as receptors, transporters and metabolizing enzymes; this might explain the differences observed in pharmacological activity and metabolic and kinetic behaviour, that is, the reduced affinity for the alpha 1-adrenoceptor and negligible noradrenaline reuptake of mirtazapine compared with mianserin.

 

[SuperStressed]

Ray has mentioned that it takes around 2 weeks for the enzymatic machinery to adapt to a new stimulus in healthy individuals,

where did he say this? would it be the same for cypro? Maybe I dont fully understand the statement but is this why it takes people weeks to feel different on some psych drugs? I'd love to understand it better.