How Does Remeron (Mirtazapine) Affect Serotonin And Norepinephrine?

CuriousAsker asked

A question about Mirtazapine (Remeron). As I understand it, it works by increasing the outflow of norepinephrine and serotonin, but does not inhibit re-uptake. Iis this mostly correct? Does influence the amount of serotonin vs norepinephrine in the brain?

Answer

Remeron (mirtazapine) has a relatively complicated mechanism of action that is not fully understood. It is classified as an antidepressant but is not chemically related to any other classes of antidepressants. In addition to its antidepressant effects, mirtazapine also possesses anti-anxiety effects and is therefore useful in those with a coexisting anxiety disorder. 

How Does Remeron (Mirtazapine) Work?

While Remeron has a variety of effects, it is thought to primarily work by antagonizing central alpha₂-receptors.

These receptors have a wide ranging function, but in the context of mirtazapine, they are involved in a negative feedback loop and activation typically causes inhibition of norepinephrine release. Since mirtazapine blocks (i.e. antagonizes) these receptors, it inhibits negative feedback, causing an overall increase in norepinephrine release.

In addition, serotonin is also affected by the blocking of central alpha₂-receptors. Blocking these receptors (by mirtazapine) also causes enhanced release of serotonin (5-HT). 

So, you are correct that mirtazapine does not affect the re-uptake of serotonin and norephinephrine, but rather, increases their release.

To complicate matters, mirtazapine is also thought to have the following effects:

• Antagonism of certain subtypes of serotonin (5-HT) receptors, including 5-HT₂ and 5-HT₃ receptors. Blockade of these receptors is though to result in a lower incidence of certain adverse effects commonly associated with SSRI antidepressants, like Zoloft. Side effects such insomnia, nausea and sexual dysfunction generally occur less frequently.

• Antagonism of histamine (H1-receptors). In other words, it has antihistamine like effects, which is why it can help with symptoms of itching. Although antihistamines are associated with sedation, the increase of norepinephrine release is thought to counteract this.

• Antagonism of alpha₁ receptors, although this is thought to be mild. Nevertheless, it may be the reason that low pressure can sometimes occur with mirtazapine.

Remeron Dosing

There haven't been many studies evaluating the degree of neurotransmitter release in regard to dosing, but it is thought the effects of mirtazapine are dose-dependent.

In general, dosing with mirtazapine starts at 15 mg and is increased based on tolerability and efficacy. Common side effects, such as sedation, are often more pronounced when starting at too high of a dose. In fact, according to the prescribing information, more than 50% of individuals experience sedation on the drug. It is therefore recommended to start at a low dose and increase slowly (i.e. "start low and go slow").

You should speak with your doctor regarding specific dosing schedules for the drug as everyone's medical situation is different. As a general point about dosing:

• Mirtazapine is most commonly initiated at 15 mg at bedtime. Individuals not responding to the 15 mg dose may benefit from doses increases, with a maximum daily dose of up 45 mg.

• Dosage adjustments are not recommended to be made more often than every 1 to 2 weeks due to the long half-life of the drug (20 to 40 hours).