Mirtazapine (Trade Name: Remeron) is a weird drug. It has a different chemical structure than most other antidepressants and doesn't fit neatly into the classes usually sold to us as something we should “consider as another option for major depression.” This article builds on what paid subscribers learned in yesterday's article, so it’s worth a review!
It might not work any differently than any other drug when it comes to relieving depression. It's got different side effects, which are the chips we have to bargain with when we're evaluating oral medications for depression.
These different side effects are primarily mediated through its histamine effects. We talk about serotonin, epinephrine, and dopamine as neurotransmitters. They're flashy. Histamine is another neurotransmitter, and benefiting the mechanism, making you sleepy and hungry—it's not a been leading molecule in pharmacology marketing.
Antihistamines: you'll be tired. But…you'll want to snack.
In the brain, histamine does the following:
histamine has been shown to critically modulate inflammatory processes as well as the properties of neurons and synapses in the brain, and is also implicated in the emergence of neurodevelopmental disorders.1
Great, another molecule that does a bunch of stuff, and in bunch of places? I’ve heard of inflammation. Something specific please?:
In the human adult brain, there are approximately 64,000 histaminergic neurons located in and around the TMN (Haas et al., 2008). These project diffusely throughout all areas of the brain, differentially modulating many distinct neuronal circuits (Blandina et al., 2012)
That's a tiny number of neurons. OK, the science writers are not helping. I'll do the short version: Histamine wakes you up. Antihistamines often do the opposite…some more science:
The H1 receptor is coupled to an intracellular Gqprotein that activates phospholipase C and inositol triphosphate (IP3) signaling pathways. The H1 receptor has been identified in the developing rat CNS from E14 within the telencephalon, mesencephalon and the spinal cord (Kinnunen et al., 1998) and expression is retained into adulthood. The H2 receptors are coupled to Gs second messenger proteins that increase the production of cyclic adenosine monophosphate (cAMP) and subsequent activation of protein kinase A.
Oh my God, are you asleep yet? It's like reading about histamine is a sedating antihistamine in and of itself! I'm kidding. A little bit. It's dull. All the histamine science stuff you just read above? Histamine = More energy, not less. Less energy is sedating, fewer cells firing, and less excitatory, broadly. Blocking H1 histamine receptors slows things down in your brain and makes you sleepy. For other reasons, it makes you hungry. I will drop the additional basic science in a footnote.2
Mirtazapine blocks histamine in addition to its serotonin and other effects. Otherwise, more or less, it is not much different from other antidepressants when it comes to “anti-depression,”…but it might work a little faster…3
This table would be much better if it were less sciencey: “Mirtazapine…it’s not worse.” But is it better? Well, we need to dig into the data pooled across individual drugs…Using the ability to read forest plots (paid subscribers learned how in my thrilling review of bupropion), we see:
This is a meta-analysis; as we recall, the diamonds and if they cross the vertical line are what we are looking for! So, digging into the above, we see a diamond crossing the line when comparing mirtazapine to…
Celexa:
Prozac:
Paxil (which sucks):
Zoloft or Luvox:
However, when we pool all of the data from all of the studies across all of the drugs, we find out that Remeron is slightly favorable to all of the other SSRIs in the treatment of depression!
Even though only one study showed a difference compared to one drug, Paxil, all of the data together demonstrates mirtazapine has a slight edge over SSRI medication if the question is around “is it better for depression?”….
“Yes, a little bit!”
In the process, I hope, as readers, you learned that you can evaluate a forest plot in a meta-analysis paper just as well as I can!
Remeron: it's sedating4 and leads to weight gain5, but it might be a slightly better antidepressant (in some people) than SSRIs. Unlike Ambien, despite being sedating, it leads to less risk of car wrecks!
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Effexor, Buspar, Risperdal, Zyprexa, Neurontin, Xanax, Klonopin, Paxil, Prozac, Clozaril, Lamictal, Lithium, Latuda, Ambien, and generally Benzos, specifically maybe Benzos leading to death by suicide, Geodon, Zoloft, Auvelity are prior articles.
The H1 and H2 receptors are important postsynaptic receptors in the brain, and they mediate many of the central effects of histamine on, e.g., alertness and wakefulness. H3 receptor is a pre- and postsynaptic receptor, which regulates release of histamine and several other neurotransmitters, including serotonin, GABA, and glutamate. H4 receptor is found in cerebral blood vessels and microglia, but its expression in neurons is not yet well established. Pitolisant, a H3 receptor antagonist, is used to treat narcolepsy and hypersomnia. H1 receptor antagonists have been used to treat insomnia, but its use requires precautions due to potential side effects. H2 receptor antagonists have shown efficacy in treatment of schizophrenia, but they are not in widespread clinical use. H4 receptor ligands may in the future be tested for neuroimmunological disorders and potentially neurodegenerative disorders in which inflammation plays a role, but clinical tests have not yet been initiated.
Watanabe, N., Omori, I. M., Nakagawa, A., Cipriani, A., Barbui, C., McGuire, H., ... & Furukawa, T. A. (2008). Mirtazapine versus other antidepressants in the acute-phase treatment of adults with major depression: systematic review and meta-analysis. Journal of Clinical Psychiatry, 69(9), 1404.
Shen, J., Moller, H. J., Wang, X., Chung, S. A., Shapiro, G. K., Li, X., & Shapiro, C. M. (2009). Mirtazapine, a sedating antidepressant, and improved driving safety in patients with major depressive disorder: a prospective, randomized trial of 28 patients. Journal of Clinical Psychiatry, 70(3), 370.
Laimer, M., Kramer-Reinstadler, K., Rauchenzauner, M., Lechner-Schoner, T., Strauss, R., Engl, J., ... & Ebenbichler, C. F. (2006). Effect of mirtazapine treatment on body composition and metabolism. Journal of Clinical Psychiatry, 67(3), 421-424.