Mirtazapine

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Mirtazapine is used primarily used as an antidepressant but it is also used for insomnia. It has a lot less sexual dysfunction than SSRIs. It also has less GI side effects and can actually improve nausea. The main two downsides are its sedation effect (if not desired) and weight gain. There is a weak effect on pain hence the Musculoskeletal Physician should be aware of it.

Indications

It is FDA approved for major depression. But it is used off label for insomnia, anxiety disorders, nausea, appetite stimulant, cancer chemotherapy patients, akathesia, methamphetamine use disorder.

For patients who are underweight and have insomnia it should be the top of the list when choosing an anti-depressant, because the downsides become upsides. It also likely has a faster onset of action than SSRIs during acute phase treatment, with effects by 1-2 weeks and maximum effect by 4 weeks. It also might be a little bit more effective than SSRIs and comparable to SNRIs.

For sleep is improves sleep latency, sleep duration, and sleep efficiency. At high doses it can disturb sleep and also cause restless leg syndrome in some, and parasomnias.

Pain

There have been several positive trials for pain in fibromyalgia. It should be considered in skinny patients with fibromyalgia and insomnia, even in those who aren't depressed. The dose needs to be 30mg, 15mg is not effective presumably due to insufficient noradrenergic activity.

The largest was a randomised trial in Japan of 430 patients with fibromyalgia without depression found a significant reduction in pain compared to placebo of -0.72 points with a dose of 30mg daily (starting at 15mg daily for one week first, taken at night). This average response is probably not clinically significant. However when looking at proportion with response of greater than 30% pain relief, this measure was seen in 45.5% of the mirtazapine group vs 30.8% of the placebo group. The responder rates for greater than 50% relief were not different between the two groups. Side effects seen in this study were drowsiness and increased appetite/weight gain. The effect sizes are similar to pregabalin and duloxetine.

The mechanism of action is through its noradrenergic and serotonergic effects, an effect similar to SNRI and TCAs. There is also a rat study showing an effect on an allodynia model.

Receptor Actions

It has three mechanisms of action - histaminergic, serotonergic, and noradrenergic.

Histaminergic: it is a very potent H1 blocker. At low concentrations it is a selective H1 antagonist.

Serotonergic: It blocks 5HT2A, 5HT2C, and 5HT3. The action here lowers drug seeking behaviour. The antagonism at 5HT2C may play a role in the weight gain effects. 5HT3 is the same receptor that ondansetron works on and helps with nausea.

Noradrenergic: At higher doses there is antagonism of α-2 presynaptically, these are largely inhibitory autoreceptors and so antagonism results in increased noreadrenaline and possibly serotonin.

Dosing

At low doses less than 7.5mg it acts as an antihistamine, at low to medium doses 7.5-15mg you also see serotonergic activity, and high doses above 15mg you also see noradrenergic activity. The optimal dose for depression is 15-30mg, with a maximum approved dose of 45mg. The response rates for depression actually decrease above 30mg. Dropout rates to adverse effects also increase with higher doses.

Binding affinities (lower is stronger)

Receptor	Action	pKi
5-HT2A	Antagonist	6.3-69
5-HT2C	Antagonist	8.9-39
5-HT3	Antagonist	8.1
α1A	Antagonist	1815
α2A	Antagonist	20
α2B	Antagonist	88
α2C	Antagonist	18
H1	Antagonist	0.14-1.6

Resources

https://www.youtube.com/watch?v=k8WnqdqnYTw