Mirtazapine is one of our four first-line antidepressants and really quite good for sleep at low doses, a great choice when sleep is a big problem and weight gain is welcome or not a concern. Weight gain, even at low doses, is the reason it is not used more, and patients need a clear warning about the zombie-like first days.
When we reach for it
One of four first-line antidepressants, with escitalopram, sertraline and bupropion, chosen by patient profile. We very rarely deviate from those four.
“In my opinion, first line medications for antidepressants, I'm thinking of escitalopram, sertraline, mirtazapine, bupropion. I think those are all reasonable first choices depending on patient profile. I very, very, very rarely deviate from those four”
46:31Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Also said in 1 more episode
“I typically consider there to be four first line in how I practice. I have pretty much four first line antidepressants that I use. As you said, it's Zoloft and Lexapro. If I'm choosing an SSRI, how I choose between those depends on how I'm feeling that day”
10:17Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 A great choice when sleep is a big issue and the patient is underweight or not concerned about weight, and almost everyone with a true major depressive disorder has a sleep problem. The weight gain risk is why it is used rarely.
“I rarely do the mirtazapine because of the weight gain risk, but if you do have someone where weight gain is not a concern and they have sleep problems, almost everybody with a true major depressive disorder has a sleep problem, then mirtazapine is a great choice”
10:57Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 Also said in 1 more episode
“for a patient who doesn't want the SSRI side effects of a little bit of weight gain or sexual side effects, then I am fine with bupropion. And then mirtazapine for a patient where sleep is a big issue and patients either underweight or not concerned with their weight. I would say underweight”
11:59Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 For sleep without aiming for an antidepressant effect, very low doses around 7.5 mg work for sleep onset and maintenance. It is really quite good.
“if you don't want to be doing antidepressant effect, you can be treating at the very low doses, you know, seven and a half range. And it can work for sleep, onset, and maintenance. It's really quite good”
37:58Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 For anxiety, a good choice in someone who could use some weight, or does not mind it, and has sleep problems.
“If you need someone that wants to gain weight or could use some weight or doesn't mind some weight gain and they have some sleep problems, mirtazapine, it's a good choice”
42:24Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 For PTSD it may be one of the best choices, as long as appetite increase and weight gain are not a concern.
“I forgot to mention mirtazapine. It's a very good choice if you don't mind the appetite increase in weight gain. It may be, in my opinion, one of the best choices as long as there's no concern about weight gain”
33:23PTSD Medications: Integrating Pharmacotherapy, Therapy, and the Treatment Frame | Episode 22Apr 2025 We consider bupropion and mirtazapine to be augmenting agents.
“To me, they're early meds to the Bupro and the mirtazapine. In my mind, I consider them to be augmenting agents”
10:45Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025
Side effects and safety
Incredibly sedating. Warn patients they will feel like a zombie: expect a hangover, usually three to four days of feeling a bit like a zombie the next day, which typically gets better after about a week. Do not start it the night before a big work meeting.
“I say expect a hangover. What I usually see is three to four days of feeling like a little bit of a zombie. I do not recommend starting this medication the night before you have a big work meeting”
38:53Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 Also said in 2 more episodes
“Incredibly, incredibly, incredibly sedating. Warn your patients that they will feel like a zombie. Now, why do I think it's important to warn patients”
46:55Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 “I do like to warn patients that it can be like overwhelmingly sedating and that like you feel like a complete zombie the next day. That's expected to get better usually after a week”
34:21PTSD Medications: Integrating Pharmacotherapy, Therapy, and the Treatment Frame | Episode 22Apr 2025 Even at low doses there is considerable appetite increase and weight gain, which is a reason to avoid it as a sleep medication.
“I find that even at low doses, there's considerable appetite increase in weight gain for both of those medications. So I avoid them”
34:11Insomnia and Sleep Medications in PsychiatryDec 2024
Compared with others
Major depression tends to have more sleep disruption baked in than generalized anxiety disorder, which may be why mirtazapine fits depression better.
“major depressive disorder, a mood disorder, tends to have more Baked in... sleep disruption than generalized anxiety disorder”
42:55Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 In bipolar disorder, be wary and careful above about 15 to 20 mg of mirtazapine (or above 150 mg of trazodone).
“I do get wary and careful if we're going to TRASM above 150 in bipolar disorder or if we're doing mirtazapine above 15 or 20-ish”
47:26Insomnia and Sleep Medications in PsychiatryDec 2024
Pearls
Mirtazapine plus venlafaxine is the famous California rocket fuel combination, coined by Stephen Stahl. Separately: if you are combining an SSRI with an SNRI, stop.
“The combo that is a little famous is the California rocket fuel as coined by Stephen Stahl, which is mirtazapine and venlafaxine. Anyone who's using an SSRI and SNRI, stop it. Stop it”
42:08Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 It has a small but statistically significant effect in meth use disorder in some populations, about three fewer meth days a month.
“also has a pathetic, but still statistically significant reduction in some populations for meth use disorder. You can get like three less meth days in the month”
49:09Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026
It also comes up on
- AugmentationAt the bottom of the evidence ladder for difficult depression sit bupropion, mirtazapine and buspirone as add-ons. Taking two antidepressants rarely works better than one, yet it is what we most often do.
- Treatment-resistant depressionAt the bottom of the evidence ladder sit bupropion, mirtazapine and buspirone augmentation. Taking two antidepressants rarely works better than one, yet that is what we most often do.
- AntipsychoticsIn the ICU or nursing home, controlling the sleep-wake cycle with trazodone, mirtazapine, melatonin or ramelteon may give a lot of the same effect without the same problems.
- AnxietyThe usual order: an SSRI, then another SSRI, then augmenting with buspirone or gabapentin. If they are still unresponsive, go by patient characteristics, such as mirtazapine for a lot of sleep trouble.
- AugmentationFor someone on an adequately dosed SSRI or SNRI, add-on options include bupropion, mirtazapine and buspirone, and then the second-generation antipsychotics, which are very popular in the US but high risk.
- BenzodiazepinesA short-term sleeper can just as easily be high-dose hydroxyzine, low-dose trazodone, higher-dose gabapentin, or mirtazapine if you have to.
- BuspironeFor an adequately dosed SSRI or SNRI that needs an add-on, buspirone sits alongside bupropion and mirtazapine. Second-generation antipsychotics are the popular but high-risk alternative.
- DementiaIn the nursing home or ICU patient, controlling the sleep-wake cycle with something like trazodone, mirtazapine, melatonin or ramelteon may give a lot of the same effect without the same problems.
From these episodes
- Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 · 2 points
- Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 · 2 points
- Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 · 4 points
- PTSD Medications: Integrating Pharmacotherapy, Therapy, and the Treatment Frame | Episode 22Apr 2025 · 2 points
- Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 · 4 points
- Insomnia and Sleep Medications in PsychiatryDec 2024 · 2 points
Every point above is something said on the Psychofarm podcast, with the words as spoken and a link to the moment in the episode. It is education, not medical advice, and an episode reflects what we thought when we recorded it.