Tricyclics are for true treatment-resistant depression and anxiety that has not responded to SSRIs and SNRIs, used by people who know what they are doing, because the side effects and overdose risk are real. Use whichever one the patient tolerates (nortriptyline is classically better tolerated), and for sleep they make sense when there is another indication and the patient can safely take one.
When we reach for it
Consider TCAs and MAOIs for true treatment-resistant depression, not for what is really trauma or personality depression, and only if you know what you are doing.
“Consider them if you have true treatment-resistant depression, not just we're calling something that's trauma and personality depression. Please consider your TCAs and your MAOIs if you know what you're doing”
1:08:17Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 We reserve them for patients who have failed even the SSRI plus second-generation antipsychotic combination.
“reserve the use, in my practice anyway, to patients who have failed even the SSRI and second-generation antipsychotic combo”
49:28Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 For a primary anxiety disorder not responding to SSRIs and SNRIs, tricyclics are the traditional answer.
“that is a method of last resort that I even placed beyond, and I will try before that, the tricyclics. And that's actually the traditional answer to what to do with someone who is having a primary anxiety disorder, who's not responding to your SSRIs, SNRs. You should be using tricyclics”
37:25Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 The traditional algorithm for GAD runs SSRI, then SNRI, then gabapentin or pregabalin, then a TCA.
“The traditional algorithm goes SSRI SSRI and SNR. SNRI, and then you try your gabapentin and Lyrica, and then you try your TCA”
1:00:20Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 For sleep: if you have another indication and the patient can take one safely (cardiac status, no constipation), a TCA will help the sleep while treating the primary disorder.
“If you have another indication for them and it's safe to use in that particular patient for cardiac reasons or they don't have constipation, for example, they'll help the sleep and you'll be able to treat the primary disorder”
44:08Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026
Side effects and safety
They have many more side effects: dangerous in high doses, QTc prolongation, anticholinergic effects like dry mouth and urinary retention, and a lot of sedation.
“they have much more side effects. They are dangerous in high doses in QTC prolongation. They make people have anticholinergic side effects like dry mouth, urinary retention, and they're very sedating”
47:35Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025
Choosing a tricyclic
Imipramine is the classic pick only because it was the most researched back in the day. Really, use whatever tricyclic is tolerated; nortriptyline is one of the classically better tolerated ones.
“What's interesting is that that's just because that was the one that was researched the most back in the day. So, you know, you can go for imipramine. But really, it's whatever tricyclic is tolerated. I believe nortriptyline is usually... one of the classically better tolerated ones”
37:54Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 For sleep you want a tertiary TCA such as amitriptyline, which is also first line for fibromyalgia pain.
“I think it's first line for fibromyalgia pain. Now, we have other TCAs on there. I almost wish we just put amitriptyline because you're really going to want a tertiary TCA”
45:01Sleep Medications Treatment Tier List: Best Insomnia Medications RankedAug 2026 Clomipramine is the most serotonergic TCA. CYP1A2 breaks it down into norclomipramine, a secondary TCA, which is less serotonergic.
“clomipramine is the most serotonergic TCA. So it consists of clomipramine, and then it's broken down by CYP1A2 into norclomipramine. So... Norclomiprimine is a secondary TCA, so it's less serotonergic”
26:04Practical OCD Psychopharmacology: Evidence‑Based (& Non Evidence-Based) Medication ApproachAug 2025
It also comes up on
- AnticholinergicsMany TCAs, paroxetine, anti-parkinsonian medications and bladder relaxants for overactive bladder are anticholinergic, and diphenhydramine is a big one.
- ClozapineMinimize other anti-muscarinic drugs: many TCAs, paroxetine, anti-parkinsonian medications, bladder relaxants for overactive bladder, and diphenhydramine is a big one.
- DoxepinAt 8 mg or below it is almost a pure antihistamine, unlike the other TCAs and antihistamines. In theory that makes it ideal for people who want to sleep but also need to wake in the middle of the night.
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 · 1 point
- Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 · 1 point
- Practical OCD Psychopharmacology: Evidence‑Based (& Non Evidence-Based) Medication ApproachAug 2025 · 1 point
- Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 · 2 points
- Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 · 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.