Sertraline is our first choice among antidepressants for depression and anxiety: it just works, has few interactions and titrates in many small steps. Start at 25 mg for a week, aim for 50 mg as the usual minimum effective dose, and prefer it over escitalopram because metabolizer status matters less.
When we reach for it
Sertraline titrates in multiple steps (eight to the FDA maximum), just works, and does not have much in the way of med-med interactions.
“you can titrate it on multiple steps. Eight steps to the FDA maximum. Pretty useful. Secondly, just works. Works pretty great. Third, does not have much in the way of med-med interactions”
6:38Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 We use four first-line antidepressants, and when the choice is an SSRI it is sertraline or escitalopram. The first two antidepressants anyone should be using are always one of those two.
“to me, the first two antidepressants anyone should be using to me are always, it's either sertraline or escitalopram”
13:03Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 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 In OCD we like sertraline or escitalopram because they have fewer med-med interactions, though any SSRI is fine, and in PTSD we use sertraline. In both we avoid paroxetine because it tends to cause weight gain.
“I like to use Zoloft or Lexapro because they tend to have less med-med interactions, but really any SSRI is fine. I avoid Paxil because Paxil tends to cause weight gain”
16:20Practical OCD Psychopharmacology: Evidence‑Based (& Non Evidence-Based) Medication ApproachAug 2025 Also said in 1 more episode
“I do like to use sertraline. I try to avoid Paxil because I don't like to give people weight gain, as you know, with medications”
4:50PTSD Medications: Integrating Pharmacotherapy, Therapy, and the Treatment Frame | Episode 22Apr 2025
Dosing and titration
A common start is 25 mg for one week, then 50 mg if tolerated, staying there for a month before judging the effect. Prescribe 50 mg tablets and have the patient break the first four in half, and email the instructions after the visit so they do not have to remember everything.
“I'll start at 25 milligrams for a week and then move up to 50, stay there for a month, and then negotiate an effect. I usually will prescribe 30 of the 50 milligrams and say break the first four and a half”
12:35Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 Also said in 1 more episode
“we're going to do 25 milligrams for one week. If you're tolerating it at one week, increase to 50 milligrams. So I usually email the patient after the appointment so they're not overwhelmed with information that they have to remember”
18:27Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 50 mg is the minimum effective dose for the average patient.
“Zoloft 50 milligrams is my minimum effective dose for the average patient. And then Lexapro, I have somewhere between 5 and 10 as the minimum effective dose”
14:12Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 How fast you go depends on severity and how soon you can see the patient. For moderate depression with a four-week follow-up, aim to have them at 50 mg by the next visit.
“It really depends on the severity of the depression and how soon I can see the patient. So let's pretend we can see people in four weeks and it's moderate severity, right? For that, I would probably try to get them to 50 milligrams before the next visit”
17:08Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 The step from 100 to 150 mg gives patients real control: if it does not work out, take the 100 and half of the 50.
“what I like about doing the step from 100 to 150 is that you can say, listen, if this doesn't work out for you, take the 100 and half of the 50, giving the patients real control”
10:41Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 In OCD you can even take it above 200 mg, but do so with caution.
“It has few interactions. It is many There's many those types. Titrations and it works. And guess what? If you have OCD, you can even take it above 200 milligrams, but do so with caution”
12:29Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026
Compared with escitalopram
We generally prefer sertraline. There is more room for titration (four steps up to 100 and four up to 200, against two up to 10 and two up to 20), and it tends to have fewer interactions.
“Zoloft and Lexapro are my favorites. I generally prefer Zoloft. Why? Because more room for titration. You have four steps up to 100 and four steps up to 200 rather than two steps up to 10 and two steps up to 20. It's just a little easier to work with in that sense and tends to have less medication interactions”
9:55Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 Several CYP enzymes metabolize sertraline, while escitalopram is broken down by 3A4 and 2C19, and 2C19 has a lot of variants. Ultra-slow and ultra-fast metabolizers have a really bad response to escitalopram more often than to sertraline.
“Sertraline has a bunch of different sips that metabolize it. For patients that have ultra-slow or ultra-fast metabolization of whatever escitalopram is metabolized by, you will get patients who have really bad response to escitalopram more often than with sertraline”
8:20Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 Also said in 1 more episode
“Zoloft is highly variable in its metabolism, whereas Lexapro is really just broken down by 3A4 and 2C19. I always zone out once I start hearing the SIP stuff, but this is pretty simple. If someone has 2C19, there's a lot of variants”
10:12Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025 Both are fine choices partly because they have relatively fewer interactions. Even in a young patient, you never know if another medication will be needed for a new medical condition down the line.
“I think they're both fine choices because on top of the things that you just mentioned, they tend to have, relatively speaking, less interactions of other medications. Even if someone's young, you never know if they're going to have to add another medication for some kind of a new medical condition down the line”
11:22Psychiatrist's Guide to Anxiety Medications: First Line to Last ResortJun 2025
It also comes up on
- EscitalopramBeing the purest SSRI does not mean the fewest side effects. Sertraline is a little better tolerated overall, and some patients tolerate citalopram better than escitalopram, against what we are taught.
- FluvoxamineStart with an SSRI such as sertraline. With a partial response, consider raising it to a supratherapeutic dose; if you want to switch, fluvoxamine is the usual switch.
- SSRIsStart with sertraline. With a partial response, consider a supratherapeutic dose. If you want to switch, fluvoxamine is the usual next step.
- Affective neuroscienceMany patients get a label and a pill that kind of works: call it generalized anxiety disorder, give sertraline, and both sides put on blinders and pretend it is a categorical thing while the real problem goes undiscussed.
- AnxietyBupropion helps anxiety for some patients but worsens it for a lot of others, and for many anxious depressed patients sertraline will be much more effective. Patients with OCD, PTSD or anxiety on bupropion often get better when you pull it.
- BupropionIt helps anxiety for some patients but worsens it for a lot of others. For some depressed patients, sertraline will be a much more effective medication.
- DSM-5Categories can let both sides put their blinders on: call it generalized anxiety disorder, give Zoloft, it kind of works, and no one talks about the real problem.
- Major depressive disorderThe classic case: a 40-year-old with her first episode, low mood all day every day, low motivation, early awakening and leaden paralysis. Put her on a little sertraline and she will start responding right away.
From these episodes
- Anxiety Medications Tier List: The Best and Worst Treatments for GADJul 2026 · 2 points
- Antidepressant Tier List: Psychiatrists Rank Depression Medications for MDDMay 2026 · 3 points
- 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 · 3 points
- PTSD Medications: Integrating Pharmacotherapy, Therapy, and the Treatment Frame | Episode 22Apr 2025 · 1 point
- Treating Depression: Practical Tips & Pearls for Anti-Depressant MedicationsJan 2025 · 5 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.