Which SSRI should I choose?

What follows is a brief summary of the clinically important differences between the SSRIs, followed by 5 patient cases that ask, “Which SSRI?”  

The five SSRIs most commonly used in the US for depression and anxiety are fluoxetine, paroxetine, sertraline, citalopram, and escitalopram.  The sixth SSRI, fluvoxamine, is mainly used to treat OCD.   All of the SSRIs are available as generic medications. As you can see in the image above, the SSRIs have very different chemical structures, with the exception of citalopram and escitalopram. Escitalopram is S-citalopram. Citalopram is a racemic mixture of S-citalopram and R-citalopram.   

Although the FDA indications vary, all the SSRIs are effective in the treatment of major depression, generalized anxiety disorder, social anxiety disorder, panic disorder, OCD, and PTSD.  The SSRIs also have similar side effects, including sexual side effects, weight gain, emotional numbing, and increased sweating.  However, individuals may benefit from different SSRIs, and get different side effects from different SSRIs.  If a patient finds one SSRI ineffective, we don’t need to avoid trying another SSRI.  And if a patient experiences anorgasmia from one SSRI, we can’t presume they will have sexual side effects from another SSRI.

To summarize: Although these medications are all part of the SSRI class of medications, they are also individual drugs that are not interchangeable.  

Clinically important differences between the SSRIs

MedicationChoice Among SSRIsSedating or activatingPearls and tidbits
Escitalopram (Lexapro)1st line, only SSRI considered “most effective” and “most acceptable”*SedatingFew drug-drug interactions
1st lineNot sedating or activatingHigher incidence of diarrhea than other SSRIs
2nd line due to potential drug-drug interactions
Long half-life** makes this a good choice for people who forget pills or prefer non-daily dosing 
ActivatingPan-CYP-450 inhibitor (2D6, 3A4, 2C19) = many drug-drug interactions
Least likely to cause SSRI withdrawal when it is stopped
Least likely to cause weight gain
3rd line due to side effect risk. 
Reasonable to use in someone who has done well on paroxetine previously
Most sedating Higher incidence of sexual side effects, weight gain, and anticholinergic side effects than other SSRIs
Higher incidence of withdrawal  symptoms when it is stopped. 
Strong CYP-450 inhibitor (2D6) = drug-drug interactions
4th line due to QTc prolongation. Choose escitalopram instead.
Citalopram 20mg is equivalent to escitalopram 10mg
SedatingBlack box warning for QTc prolongation at higher doses. 
If someone is stable on high dose citalopram(60mg+), get an EKG.  If the QTc is normal, there is no need to change the med.
Commonly used for OCD
Use the ER formulation to reduce GI side effects and allow for once daily dosing 
SedatingCYP-450 inhibitor (1A2, 3A4, 2C9, 2C10) = many drug-drug interactions
*Based on a network meta-analysis (Cipriani 2018).  [Because I know you’re curious, vortioxetine (Trintellix) is the other medication on both of these lists.]
**The half life of fluoxetine is about 5 days, and of the half-life of its active metabolite norfluoxetine is more than a week


A 28 yo woman who agrees she needs a medication for depression, but doesn’t want to take a medication every day.  “It makes me feel like a sick person.”  Which SSRI?

Fluoxetine: All of the SSRIs other than fluoxetine have half-lives of less than a day.  The long half life of fluoxetine allows it to be dosed every other day, or even once a week for low-dose fluoxetine.   I would ask this woman how many days a week she thinks that she can take medication, and then make a plan.   For example, if she told me she can take a pill 3 times a week, M/W/F.  I would recommend that she take fluoxetine 20mg daily for a couple of weeks, and then switch to taking fluoxetine 40mg on M/W/F.

A 68 yo man has a complicated medical history, including HTN, CAD on clopidogrel, DMII. He benefited from escitalopram for his generalized anxiety, but found that it made him “too darn sleepy during the day.”  You advise him to try taking it at night, which helps a little bit with daytime sedation, but not enough.  He is open to trying a different medication.  Which SSRI? 

Sertraline:  If escitalopram is too sedating, sertraline or fluoxetine would be reasonable alternatives that are likely to be less sedating.  However, I would choose sertraline for this patient because of drug-drug interactions. Fluoxetine is a CYP 450 2C19 inhibitor that may decrease the serum concentrations of the active metabolites of clopidogrel.

A 50 yo woman has a history of 5 episodes of severe major depression. She presents to establish primary care.  She has been stable for years on citalopram 60mg daily. Which SSRI?

Citalopram + EKG: This woman has a serious history of depression that is fully controlled on a citalopram 60mg daily.  The recommended maximum dose of citalopram is 40mg daily because of the cardiac side effect of QTc prolongation.  With an EKG, we can test whether this dose of citalopram is causing QTc prolongation in this woman.  If it’s not, there’s no reason to change what is working.

 A 33 yo woman has panic disorder and IBS with predominant diarrhea. She is very fearful about starting any medication. Which SSRI?

Escitalopram: The first line treatment for panic disorder is an SSRI.   In this patient, any SSRI other than sertraline (which causes more diarrhea than other SSRIs) would be ok.  But for all the reasons above that make escitalopram “first line” among the SSRIs, I would choose escitalopram. 

A 42 yo person had 2 prior episodes of severe major depression with prominent insomnia, both of which resolved with paroxetine 40mg daily without significant side effects.  Which SSRI?

Paroxetine, titrated to 40mg daily:  Because of the higher rate of side effects, drug-drug interactions, and more severe withdrawal syndrome when stopped, I don’t often reach for paroxetine.  But in a patient who previously found paroxetine effective, tolerated it well, and was able to stop it without problems,  I would absolutely choose paroxetine.  Which antidepressant to choose? Whatever worked before.


Cipriani, Andrea, et al. “Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.” Focus 16.4 (2018): 420-429.

Chemical structures of the SSRIs in the image are from “Selective serotonin inhibitor.” Wikipedia, Wikimedia Foundation, 03 February 2023, https://en.wikipedia.org/wiki/Selective_serotonin_reuptake_inhibitor

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