13 Nov 2025 [159] Escitalopram vs. citalopram: one enantiomer’s dominance reflects marketing, not evidence

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Plain Language Summary

Escitalopram vs. citalopram: one enantiomer’s dominance reflects marketing, not evidence

What is this research about?

This research looks at two drugs, escitalopram and citalopram, to see if one works better or is safer than the other.

What are these drugs used for?

Both medicines are used to treat depression and anxiety. They belong to a group of drugs called SSRIs (selective serotonin reuptake inhibitors). Serotonin is a chemical messenger found in the brain and elsewhere in the body. It is believed to influence mood and has many other actions throughout the body.

What are escitalopram and citalopram?

Citalopram (often sold as Celexa) is a common antidepressant. It includes two “mirror-image” molecules, like a pair of left and right shoes.

The newer, more expensive version is escitalopram (often sold as Cipralex in Canada). It is made of only the “left shoe” molecule. The drug company patented this new “single shoe” version so that it could continue to make money when the original patent on citalopram ran out.

Why was the Therapeutics Initiative (TI) research needed?

Even though the newer drug escitalopram costs more, it has become the most prescribed SSRI in British Columbia. This happened because of the company’s marketing efforts that said it works faster, is more effective, and causes fewer side effects. The TI researchers wanted to find out if the marketing claims are true.

How did the researchers check the marketing claims?

The researchers did a “systematic review.” They identified 17 clinical studies that compared the two drugs with each other and analyzed the results. Almost all of these studies were paid for by drug companies and had a high chance of bias because the studies were designed in a way that could make the new drug look better than it really is.

What did the researchers find?

They found no real difference between citalopram and escitalopram in how well they work or how safe they are. This means that for the average patient, the newer more expensive drug does not work better, does not work faster, and is not any safer than the older less expensive drug.

What do the TI researchers recommend?

Because the two drugs work the same, citalopram is the better choice for most new patients who are just starting an SSRI to see if it will help them. It costs less and works just as well.

If a patient is already taking escitalopram, prescribers and pharmacists can think about switching to citalopram, using twice the dose in milligrams. This can achieve the same effect, while saving money for a patient.

Escitalopram vs. citalopram: one enantiomer’s dominance reflects marketing, not evidence

Abstract

Background: Citalopram is a racemic selective serotonin reuptake inhibitor (SSRI). Its S-enantiomer, escitalopram, was introduced as an “evergreened” product to extend patent life. Despite a higher cost, escitalopram has become the most prescribed SSRI in British Columbia, largely due to marketing claims of faster onset, superior efficacy, and fewer adverse effects. This shift in prescribing occurred despite clear evidence that escitalopram is no more efficacious, nor safer, than citalopram.

Aims: This Therapeutics Letter reassesses the comparative efficacy and safety of escitalopram and citalopram for treatment of major depressive disorder and anxiety disorders through a systematic review of head-to-head randomized controlled trials (RCTs). We appraised study quality, publication bias, and reported outcomes to determine whether any clinically meaningful differences in efficacy or safety justify escitalopram’s market dominance, despite its higher cost.

Recommendations: A review of 17 RCTs (all at high risk of bias) showed that escitalopram has no clinically meaningful advantage over citalopram. For new prescriptions, citalopram is the recommended choice, as it is significantly less expensive. To achieve cost savings for patients, clinicians should consider switching escitalopram prescriptions to citalopram at a 2:1 equipotent dose.

Escitalopram vs. citalopram: one enantiomer’s dominance reflects marketing, not evidence

Vignette: A patient who has taken escitalopram for years is concerned about rising prices of everything. She asks whether she could save money by switching to an antidepressant that costs less but will work as well as escitalopram for depression. She heard somewhere that citalopram is “the same thing,” but less expensive. As her prescriber or pharmacist, how do you answer the question?

Summary and conclusions

• Data from industry-sponsored and inherently biased randomized clinical trials (RCTs) show no significant difference in benefit or harm between escitalopram (one enantiomer) and racemic citalopram (both enantiomers of the parent drug).
• Generic escitalopram costs substantially more than citalopram, but is far more popular in British Columbia (BC).
• Tablet splitting could reduce costs for patients motivated to save money.

In 2002, Therapeutics Letter 45 concluded that escitalopram, the pure S-enantiomer of the racemic mixture citalopram, had no proven advantage over its parent drug.¹ Ten years later, the independent French drug bulletin La Revue Prescrire reached an identical conclusion, that we shared in Therapeutics Letter 85.²

Despite its substantially higher price, escitalopram has usurped citalopram as the most popular SSRI antidepressant in BC. During 2024, 185,502 British Columbians were treated with escitalopram, more than 3 times the 57,453 who received citalopram.³ (Figure)

But was this trend based on new evidence, or on marketing? This Letter updates our original findings with a fresh systematic review of evidence from randomized controlled trials (RCTs).⁴

British Columbia dispensing 2005-2024 escitalopram vs. citalopram

Racemic drugs vs. enantiomers

Many drugs are racemic mixtures, usually 50/50 blends of 2 mirror-image molecules known as enantiomers. Pharmacological effects of enantiomers can differ.^5,6 Some manufacturers isolate and market only one enantiomer, under a different brand name – claiming greater efficacy, faster onset, or fewer adverse effects. However, purported clinical superiority is not typically evidence-based.⁷

Citalopram is a racemic mixture of the S (+) and R (–) enantiomers.⁸ Escitalopram, the pure S-enantiomer, inhibits neuronal serotonin reuptake much more potently than R-citalopram.⁹ Thus, 10 mg of escitalopram is pharmacologically equivalent to 20 mg of citalopram.

Adjusting marketing to extend a patent

Citalopram entered the Canadian market in 1999, quickly becoming BC’s most prescribed antidepressant. With patent expiry and generic competition imminent, the Danish patent holder and original manufacturer (Lundbeck) introduced escitalopram in 2002, allowing it to remain a profitable competitor in the burgeoning antidepressant/anxiolytic market.¹⁰ This so-called “evergreening” is a widespread strategy to extend a product’s commercial lifecycle.¹¹ Other examples of substitution of a pharmacologically dominant enantiomer for the original racemic mixture include esomeprazole (Nexium) for omeprazole and dexlansoprazole (Dexilant) for lansoprazole.

A future Therapeutics Letter will review evidence about drugs re-marketed with other evergreening strategies, including lisdexamfetamine/Vyvanse, a “prodrug” or metabolic precursor of d-amphetamine, and the active metabolites of venlafaxine (desvenlafaxine/Pristiq), and of risperidone (hydroxyrisperidone/paliperidone/Invega).

Although racemic citalopram is often prescribed to treat anxiety, Health Canada never approved it for this indication.⁸ And without evidence of superiority over citalopram, it granted the anxiety indication to escitalopram.⁹ This facilitated the evergreening of what was essentially the same drug.¹⁰

Were we bamboozled?

First marketed in Europe in 2002, and in Canada in 2005, escitalopram was pitched as a “cleaner,” more effective version of citalopram. The Danish pharmaceutical company Lundbeck, and its United States (US) partner Forest Laboratories, claimed that removing the R-enantiomer would enhance and accelerate the onset of beneficial effects while reducing adverse effects in people treated for depression, anxiety, and panic disorder. Medical journal articles described escitalopram as a “refined” SSRI with greater receptor selectivity and therapeutic potency.^12-14

These claims were part of a comprehensive marketing campaign to prescribers, guideline developers, and policymakers.^15,16 But careful inspection of randomized controlled trials that compare escitalopram directly with citalopram leads to a different conclusion.

Marketing claims not justified

Lundbeck’s advertising claimed that escitalopram was “significantly more effective” than citalopram. Based on RCTs completed by 2002, Danish and Swedish regulators concluded simultaneously that evidence did not justify claims for the single enantiomer’s superiority.¹⁰ A Swedish academic pharmacologist also pointed this out in 2002.¹⁷ In 2003, the United Kingdom (UK) Prescription Medicines Code of Practice Authority ruled that claims of escitalopram’s superiority were misleading, and required their withdrawal.^18,19

Reassessing the evidence

During June 2024 we searched MEDLINE, Embase, PubMed, Epistemonikos, and Cochrane CENTRAL for head-to-head RCTs comparing citalopram with escitalopram for major depressive disorder (MDD) or anxiety in adults. We used the Cochrane risk-of-bias tool 2 (ROB-2) to assess study quality.²⁰

We identified 16 RCTs that compared escitalopram directly with citalopram for depression,^21-35 and 1 RCT for treatment of panic disorder.¹³ One RCT was published twice.^21,24

Lundbeck and its partner, Forest Laboratories, sponsored the initial RCTs in Europe and North America.^{13,21-24,26,27} All or most of the named investigators were Lundbeck or Forest employees, closely affiliated, or disclosed other conflicts of interest. Local manufacturers in India and Russia sponsored 2 published RCTs.^25,29

We identified 9 published Chinese RCTs,^28,30-35 including 3 described in a single English language report.³⁵ Translation of 5 Chinese language publications^28,30-32,34 allowed us to extract data. Of the 9 Chinese trials, non-commercial sponsorship was apparent for only the 3 RCTs pooled in a single English language publication.³⁵

Major depressive disorder: no meaningful difference

Sixteen RCTs (N=3,774 adults) compared escitalopram with citalopram for depression. We rated all 16 as at high risk of bias, warranting caution in interpreting their findings.^21-35 In no RCT did a difference in efficacy exceed the accepted threshold for a minimal clinically important difference (MCID) in depression. One of 2 US RCTs, the so-called SCT-MD-02, was not published. But in 2001, Forest Laboratories submitted its unpublished results to Health Canada and to the US FDA.²² This early direct comparison (8 weeks, N=386) found no difference between escitalopram and citalopram. The 2014 pooled analysis of 3 apparently unconflicted Chinese RCTs (total N=777) also reported no advantage of escitalopram over citalopram – neither in any individual trial, nor in the combined results.³⁵

Of 16 RCTs, 3 reported statistically significant benefits for escitalopram in response and remission.^24,26,29 Our detailed critical appraisal suggested that these published results are unlikely to reflect a true advantage of escitalopram for depression.⁴

Chinese language reports of 3 RCTs suggested that escitalopram might produce earlier symptom improvement than racemic citalopram.^30-32 However, these trials were not designed to investigate the timing of therapeutic onset; and at later evaluations the reported early differences were not sustained. In 2 of these 3 RCTs, the week 1 differences did not surpass the threshold of a MCID.^30,31 Data reported from the third³² were insufficient for us to evaluate any possible clinically meaningful advantage of escitalopram.

Safety profiles of escitalopram and citalopram are comparable. A 2012 US FDA Safety Announcement reported that citalopram at equivalent doses prolongs QTc by about 4-6 ms more than escitalopram.³⁶ But the FDA did not consider this clinically significant at or below the recommended maximum daily doses. We found no evidence that R-citalopram causes unique adverse drug reactions.

Anxiety disorders: thin, inconclusive evidence

A single RCT, published in 2003 before escitalopram was licensed in Canada, compared it with citalopram and placebo for panic disorder.¹³ This 3-way trial (total N randomized >366) evaluated pharmacologically equivalent doses of escitalopram (mean 10.8 mg/d) and citalopram (mean 21.3 mg/d) separately against placebo, but did not compare them with each other. The authors, all Lundbeck and Forest Laboratories employees or closely affiliated, did not claim superiority of escitalopram over citalopram for the primary outcome of weekly panic attacks. And for escitalopram vs placebo, the reported mean difference was a reduction of less than 0.3 panic attacks per week – from a baseline mean of 5 attacks per week.

While the authors reported trivial differences favouring escitalopram on some secondary outcomes, reporting of this experiment was substandard. The numbers of patients remaining in the trial over 6 assessments up to 10 weeks were not reported, and a pre-specified statistical analysis plan was not described. Without valid evidence, the journal report implies that escitalopram reduced panic and anxiety scores faster than citalopram. But a minimal clinically important difference has not been validated for the Modified Sheehan Panic and Anticipatory Anxiety Scale scale used for the RCT. As with the 16 RCTs of depression treatment, this report in the influential Journal of Clinical Psychiatry does not meet publication standards long accepted by 2003.

Agitation in Alzheimer’s disease: no difference

A RCT published in 2014, funded by the United States National Institute on Aging and the National Institute of Mental Health, compared citalopram at 30 mg/d with placebo for agitation in people with probable Alzheimer disease (N=186). Results suggested that citalopram might reduce patients’ agitation, and distress in their caregivers.³⁷ However, slightly worsened cognitive scores and QT prolongation led the investigators to hypothesize a specific adverse effect of R-citalopram.³⁸

These findings engendered a second RCT (N=173) that compared escitalopram at the equivalent dose of 15 mg/d with placebo for people with Alzheimer’s dementia. Published in March 2025, this RCT found that escitalopram was “not effective in treating agitation in AD,” and was also associated with cardiac conduction delays, and more falls and diarrhea than placebo.³⁹ Refuting their experimental hypothesis, the investigators concluded that their results “provide no reason to think that escitalopram is superior to citalopram, and, in fact, it might be inferior.”

Adverse effects: no advantage to escitalopram

Product monographs indicate that compared with placebo, both escitalopram and racemic citalopram cause more nausea, diarrhea, insomnia, dry mouth, dizziness, fatigue, somnolence, sweating, sexual problems, and total withdrawals due to adverse effects. In all 17 RCTs comparing escitalopram with citalopram, the incidence of adverse effects was similar. QT interval prolongation has often been cited as a concern for citalopram, but was not adequately reported in most of the 17 RCTs that compared citalopram with escitalopram. None identified a lower risk of QT-related adverse effects from escitalopram. There is also no observational evidence to suggest a difference.

Evidence summary

Our analysis of RCTs that compared escitalopram with racemic citalopram is the most comprehensive performed.⁴ By including unpublished regulatory submissions and translating trials available only in Chinese, we resolved errors and omissions in previous reviews. This expanded evidence base shows that selective publication and industry sponsorship have facilitated unsupported marketing claims that the single enantiomer escitalopram is superior to the original racemic mixture. Despite its remarkably successful promotion, there is no valid evidence that escitalopram offers a clinically meaningful advantage for efficacy or safety outcomes in depression, anxiety, or panic disorder.

Price favours citalopram

The Table shows a range of 2025 retail prices in BC. At equivalent doses, escitalopram is significantly more expensive than citalopram. For example, 20 mg of generic citalopram costs less than half as much as 10 mg of generic escitalopram. Branded versions are far more expensive. Splitting higher dose tablets could reduce ingredient costs for patients taking either drug.

BC price comparison 2025 – equivalent doses

Implications for clinical practice if you prescribe either drug

• For new prescriptions: Choose citalopram – equally effective and safe, but significantly less expensive.
• When ongoing drug treatment is clinically indicated for patients already taking escitalopram, 2 options are rational:
  a) To save money, switch to citalopram at a 2:1 equipotent dose e.g., citalopram 20 mg/d = escitalopram 10mg/d.
  b) If cost is not a concern, continue escitalopram.
• Splitting tablets can save money for patients taking long-term drug therapy. Because their half-lives exceed 1 day, neither citalopram nor escitalopram require controlled release formulations.

Vignette resolution: For once, it is easy to answer your patient’s question. Escitalopram is no better than citalopram, but it does cost more. While potential savings are modest, your patient is pleased, and wants to switch. At a time of economic uncertainty, you are inspired to check your electronic records for other patients who might like to save money, or for whom an SSRI may no longer be clinically necessary.

Data availability statement

Access to data provided by the BC Ministry of Health is subject to approval but can be requested for research projects through the Data Stewards or their designated service providers. The following data sets were used in this study: PharmaNet, MSP, DAD, NACRS, Client Roster. All inferences, opinions, and conclusions drawn in this publication are those of the authors, and do not reflect the opinions or policies of the Data Stewards. The data was provisioned under ISA 16-036.

The Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.

Video

Watch the recording of a presentation on this topic (30 min) given by Dr. Aaron M Tejani at the TI Best Evidence for Clinicians Annual Course on November 28, 2025:

References

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