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What Is the Best Antidepressant?

A new review study compares 21 antidepressants.

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Do antidepressants work? If so, which are most effective? These two questions have been posed again and again over the last few decades, but the answer has remained elusive.

The latest answer to the question of which antidepressants are most effective and well-tolerated comes from a 2018 paper. Published in The Lancet, the paper reports the results of the largest meta-analysis conducted to date on the acceptability and efficacy of 21 antidepressant treatments.1

Antidepressant Trials: Methods

In the study, acceptability (i.e. treatment-discontinuation)—which may serve as a proxy for the severity of side effects—was determined by measuring the percentage of participants who quit the treatment. Efficacy was determined by measuring the number of patients whose depression scores dropped by 50% or more.

The authors, Cipriani and colleagues, examined 522 double-blind studies—some of which were placebo-controlled (they compared a drug against an inactive substance) and some were head-to-head trials (they compared one antidepressant against another).

The trials involved 116,477 patients (mean age of 44 years; 62% women) who had been randomly assigned to one of 21 antidepressant drugs or placebos. Nearly half of the studies had recruited patients from North America, 27% from Europe, and 7% from Asia. Most of the participants had moderate or severe major depressive disorder. The median duration of the antidepressant treatment was 8 weeks.2

The antidepressants evaluated in these clinical trials included:

Agomelatine (Valdoxan), amitriptyline (Elavil), bupropion (Wellbutrin), citalopram (Celexa), clomipramine (Anafranil), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), levomilnacipran (Fetzima), milnacipran (Savella), mirtazapine (Remeron), nefazodone (Serzone), paroxetine (Paxil), reboxetine (Edronax), sertraline (Zoloft), trazodone (Desyrel), venlafaxine (Effexor), vilazodone (Viibryd), and vortioxetine (Brintellix).

To reduce bias, the authors tried to use not only published but also unpublished data, such as from trial registries, on these medications. They could only do so, however, for “agomelatine, escitalopram, paroxetine, reboxetine, sertraline, venlafaxine, vilazodone, and vortioxetine” (p. 1365).2

Antidepressant Trials: Findings

In head-to-head trials, the results showed that seven antidepressants—agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine—were more effective than other antidepressants.

The results showed the most acceptable antidepressants were agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine; least acceptable (ones with the highest dropout rates) were amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine. Only fluoxetine and agomelatine had fewer dropouts as compared to placebo.

In the treatment of major depressive disorder, all the antidepressants reviewed were more effective than placebo; however, some (escitalopram, paroxetine, mirtazapine, sertraline, and agomelatine) were associated with a low dropout and high response rate, while others (trazodone, reboxetine, and fluvoxamine) were associated with inferior acceptability and efficacy.

After considering acceptability, the authors suggested that the antidepressants agomelatine, vortioxetine, and escitalopram should be considered first-choice treatments for depression.3

Agomelatine, which appears to act on both the melatonin and serotonin systems, has not been approved by the FDA (perhaps because several previous studies concluded agomelatine had a smaller effect size than other antidepressants examined).

Vortioxetine is considered a serotonin modulator and was approved by the FDA in 2013.

Escitalopram, a well-known selective serotonin-reuptake inhibitor (SSRI), was approved by the FDA in 2002.

Source: Vitabello/Pixabay

What Is the Best Antidepressant Treatment?

Does the 2018 study provide the ultimate answer to “what is the best antidepressant for people with depression?” Not exactly. For one, it focuses on adults only. A 2016 review of 14 antidepressants (34 trials, 5,260 patients) in children with depression concluded that fluoxetine was the best option for this age group.4

Another criticism is that the researchers did not examine how antidepressants affect depression subtypes.5 The diagnosis of depression says nothing of the cause of depression, writes Gordon Parker, just as a diagnosis of “major breathlessness” does not specify whether breathlessness is caused by asthma or pneumonia.

Why does this matter? Because treatments helpful in some subtypes of depression (e.g., subtypes with a strong genetic component) may not be effective in other forms of depression (e.g., depression associated with situational components like poverty or childhood abuse).

In contrast to the view above, a 2015 paper found a very significant overlap in how people with different subtypes of depression respond to treatment; the authors concluded, “subtypes may be of minimal value in antidepressant selection” (p. 743).6

Aside from subtypes, another issue is the applicability of the review’s findings. One writer argues the findings of this meta-analysis do not make it easier to choose an antidepressant, given that the most effective medications were not necessarily the most acceptable ones, and the most effective one (amitriptyline) carries major overdose risks.7

Other researchers, like Parikh and Kennedy, have criticized the statistical method (network meta-analysis) used in the study, noting that while it has many advantages, it does not allow for “analysis at the individual patient level and so cannot provide finer detail on who might preferentially respond or who might be more vulnerable to side-effects” (p. 1333).3

Concluding Thoughts

The choice of antidepressant treatment depends on a number of factors, some of which are specific to the individual. Even a medication considered highly effective may not work for some people or might cause serious side effects. Therefore, it's necessary to consult with your treating physician before choosing an antidepressant.

Having said that, the study reviewed found the antidepressants agomelatine, escitalopram, and vortioxetine effective and tolerated well enough to be considered a first-line antidepressant treatment for depression. The authors note that their findings “represent the most comprehensive currently available evidence base to guide the initial choice about pharmacological treatment for acute major depressive disorder in adults” (p. 1366).2


1. Moncrieff, J. (2018). What does the latest meta-analysis really tell us about antidepressants? Epidemiology and Psychiatric Sciences, 27, 430-432.

2. Cipriani, A., Furukawak, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y.,...Geddes, J. R. (2018). 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. The Lancet, 391, 1357–66.

3. Parikh, S. V., & Kennedy, S. H. (2018). More data, more answers: picking the optimal antidepressant. The Lancet, 391, 1333-1334.

4. Cipriani, A., Zhou, X., Del Giovane, C., Hetrick, S. E., Qin, B., Whittington, C., . . . Xie, P. (2016). Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet, 388, 881-890.

5. Parker, G. (2018). The benefits of antidepressants: news or fake news? The British Journal of Psychiatry, 213, 454-455.

6. Arnow, B. A., Blasey, C., Williams, L. M., Palmer, D. M., Rekshan, W., Schatzberg, A. F.,...Rush, J. (2015). Depression subtypes in predicting antidepressant response: A report from the iSPOT-D trial. American Journal of Psychiatry, 172(8), 743–750.

7. Payne, R. (2018). Antidepressants—new answers, new questions. Prescriber, 29(6), 4.

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