SSRI Doses – Higher May Be Better

Peter Forster Major Depression, Treatments of Depression

SSRI Doses – Optimal Doses May Be Higher than Usual Doses

One of the questions that often comes up has to do with the patient who has a partial response to a serotonin antidepressant but who remains depressed. Should we increased the dose about the standard initial dose, should wait and see if there’s further improvement? Should we add a new medication, or should we switch to a different antidepressants? Because these medications are usually better tolerated than tricyclic antidepressants, when they were first released it was common to rapidly titrate the medications upward. A study done and reported in the Journal of Clinical Psychopharmacology soon after the release of fluoxetine compared waiting to see if fluoxetine would have a delayed improvement in people who had not had a full response to 20 mg a day to titrated upward by 20 mg a day every two weeks. That study suggested that increasing the dose relatively rapidly was not associated with significant further improvements in mood but was associated with more side effects.

An important meta-analytic review suggests that higher doses of SSRIs may be more effective, although at a cost of more side effects.

The authors came up with the following table of dose equivalents for the SSRIs.

Medication Imipramine Sertraline Fluvoxamine Paroxetine Fluoxetine Citalopram Escitalopram
Dose 100 mg 120 mg 100 mg 20 mg 20 mg 33.3 mg 16.7 mg

They then looked at outcomes using a sophisticated model that considered outcomes adjusted for duration of treatment.

In dose-by-time interaction analyses, higher doses were associated with higher treatment response (lower number needed to treat or NNT). The greatest effects were found at around  200–250-mg imipramine equivalents, the improvement in outcomes was not insignificant. At higher doses the NNT compared with placebo was 3, which is a very strong effect, whereas at lower (or standard) doses the NNT was 14-16 which is a small effect.

Higher dose was associated with greater likelihood of dropout due to side effects (Although the number needed to harm, or NNH, was 45–48 which is a pretty small risk)

However, all-cause dropouts were fewer at higher doses, again suggesting that higher doses had more efficacy.

Optimal doses would then be sertraline 250 mg, paroxetine 40 mg, fluoxetine 40 mg, escitalopram 30 mg.

Citalopram carries an FDA warning against higher doses due to the potential of this agent to increase QTc and therefore the possibility it may be associated with heart arrhythmias.

This is a summary of the study that was published online in the American Psychiatric Association’s Psychiatric News Alerts:

“A team of researchers in the United States and London searched PubMed for randomized, placebo-controlled trials that examined the efficacy of SSRIs for treating adults with major depressive disorder and assessed improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses.

Based on an analysis of 40 studies involving 10,039 participants, the investigators found a statistically significant positive association between SSRI dose and measured efficacy of SSRIs in reducing depression severity, with the greatest measured efficacy of SSRIs observed in the dosing range of 200–250 imipramine equivalents.”


Jakubovski E et al. Systematic review and meta-analysis: Dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry 2015 Nov 10; [e-pub]. (

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