Increasing Antidepressant Doses May Not Produce More Effective Results

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Although physicians are often faulted for failing to prescribe antidepressants at high enough doses, research has found that there may be no benefit to increasing doses beyond the calculated beneficial dose for a particular drug.

Many practitioners believe that when prescribing fluoxetine, if 20 mg is ineffective, the dose should be increased to 40 mg before ruling it out as ineffective. Based on this dosage, Yu Hayasaka, MD from the Kyoto University Graduate School of Medicine/School of Public Health and colleagues calculated equivalent doses for several other drugs, including bupropion at 300 mg, paroxetine at 30 mg, and sertraline at 100 mg. Based on these results, it might seem that these are the doses necessary to give a drug a fair trial.

However, data examining doses and their effectiveness does not support these amounts. Compilations of fixed-dose randomized trials conducted by Sheldon Preskorn, MD, of the Clinical Research Institute and Department of Psychiatry at the University of Kansas School of Medicine in Wichita show that doses beyond 5 mg of fluoxetine, 20 mg of paroxetine, and 50 mg of sertraline showed no further benefit.

Patricia Berney, MD, from the Clinical Psychopharmacology Unit at Geneva University Hospitals in Switzerland concludes that none of these medications warrant an increased dose if the initial dose is ineffective. When tricyclic antidepressants were prescribed in the past as treatment for depression, there were demonstrable minimum thresholds for effectiveness based on blood levels, meaning that an increased dose may have increased effectiveness. But for medications with flat dose-response relationships, a low dose may provide the same improvement as a higher dose.

However, Hugh Solvason, MD, and Charles DeBattista, MD, from Stanford University Department of Psychiatry explain that the lack of evidence for increasing doses does not directly argue against trying a higher dose. They point out that dosing trials are generally meant to demonstrate non-inferiority, and that detecting small differences between doses would require sample sizes in the hundreds, higher than the norm for these types of trials.

In conclusion, while trying higher doses of antidepressants may not be wrong, there is not currently evidence supporting higher doses as more effective. Clinicians should keep in mind that if a patient improves with a higher antidepressant dose, there may be other factors to account for it.

In the treatment of depression, primary care providers are often faulted for failing to give an antidepressant medication at a high enough dose. What is high enough? Answering this question turns out to be tricky.

Defining roughly equivalent doses of antidepressants is challenging enough. A Cochrane review team undertook a detailed analysis based on randomized trials.1 Their arduously computed value is shown in the middle column of the table, with clinically practical approximations on the right. (Available studies did not allow calculations for citalopram or duloxetine).

Many practitioners regard 20 mg of fluoxetine an inadequate dose for a full trial. They would routinely increase to 40 mg before allowing a conclusion of “been there, done that.” By extension, the dose equivalence table might suggest that doses in the right-hand column are minimums for fairtrials of each of these medications. But an examination of available data does not support this practice. Indeed, 5 mg of fluoxetine might be enough.

This article originally appeared here.
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