The debate over the effectiveness of antidepressants for mild to moderate depression

March 3, 2011

Ever since fluoxetine (Prozac) came on the scene in 1988 and was touted as something of a "miracle" drug, the use of antidepressants has skyrocketed. By 2005 (the most recent year for which statistics are available), these depression medications were being prescribed for one out of 10 Americans, an all-time high. With this massive increase in usage, however, has also come controversy over whether antidepressants work for mild to moderate depression.

First, the U.S. Food and Drug Administration (FDA) mandated a black-box warning on all antidepressants to alert users and doctors to a possible increased risk of suicides in children, teenagers, and young adults. More recently, accumulating research indicates that antidepressants are often just as effective for mild to moderate depression as placebos —the inert, dummy pills that the medications are tested against.

The National Institute of Mental Health estimates that nearly 15 million Americans have major depression and more than three million struggle with milder forms of the disease each year. If you're in the latter group, you might wonder what to make of the recent research. Is there a place for antidepressants in your depression treatment?

Research on Antidepressants for Mild to Moderate Depression

A January 2010 review in the Journal of the American Medical Association (JAMA) added fuel to the fire by concluding that not only people with mild to moderate depression but also those with severe depression received no more benefit from taking an antidepressant than a placebo. For those with very severe depression, however, the benefits of antidepressants were significant.

Researchers pooled the results of six randomized, controlled trials that compared the effects of antidepressants with those of a placebo in people with varying degrees of depression. In total, the studies included 718 adults who rated their depression from mild to severe using the widely accepted Hamilton Depression Rating Scale; a score in the low to high teens is considered mild to moderate depression and over 23 is very severe. Compared with placebos, the drugs were found to cause a much more significant reduction in symptoms among those with scores of 25 or higher; participants with scores of less than 25 reported little or no benefit from the medications.

One criticism of the JAMA analysis is that the studies focused on only two of the more than 25 antidepressants on the market: the selective serotonin reuptake inhibitor (SSRI) paroxetine (Paxil, Pexeva) and the older tricyclic imipramine (Tofranil). In addition, imipramine is rarely used today, and because of its side effect profile, paroxetine is not a commonly used SSRI.

Second, successfully treating depression with medications often requires trial and error; many individuals do not experience an improvement in symptoms with the first antidepressant prescribed. For example, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, only 37% of participants found relief with the first drug they tried. By the time the remaining participants had tried up to three other medications, 67% of them had recovered.

Depression Treatment: The Placebo Effect

The JAMA study shows that a substantial portion of the effect of antidepressants in people with mild to severe —but not very severe —depression can be attributed to the placebo effect. While almost any disorder can respond to a placebo, the percentage of those in depression studies who improve while taking a dummy pill is generally higher than with other conditions.

A 2002 review in JAMA of 75 placebo-controlled antidepressant trials found that 32 to 70% of participants (average 50%) responded to antidepressants, but so did 13 to 52% (average 30%) of those who received a placebo, showing that the placebo effect is strong in the treatment of depression. This analysis likely underestimates the effectiveness of placebos for depression, since studies that show positive results for a drug are more likely to be published than those with negative results. What's more, the placebo effect for antidepressants may be even higher among older adults, according to the findings of a 2005 review of 68 randomized, placebo-controlled trials published in the Journal of Clinical Psychopharmacology.

Why do so many people with depression respond to placebos? Simply being included in a study has a therapeutic effect: The participants feel listened to and cared for and obtain an evaluation of their condition and an explanation for their symptoms. This education and support offer important forms of treatment for depression. The participant's and the doctor's anticipation of an improvement also contributes to the placebo effect.

Natural Fluctuations in Depression Symptoms

In people with depression, symptoms tend to fluctuate and can get better on their own. Some studies have shown that bouts of clinical depression last about six to 10 weeks in half of the people who do not receive treatment. Thus, a significant number of people who begin taking an antidepressant or a placebo may show improvement weeks later because of the natural course of the disorder. Also, because individuals tend to come in for treatment when their symptoms are at their worst, they are more likely to show improvement when they are subsequently re-evaluated, whether they are taking the medication or a placebo.

Based on these findings, some researchers have concluded that about half of an antidepressant's effect is due to the placebo effect, a quarter is due to natural fluctuations in depressive symptoms, and another quarter is the result of the active medication.

Publication Review By: Karen L. Swartz, M.D.

Published: 03 Mar 2011

Last Modified: 20 Aug 2013