How Well Do Antidepressants Really Work?
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How Well Do Antidepressants Really Work?

Approximately seven million Americans take antidepressant drugs for depression and a variety of other disorders. A study, however, puts the effectiveness of antidepressants in question. Do they really work or is their purported effectiveness little more than marketing hype?

For the past couple of decades, antidepressant drugs have been credited for helping millions of people manage depression . In addition to being prescribed for depression, selective serotonin reuptake inhibitors (SSRIs) and newer antidepressants are increasingly being prescribed for anxiety disorders , eating disorders , premenstrual syndrome (PMS) , and other disorders. In spite of growing numbers of prescriptions for antidepressants, recent research suggests that they may not be any more effective for relieving depression than a dummy pill (placebo).

Please Note: On March 22, 2004, the US Food and Drug Administration (FDA) issued a Public Health Advisory that cautions physicians, patients, families, and caregivers of patients with depression to closely monitor both adults and children receiving certain antidepressant medications. The FDA is concerned about the possibility of worsening depression and/or the emergence of suicidal thoughts, especially among children and adolescents at the beginning of treatment, or when there’s an increase or decrease in the dose. The medications of concern—mostly SSRIs (Selective Serotonin Re-uptake Inhibitors)—are: Prozac (fluoxetine), Zoloft (sertraline), Paxil (paroxetine), Luvox (fluvoxamine), Celexa (citalopram), Lexapro (escitalopram), Wellbutrin (bupropion), Effexor (venlafaxine), Serzone (nefazodone), and Remeron (mirtazapine). Of these, only Prozac (fluoxetine) is approved for use in children and adolescents for the treatment of major depressive disorder. Prozac (fluoxetine), Zoloft (sertraline), and Luvox (fluvoxamine) are approved for use in children and adolescents for the treatment of obsessive compulsive disorder. For more information, please visit

Researchers Analyzed 47 Studies

Psychologists Irving Kirsch, PhD, of the University of Connecticut and Thomas Moore, PhD, of George Washington University analyzed the results of 47 studies on antidepressant drugs. The FDA used these studies for approval of the following antidepressants, which were prescribed most widely between 1987-1999:

  • Sertraline (Zoloft)
  • Paroxetine (Paxil)
  • Fluoxetine (Prozac)
  • Citalopram (Celexa)
  • Venlafaxine (Effexor)
  • Nefazodone (Serzone)

In each of the 47 studies, participants were given either an antidepressant or an inactive dummy pill (known as a placebo), but neither they nor the researchers knew which one they were taking.

Little Difference in Depression Scale Scores

At the beginning and follow-up of these studies, both sets of participants took the 50-point Hamilton Depression Scale to compare rates of depression before and after treatment. Overall, for participants taking the placebo (inactive dummy pill), the average improvement on the Hamilton Depression Scale was 8 points, whereas those given antidepressants had an average improvement of 10 points. According to lead researcher Dr. Kirsch, the difference is clinically negligible.

What Does This Mean?

According to Dr. Kirsch, although the mean differences between the antidepressants and placebo were small, statistically the drugs appear to be more effective than the placebo. However, the small difference between the drug and placebo can be viewed in two different ways:

  • The antidepressants actually had an effect, albeit a small one. OR
  • The antidepressants had little effect and the difference resulted from an enhanced placebo effect.

The Placebo Effect: Reflecting the Powers of the Mind

Placebos are substances with no known pharmacologic value. The placebo effect occurs when participants in a study experience improvement after taking what they think could be a powerful treatment when, in fact, they are only taking a placebo. This effect has been studied extensively for the treatment of pain. Most recently the wider use of functional MRI’s has shed some additional light on possible mechanisms of placebo action. From these studies we know that taking a placebo for the treatment of pain leads to release of endogenous morphine-like substances called endorphins that are able to modulate the pain perception. In this sense, placebo has a valid and real biological basis. Its effects are less clear for the treatment of depression, however the above mentioned endorphins have not only pain-killing properties, but also are able to elevate mood and therefore might be responsible for improvement of depressive symptoms.

Possible Enhanced Placebo Effect

In the antidepressant study, it is possible that the placebo effect was enhanced. Although participants were not told whether they were taking a placebo or an antidepressant, many were aware that antidepressants produce side effects. Participants having side effects could have concluded that they received the antidepressant and therefore expected to feel better, a belief that ultimately improved their mood. In this study, the enhanced placebo effect may be small, but the drug/placebo difference on the Hamilton Depression Scale was also small (only 2 points).

More Effective Measures May Be Needed

So how effective are antidepressants? According to the research presented by Dr. Kirsch and his colleagues, we really don’t know. Dr. Kirsch admits that there may be problems with the way drug trials are conducted. The design of the placebo-controlled studies may overshadow the true effectiveness of the antidepressants. In this study, it is assumed that the difference between the placebo’s effect and the drug’s effect is due to the efficacy of the drug. It’s possible that the placebo effect played a smaller role in the participants taking the antidepressant. This would mean that the antidepressants had a greater effect, which was indicated by the difference between the two figures.

The researchers concluded that better ways are needed to measure the effectiveness of treatments for depression. In addition to medication, depression is often treated with psychosocial interventions, exercise, and psychotherapy.

When considering the value of an intervention, such as antidepressant medications, the benefits and risks must be considered. The benefit s should be assessed according to the likelihood of beneficial effect (outcome) in a particular patient, the strength of the effect, and the quality of evidence. The highest quality of evidence comes from multiple studies that are placebo-controlled randomized controlled trials—such as the analysis of 47 studies described here. Intervention effects—in this case, the effect of medications—are assessed by statistical significance, but it’s important to consider “clinical significance” as well, which refers to the real world measure of benefit.

The risks to be considered include side effects, costs, and other issues. And, as noted above, the FDA placed a warning on SSRI-type antidepressants stating that the incidence of suicide is higher during the first few weeks of their administration. Given all these considerations, each individual patient should have an opportunity to discuss the likely benefits and risks of antidepressants in their individual situation with their doctor.

If you think you may be depressed or have concerns about your antidepressant medication, see your doctor.


American Psychiatric Association

American Psychological Association


American Psychological Association website. Available at: .

Kirsch I, Moore T, et al. The emperor’s new drugs: an analysis of antidepressant medication data submitted to the US. Food and Drug Administration. Prevention and Treatment. 2002; 5:1-11.

Last reviewed May 2006 by Marcin Chwistek, MD

Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.

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