News About the Blues? The Power of Placebo

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant to Cephalon and Ventus and serves on the speakers bureaus of Cephalon and Boehringer Ingelheim.

Synopsis: While antidepressants are clearly effective in patients with severe depression, their effects on those with mild or moderate depression may be insignificant.

Source: Fournier JC, et al. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA 2010;303:47-53.

These authors set out to evaluate the effects of anti-depressants on patients with a wide range of severity of depression. They hypothesized (based on previous studies) that more severely depressed patients would benefit most from medications, but they wanted to investigate the effects of antidepressants on the entire range of patients for whom antidepressants are now commonly prescribed in clinical practice.

To accomplish this, they did a literature search of a nearly 3 decades-long period (1980-2009), and found six studies that met their inclusion criteria (randomized placebo-controlled trials of an FDA-approved antidepressant in the treatment of the full range of adult patients with major or minor depressive disorder).1-6 They only included studies that provided data for a patient-level meta-analysis (this is known as a mega-analysis), which used the Hamilton Rating Scale for Depression (HAM-D),7 lasted at least 6 weeks, and did not eliminate participants based on a placebo washout period (which can results in an underestimation of the placebo response). Three of these studies used the tricyclic antidepressant imipramine, and three used the selective serotonin reuptake inhibitor paroxetine. The total pooled sample included 434 patients who received active antidepressant medication and 284 patients who received placebo. Individual baseline HAM-D scores ranged from 10 to 39. A word about HAM-D scores: The American Psychiatric Association defines mild depression as HAM-D scores of 8-13, moderate depression as scores of 14-18, severe depression as scores of 19-22, and very severe depression as scores of 23 or higher.8 The National Institute for Clinical Excellence (NICE) of the National Health Service in England has defined the threshold for clinical significance of a HAM-D score change as a drug/placebo difference of 3 points.9

There was a strong correlation between baseline severity of depression (as assessed by HAM-D score) and improvement with treatment with both active drug and placebo (e.g., the more depressed an individual was at the beginning of the study, the more he/she improved with any kind of treatment). But the critical difference in improvement of at least 3 points difference between placebo and active drug was only met for HAM-D scores of 25 (very severe depression) or higher. This relationship persisted even after controlling for dropouts and after elimination of the mildest patients from analysis. And it was true both for imipramine and paroxetine.


In other words, antidepressants don't help much except for those patients who are severely depressed, but they help those patients quite a bit. The authors conclude this paper with the following rather startling comment, "Prescribers, policy makers, and consumers may not be aware that the efficacy of medications largely has been established on the basis of studies that have included only those individuals with more severe forms of depression. This ... is not reflected in the implicit messages present in the marketing of these medications to clinicians and the public. There is little mention of the fact that efficacy data often come from studies that exclude precisely those MDD [major depressive disorder] patients who derive little specific pharmacological benefit from taking medications." What is so compelling about this statement to me is that these particular authors appear to have been around the block a few times with regard to antidepressant use. The three MD authors of this paper have had significant interaction with the pharmaceutical industry, according to disclosures at the end of the paper. These authors have published extensively in this particular field. They probably know what they are talking about, and they appear to be sounding a warning about overprescription of antidepressants.

They do note, however, that antidepressants appear to be effective for dysthymia, which is a chronic condition characterized by lower symptom levels than major depression; they point out that antidepressants produce a true drug effect in patients with mild or moderate dysthymic symptoms, and they attribute this to the fact that dysthymia is a chronic condition, and chronicity is associated with poor response to placebo.

Am I the only one confused about the difference between depression and dysthymia? Isn't dysthymia just a milder form of depression (exactly what the authors of the current paper say doesn't respond any better to antidepressants than to placebo)? According to the National Institutes of Mental Health, "There are several forms of depressive disorders ... [including] ... major depressive disorder and dysthymic disorder. Minor depression is also common.

"Major depressive disorder, also called major depression, is characterized by a combination of symptoms that interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities. Major depression is disabling and prevents a person from functioning normally. An episode of major depression may occur only once in a person's lifetime, but more often, it recurs throughout a person's life.

Dysthymic disorder, also called dysthymia, is characterized by depressive symptoms that are long-term (e.g., 2 years or longer), but less severe than those of major depression. Dysthymia may not disable a person, but it prevents one from functioning normally or feeling well. People with dysthymia may also experience one or more episodes of major depression during their lifetimes.

Minor depression may also occur. Symptoms of minor depression are similar to major depression and dysthymia, but they are less severe and/or are usually shorter term."10

Frankly, I find the distinction between dysthymia and minor depression somewhat vague, but it appears to rely largely on the longer duration of symptoms with dysthymia (which may, of course, be difficult to sort out).

Where does this leave us in caring for the patient with mood disturbances? It suggests that milder, acute depression may not respond any better to drugs than to placebo. But chronic mood disturbance and more severe depression probably do.


1. Barrett JE, et al. Treatment of dysthymia and minor depression in primary care: A randomized trial in patients aged 18 to 59 years. J Fam Pract 2001;50:405-412.

2. DeRubeis RJ, et al. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry 2005;62:409-416.

3. Dimidjian S, et al. Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression. J Consult Clin Psychol 2006;74:658-670.

4. Elkin I, et al. National Institute of Mental Health Treatment of Depression Collaborative Research Program: General effectiveness of treatments. Arch Gen Psychiatry 1989;46:971-982.

5. Philipp M, et al. Hypericum extract versus imipramine or placebo in patients with moderate depression: Randomised multicentre study of treatment for eight weeks. BMJ 1999;319:1534-1538.

6. Wichers MC, et al. Reduced stress-sensitivity or increased reward experience: The psychological mechanism of response to antidepressant medication. Neuropsychopharmacology 2009;34:923-931.

7. Hamilton MA. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.

8. American Psychiatric Association Task Force for the Handbook of Psychiatric Measures. Handbook of Psychiatric Measures. Washington, DC: American Psychiatric Association; 2000.

9. National Institute for Clinical Excellence. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence; 2004.

10. National Institutes of Health. What are the different forms of depression? Available at: Accessed Jan. 11, 2010.