Antidepressants Not Effective for Some Types of Depression

Antidepressant medications have been the mainstay of treatment for depressive disorders for decades. But these drugs may not be as effective as once believed, according to a new analysis published in the Journal of the American Medical Association (JAMA). Researchers at the University of Pennsylvania conducted a meta-analysis of data from trials of antidepressants and concluded that the drugs are not effective in mild to moderate depression.

The investigators examined the results of six randomized, placebo-controlled trials published from 1980 to 2009: three involving imipramine, a tricyclic antidepressant (TCA), and three involving paroxetine, a selective serotonin reuptake inhibitor (SSRI). Each trial lasted at least six weeks. In total, the meta-analysis included 718 adult patients with a Hamilton Depression Rating Scale (HDRS) score ranging from 10 to 39 at baseline. (The HDRS is a clinical standard used to measure the severity of depressive symptoms; a score of less than 7 is considered normal, or symptom remission, and a score of greater than 20 generally denotes at least moderate depression.) Slightly more than half (434) of the total number of patients in the meta-analysis were administered an active drug during their respective clinical trial, with the remaining 284 patients receiving a placebo.

Overall, the authors concluded that as the severity of depression increased, the effect of the antidepressant treatment increased. The authors noted a clinically significant difference with antidepressant treatment compared to placebo only in patients with baseline HDRS scores above 25, which indicates very severe depression. Treatment effects of antidepressants were negligible or nonexistent in patients with HDRS scores between 19 and 22 (severe depression) and less than 18 (mild to moderate depression). The authors speculate that any benefit from antidepressant therapy in mild to moderate depression may be due to the placebo effect.

So what is a patient with depression to do? The longest-standing treatment options may not be effective, and taking the drugs places patients at risks of drug interactions and harmful side effects, including suicidality and type 2 diabetes. With safe medications unavailable, patients with mild to moderate depression may achieve the most benefit from psychotherapy as first-line treatment. Some studies have even reported that psychotherapy is as effective as drug therapy in moderate and severe depression, though many maintain that a combination of psychotherapy and medication is the most effective treatment plan for more severe cases.

Patients with chronic depression, older patients, and patients with lower intelligence achieve less success with psychotherapy than comparative groups in moderate to severe depression. Alternatively, patients with depression who are married or experienced unemployment or recent stressful life events achieve significant success with psychotherapy alone. Though findings from these randomized, controlled trials support the effectiveness of psychotherapy in some cases depression, a related trial finds that the effectiveness of psychotherapy is only realized in the controlled setting of a clinical trial, and not in a normal outpatient setting. Findings like these underscore the need for individualized therapies and treatment settings for patients with all severities of depression.

Patients are not advised to change their depression treatment as a result of the new meta-analysis. The analysis only evaluated two drugs, each in three settings. It is not clear whether the results of the study can be extended to other TCAs or SSRIs or other classes of antidepressants. More research is needed to identify the etiology and pathology of depression, as well as the subgroups related to depression severity. Treatment options should always be tailored to individual needs and outcomes.


Fournier, J., DeRubeis, R., Hollon, S., Dimidjian, S., Amsterdam, J., Shelton, R., & Fawcett, J. (2010). Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis JAMA: The Journal of the American Medical Association, 303 (1), 47-53 DOI: 10.1001/jama.2009.1943

Fournier JC, DeRubeis RJ, Shelton RC, Hollon SD, Amsterdam JD, Gallop R. Prediction of response to medication and cognitive therapy in the treatment of moderate to severe depression. J Consult Clin Psychol. Aug 2009;77(4):775-787.

Gibbons CJ, Fournier JC, Stirman SW, Derubeis RJ, Crits-Christoph P, Beck AT. The clinical effectiveness of cognitive therapy for depression in an outpatient clinic. J Affect Disord. Jan 15.

Torpey, D., & Klein, D. (2009). Chronic depression: Update on classification and treatment Current Psychiatry Reports, 10 (6), 458-464 DOI: 10.1007/s11920-008-0074-6

Jennifer Gibson, PharmD

Jennifer Gibson, PharmD, is a practicing clinical pharmacist and medical writer/editor with experience in researching and preparing scientific publications, developing public relations materials, creating educational resources and presentations, and editing technical manuscripts. She is the owner of Excalibur Scientific, LLC.
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