Efficacy and Effectiveness of Antidepressants

Pharmacy TimesMarch 2011 Central Nervous System
Volume 77
Issue 3

Drug therapy for depression is steeped in controversy. As the debate about antidepressants' effectiveness continues, pharmacists must familiarize themselves with their complexity.

With more than 100 million prescriptions written each year for antidepressants, what should pharmacists know about the debate concerning benefits?

For the past several years, debate has raged on the subject of antidepressants. First, there was concern about the potential for increased suicide. Then, some studies were published suggesting that antidepressants may be less effective than previously believed, except in those patients who have the most severe depression.

• A placebo-controlled study published in January 2010 concluded that antidepressants’ benefits increase as the severity of patients’ depression increases, and they provide substantial relief for those with the most severe depression.1 In this meta-analysis, patients suffering from mild to moderate depression seemed to benefit little, if any, from antidepressants.

• Kirsch’s 2008 meta-analysis of antidepressant medications reviewed published and unpublished clinical trials. It also found that drug—placebo differences in antidepressant efficacy increase as a function of baseline severity. Further, researchers found that even in severely depressed patients, the effects are relatively small and possibly attributable to decreased responsiveness to placebo, rather than to increased responsiveness to antidepressants.2

• The very large government-funded 2006 Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study determined that only 1 in 3 patients who remained on treatment responded favorably to the first antidepressant prescribed, noting dropout rates were high. Only about half of the participants became symptom- free after 2 treatment levels.3,4

Thus, these 3 studies cast aspersions on the belief that antidepressants are effective. Patients—and clinicians—may be understandably confused. With more than 100 million prescriptions written each year for these drugs, what should pharmacists know about this debate?

Limitations, Always Limitations

Every study has limitations, and each study’s investigators do their best to recognize those limitations. Additionally, others—researchers, statisticians, clinicians, and patient advocates—often publish papers and analyses critiquing the study’s findings. This back-and-forth is the art of medicinal science. It helps to consider factors other than those that were or can be measured. Table 11,5-7 lists some of the comments that ameliorate, soften, or support the study findings described above.

Critiques of Antidepressant Efficacy Studies

Dropout Rates

Although today’s selection of antidepressants is larger—and safer—than ever before, side effects can still influence a patient’s adherence, even if the drug is helping the depression. Additionally, every patient is unique and will need a treatment plan tailored to his or her unique constellation of symptoms.

One of the best ways to approach this is to realize that absent laboratory tests or other physical monitoring methods that “prove” the depression is lifting, prescribers need to communicate clearly, encourage the patient to be a partner in his or her care, and use other available tools. Interventions rarely work like magic in any condition. In the case of mental illness, prescribers may need to try treatment steps sequentially to find a drug regimen that the patient tolerates and help the patient obtain remission.3,4

Step by Step

Spending a sufficient amount of time and asking pointed questions can help prescribers identify medications that have side-effect profiles acceptable to the patient. Titrating to optimal doses is essential, and if side effects become a problem, offering treatment choices is also important, especially given the number of alternative drugs and other interventions now available. Throughout treatment, but especially at treatment initiation, vigilant monitoring is important.3,4

For most antidepressants, we generally counsel patients that it may take up to 6 weeks to see improvement. In actuality, it can take longer—up to 3 months—for some patients to feel better. This can be a frustrating time for prescribers and patients.3,4 During this time, nondrug interventions can be a virtual lifeline for patients. Cognitive behavioral therapy, group therapy, a realistic exercise plan, and other similar interventions can help the patient cope and allow clinicians to monitor for worsening symptoms and suicidal tendencies. They may also keep the patient from stopping a treatment prematurely.

Don’t Give Up

It’s important to coach people who have depression if initial treatment attempts are insufficient or fail. This takes the form of reminding them that there are many available drugs and treatment strategies and that it may take time to find the best treatment strategy.3,4 It’s also essential to plan carefully when stopping or switching antidepressants. Some antidepressants, particularly short-acting medications, are associated with withdrawal symptoms (dizziness, nausea, sweating, chills, loss of appetite, etc).8 Patients may decide on their own to discontinue medication abruptly; this may lead to a plethora of uncomfortable withdrawal symptoms, and depression’s return weeks or months later.9

So although there is debate about antidepressants’ efficacy and effectiveness, there is also some debate about the studies and findings themselves. It is clear that in the real world, there are patients who benefit greatly from antidepressants, especially if their illness is severe and/or if they are prescribed and are adherent to other concurrent treatment modalities.

The Bottom Line

Depression is not easily treated and can be debilitating. For many people who present with mild to moderate depression, nondrug approaches such as exercise, psychotherapy, cognitive-behavioral therapy, or controlled light exposure may be helpful. (Note that the use of psychotherapy, although proved effective, has declined.10)

Pharmacists need to be aware that the first antidepressant prescribed for a patient is unlikely to be the last, either because it yields no results or the side effects are intolerable to the patient. Seeking help seems to be the pivotal point when patients have depression—that is, doing something is better than doing nothing. We need to remember that placebo in depression studies is not just a sugar pill. It comes with increased contact and attention, which may explain why placebo works as well as some drugs appear to work.3,4,6,7

Final Thought

Antidepressants are a first-line therapy, but they are not necessarily the only first-line therapy. A good part of the problem is that we do not know what causes depression, and we have been unable to target drugs to an exact cause. As we learn more about the causes of depression and the populations most likely to respond to antidepressants, treatment will improve. Until then, clinicians do best to tailor treatment to patients’ unique presentation, symptoms, family history, length and severity of symptoms, preferences, and sadly, financial resources, because insurance often does not cover psychotherapy. PT

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not those of any government agency.


1. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47-53.

2. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5:e45.

3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.

4. National Institute of Mental Health. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study. www.nimh.nih.gov/trials/practical/stard/index.shtml. Accessed December 28, 2010.

5. Horder J, Matthews P, Waldmann R. Placebo, Prozac and PLoS: significant lessons for psychopharmacology [published online ahead of print June 22, 2010]. J Psychopharmacol.

6. Fisher S, Lipman RS, Uhlenhuth EH, Rickels K, Park LC. Drug effects and initial severity of symptomatology. Psychopharmacologia. 1965;7:57-60.

7. Benjamin LS. Statistical treatment of the law of initial values (LIV) in autonomic research: a review and recommendation. Psychosom Med. 1963;25:556-566.

8. Freedman R. Abrupt withdrawal of antidepressant treatment. Am J Psychiatry. 2010;167:886-888.

9. Baldessarini RJ, Tondo L, Ghiana C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry. 2010;167(8):934-931.

10. Marcus SC, Olfson M. National trends in the treatment for depression from 1998 to 2007. Arch Gen Psychiatry. 2010;67:1265-1273.

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