How Effective Are Antidepressants for Depression?

Antidepressants are now the third most widely used class of chronic medications in the U.S., with nearly 22 million users as of 2012.[1] Their use increased more than fourfold between 1988 and 2008.[2] Clearly, so many patients would not continue to take the drugs, and doctors would not prescribe them, in the absence of some perceived benefit. But how much of this perception is due to a true biological effect of the drugs as opposed to a placebo effect?

This question has been the focus of a growing debate in the medical community, sparked in part by the publication of two studies suggesting that although some severely depressed patients are undoubtedly helped by antidepressants, for a great many others with milder depression, the medications may be no better, but clearly more dangerous, than a sugar pill. The studies also raised serious concerns about the integrity of the evidence for the drugs’ effectiveness presented in the published literature on which so many physicians rely.

Benefits more modest than initially thought

Fluoxetine (PROZAC), approved in 1987,[3] was the first[4] of a wave of newer-generation antidepressants known as selective serotonin reuptake inhibitors (SSRIs), which work by increasing the amount and action of a chemical known as serotonin in certain areas of the brain. SSRIs were considered a breakthrough advancement in the treatment of depression because they seemed effective while being considerably safer than an earlier generation of antidepressants known as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), both of which had severe side-effect profiles and were fatal in excessive doses. (The possibility of intentional overdose is always a paramount concern in severely depressed patients.)

Fluoxetine’s approval heralded a flood of further approvals of “me-too” SSRIs, of which there are now seven different varieties, including fluoxetine (see table below). Another class of antidepressants known as selective serotonin-norepinephrine reuptake inhibitors (SNRIs) also amplify the activity of serotonin — as well as another chemical known as norepinephrine — within certain areas of the brain.

For the past two-and-a-half decades, the effectiveness of these newer-generation antidepressants in treating depression was generally assumed by the medical community based on a plethora of published studies. However, a study published in January 2008 in the New England Journal of Medicine (NEJM) revealed that this source of information may have presented a falsely positive picture.

The NEJM study analyzed a large number of pre-approval clinical trials for antidepressants submitted to the Food and Drug Administration (FDA) to determine how many of these trials were ultimately published and how accurately this subset of published reports represented the results of all of the trials.[5] The study reviewed 74 trials submitted to the FDA involving more than 12,000 adult subjects for 12 different antidepressants approved by the FDA between 1987 and 2004. The authors searched the medical literature for published reports of each trial. The study classified the clinical trial results in the FDA submissions as “positive,” “negative” or “questionable,” as far as effectiveness based on the FDA’s assessments for the purposes of approval.

There were 38 trials labeled positive, and all but one of them (97 percent) were published. Of the 36 studies whose findings were deemed either negative or questionable by the FDA, a mere 14 (39 percent) were published, 11 of which presented the findings in the publication as positive despite the FDA’s determination of negative or questionable results. The published findings for only three of these 14 concurred with the FDA’s analysis. (Overall, of the 74 pre-approval clinical trials, 22 [30 percent] were never published.)

This selective publication of positive studies and results, also known as publication bias, undoubtedly came as a surprise to many in the medical and psychiatric community who had taken the efficacy of antidepressants for granted. The study also begged the question: Just how effective are antidepressants when considering the totality of the evidence?

An answer to this important question was provided by a study published in the journal PLoS Medicine in February 2008, one month after the publication of the NEJM study. The PLoS Medicine study examined all pre-approval randomized controlled trials of antidepressants for which complete data on the trials’ outcomes were available.[6] The study reviewed 35 trials of more than 5,000 subjects conducted with four antidepressants: fluoxetine, paroxetine (PAXIL), venlafaxine (EFFEXOR) and nefazodone (SERZONE). The primary outcome of interest was the difference in subjects’ responses to a commonly used depression assessment scale, known as the Hamilton Rating Scale of Depression (HRSD), before and after subjects took either an antidepressant medication or a placebo over the four-to-eight-week trials.

The study found that subjects given one of the four antidepressants displayed an average improvement of 9.6 points on the HRSD, while those given placebo improved by an average of 7.8 points — a difference of just 1.8 points. Although this treatment effect was statistically significant, it was considerably smaller than the three-point threshold deemed clinically relevant by the U.K.’s National Institute for Health and Care Excellence (NICE), a standards-setting body that formulates recommendations for that country’s National Health Service.[7]

Furthermore, the less depressed subjects were at the start of the trial, the less effective the drugs were relative to placebo. For moderately depressed individuals, and even many severely depressed subjects, the antidepressants were not meaningfully, clinically more effective than placebo. It was only in the most severely depressed patients that the drugs reached the NICE threshold for clinically significant effectiveness compared to a placebo.[8] Thus, the effectiveness of the antidepressants in less depressed patients was largely due to a placebo effect. Interestingly, the net effectiveness in the sickest population was due not to an increased response to the drugs but to a decreased response to placebo.

In 2011, another study in the Journal of Clinical Psychiatry undertook a similar analysis with a larger sample of trials and confirmed the conclusions of the PLoS Medicine paper.[9] The study evaluated 81 randomized controlled trials, involving more than 21,000 subjects, submitted to the FDA for approval to treat depression between 1983 and 2008. The review showed that antidepressants were statistically (not necessarily clinically meaningfully) better than placebo in improving HRSD scores in only 53 percent of all trials. The average improvement in HRSD scores (drug versus placebo) across all trials was only 2.5 points, again lower than the NICE three-point threshold for clinical relevance. As in the 2008 PLoS Medicine article, the severity of the depression at the start of the study tended to be the best predictor of treatment response, and the drugs were less effective in milder cases of depression.

Medications Approved to Treat Depression in the U.S. as of December 2013[10]

† The SSRI fluvoxamine (LUVOX) is commonly used off-label in depressed patients and therefore carries the same black box warning on suicidality as approved antidepressants.
* Do Not Use
** Limited Use (offers limited benefit or benefits certain people or conditions)
*** Do Not Use Until Seven Years After Approval

Long-term risks and costs

While the studies discussed up to this point have focused on the effectiveness of antidepressants over the several-week periods studied in the pre-approval clinical trials, less is known about the drugs’ effectiveness for longer periods.

The FDA does not require trials on antidepressants for depression to last more than a few weeks to demonstrate short-term efficacy.[11] Furthermore, some antidepressants (such as fluoxetine and paroxetine) are approved for long-term use for depression on the basis of clinical trials that assessed long-term efficacy (six months to one year) only in those patients who initially responded to the drug in the first place.[12] Therefore, the studies’ findings cannot be generalized to all prospective patients.

In addition, all subjects in the fluoxetine and paroxetine maintenance trials initially received the drugs in an unblinded fashion — they knew they were receiving the drugs as opposed to placebo pills — and were then randomized to continue the same drugs or switch to placebo pills.[13] Given the drugs’ readily recognizable side effects, many subjects therefore probably knew whether they were continued on the drugs or given a placebo, potentially falsely inflating the drug’s effectiveness in these long-term studies.

In practice, antidepressants are routinely used for much longer periods of time than were tested in the trials. Their effectiveness for chronic use is therefore uncertain, but their risks persist for as long as they are used.

All antidepressants carry a black box warning on an increased risk of suicidal thinking and behavior in children, adolescents and young adults.[14] Other risks, not included in the black box warning, include weight changes, anxiety, insomnia and sexual dysfunction, as well as potentially fatal side effects such as high blood pressure, heart rhythm disturbances, abnormal bleeding, low blood sodium, seizures, a disorder known as serotonin syndrome and numerous drug interactions.[15] In many cases, patients end up continuing the medications because of the uncomfortable withdrawal symptoms (including headache, nausea, agitation or dizziness) characteristic of several antidepressants.[16]

This is not to mention the economic costs of long-term antidepressant use, especially for newer, still-patented versions. To take just one example, according to a June 2013 analysis by the Medical Letter health news publication, the price of a 30-day supply of duloxetine (CYMBALTA), a brand-name SNRI antidepressant with no generic competition at the time was $199, compared with $4 to $7 for the same month supply of any of five different generic SSRIs.[17]

What You Should Do

Not everyone who is sad is depressed, especially in cases of a legitimate response to a distressing life event. The National Institute of Mental Health defines major depression as a “severely depressed mood and activity level that persists two weeks or more” and that interferes with daily functioning.[18] It is estimated that 1 in 6 U.S. adults will experience a bout of major depression at some point in their lives.[19] Dysthymic disorder, or dysthymia, refers to milder (not necessarily disabling) depressive symptoms that last two years or more.[20] Symptoms of minor depression can include poor school or work performance, social withdrawal, shyness, irritable hostility, conflicts with family and friends, and sleep irregularities.

There are many causes for depression, and although it is an often debilitating condition, not everyone who is depressed is a suitable candidate for antidepressant therapy. One cause of depression that should not be treated with drugs is depression caused by other kinds of drugs. When depression starts after beginning a new drug, the drug may well be the culprit. Drugs that may cause depressive symptoms include (but are not limited to) corticosteroids, oral contraceptives, beta-blockers and other blood pressure medications, and varenicline (CHANTIX).[21] This is not a comprehensive list, so speak with your doctor to find out whether a medication you are taking may be causing your symptoms. Alcoholism or drug abuse are other potential causes, and those should be treated before resorting to antidepressants. Certain medical conditions, such as hypothyroidism, also can cause depression symptoms.

If you are depressed, see a doctor or psychologist to rule out physical causes and to inquire about psychotherapy as an initial treatment. Psychotherapy should be tried first for minor depression[22] and should always be pursued to treat depression of all severities, even if medication is ultimately added. If you and your health care provider decide to try antidepressants, be sure to review the benefits and risks of each treatment option. As a general rule, SSRIs should be tried first, as these are the safest antidepressants. If symptoms do not improve sufficiently on an SSRI and remain severe, further treatment with other antidepressants is warranted.

All antidepressants carry a black box warning of an increased risk of suicidal thinking and behavior in children, adolescents and young adults. If you experience suicidal thoughts or urges (whether on or off an antidepressant), go to the emergency room or call the National Suicide Prevention Lifeline at 1-800-273-TALK (8255) immediately.[23]

References

[1] IMS Health. Declining Medicine Use and Costs: For Better or Worse? May 2013. Treated Patients in Selected Therapies. http://static.correofarmaceutico.com/docs/2013/05/20/usareport.pdf. Accessed December 9, 2013.

[2] Centers for Disease Control and Prevention. National Center for Health Statistics Data Brief. Antidepressant Use in Persons Aged 12 and Over: United States, 2005–2008. Number 76, October 2011. http://www.cdc.gov/nchs/data/databriefs/db76.htm. Accessed December 9, 2013.

[3] Fluoxetine label, updated July 2013.

[4] Food and Drug Administration. Anti-depressant Drug Use in Pediatric Populations. http://www.fda.gov/newsevents/testimony/ucm113265.htm. Accessed December 16, 2013.

[5] Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008 Jan 17;358(3):252-60.

[6] 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 Feb;5(2):e45.

[7] National Institute for Health and Care Excellence. What We Do. http://www.nice.org.uk/aboutnice/whatwedo/what_we_do.jsp. Accessed December 8, 2013.

[8] 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 Feb;5(2):e45.

[9] Khin NA, Chen YF, Yang Y, Yang P, Laughren TP. Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. J Clin Psychiatry. 2011 Apr;72(4):464-72.

[10] Updated through December 2013. Source: Drugs@FDA. Search of all possible variations of “root word” segments within generic name (e.g. “xetine”) for every antidepressant class. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed January 3, 2014.

[11] Based on the length of the pre-approval trials of the antidepressants in the Kirsch meta-analysis.

[12] Fluoxetine label, updated July 2013; Paroxetine label, updated December 2012.

[13] Fluoxetine label, updated July 2013; Paroxetine label, updated December. 2012.

[14] Fluoxetine label, updated July 2013; Desipramine label, updated November 2012. Confirmed: http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/drugsafetyinformationforheathcareprofessionals/publichealthadvisories/ucm161679.htm.

[15] Fluoxetine label, updated July 2013; Paroxetine label, updated Dec. 2012; Desipramine label, updated Nov. 2012; Venlafaxine, updated December 2012.

[16] Desipramine label, updated November 2012; Paroxetine label, updated December 2012; Venlafaxine label, updated December 2012.

[17] Medical Letter. Volume 11 (Issue 130) June 2013. Table 1, p. 2.

[18] National Institute of Mental Health. Major Depressive Disorder Among Adults. http://www.nimh.nih.gov/statistics/1mdd_adult.shtml. Accessed December 9, 2013.

[19] Institute of Mental Health. Major Depressive Disorder Among Adults. http://www.nimh.nih.gov/statistics/1mdd_adult.shtml. Accessed December 9, 2013.

[20] National Institute of Mental Health. What Is Depression? http://www.nimh.nih.gov/health/topics/depression/index.shtml. Accessed December 19, 2013.

[21] UpToDate. Unipolar minor depression in adults: Epidemiology, clinical presentation, and diagnosis. Citing: Agency for Health Care Policy and Research. Depression Associated with Medications. In: Depression in Primary Care: Detection and Diagnosis. AHCPR Publication No. 93-0550. US Department of Health and Human Services, Washington, DC, 1993. Vol 1, p.67.

[22] Worst Pills, Best Pills News. Antidepressants: Effective for Major Depression, Not for Minor Depression. May 2011. /newsletters/view/741##criteria. Accessed January 8, 2014.

[23] National Suicide Prevention Lifeline. http://www.suicidepreventionlifeline.org/. Accessed December 9, 2013.