Posted on 10/08/2002 1:37:29 PM PDT by shrinkermd
Antidepressants are widely believed to be exceptionally effective medications. The data, however, tell a different story. Kirsch et al. (2002a) analyzed the data sent to the U.S. Food and Drug Administration by the manufacturers of the six most widely prescribed antidepressants (fluoxetine [Prozac], paroxetine [Paxil], sertraline [Zoloft], venlafaxine [Effexor], nefazodone [Serzone] and citalopram [Celexa]). Their research showed that although the response to antidepressants was substantial, the response to inert placebo was almost as great. The mean difference was about two points on the Hamilton Rating Scale for Depression (HAM-D). Although statistically significant, this difference is not clinically significant (Jacobson et al., 1999). More than half of the clinical trials sponsored by the pharmaceutical companies failed to find significant drug/placebo difference, and there were no advantages to higher doses of antidepressants. The small difference between antidepressant and placebo has been referred to as a "dirty little secret" by clinical trial researchers (Hollon et al., 2002), a secret that was believed by FDA officials to be "of no practical value to either the patient or prescriber" (Leber, 1998, as cited in Kirsch et al., 2002b).
Previous reports of vanishingly small drug/placebo differences (Kirsch and Sapirstein, 1998) were met with skepticism (e.g., Klein, 1998). In contrast, the basic findings from this new meta-analysis have been accepted as accurate (e.g., Thase, 2002). The dispute is no longer about the small size of the average drug/placebo difference, but rather about how to interpret this fact and what to do about it.
Various interpretive possibilities have been raised. One of the most popular theories is that there may be a subset of patients for whom at least some antidepressants are very effective, but that their relative lack of efficacy with other patients masks effect (e.g., Thase, 2002). Specifically, whereas mildly depressed patients respond to both drugs and placebos, more severely depressed patients respond only to active drugs. The FDA data contradict this hypothesis. Although severely depressed patients benefited more from medication than mildly depressed patients due to a phenomenon known as regression toward the mean, they also benefited more from placebo than their more mildly depressed counterparts.
Of course, one can never rule out the possibility of undetected moderator variables. But if there are hidden moderators, the overall mean difference between drug and placebo (two points on the HAM-D) constrains the conclusions that can be drawn from them. If the mean drug/placebo difference is greater than two points for a subset of medications or patients, then it must be less than two points for the others. For example, if the mean difference between drug and placebo is four points for half of the patients (which is still a rather small drug effect), then the mean effect of antidepressants on the other patients must be zero, and if it is more than four points for half the patients, then the medications must be interfering with responsiveness in at least some others who would fare better on placebo.
Another popular hypothesis is that drug effects are more stable than placebo effects, resulting in lower relapse rates. This hypothesis is also contradicted by the data. A meta-analysis of relapse prevention trials published between 1973 and 1990 indicated that 71% of the drug response was duplicated by placebo (Walach and Maidhof, 1999). Kirsch et al.'s meta-analysis also examined response to treatment as a function of the duration of the trial. The data indicated that responses to both drug and placebo decrease over time. Contrary to conventional wisdom, however, the correlation between duration of the trial and response to treatment was higher for active medication (r=-0.84) than for placebo (r=-0.62), suggesting a steeper decline in effectiveness for active drugs than for placebo (Kirsch et al., 2002b).
In light of these data, what should be done in clinical contexts? Some have suggested that antidepressants continue to be prescribed, even if their effects are largely placebo effects. If nothing else, these agents can be used as active placebos. Given the side effects of these medications, we suggest an alternative approach. There are many interventions that seem to be as effective or nearly as effective as antidepressants. These include physical exercise, bibliotherapy and psychotherapy (Kirsch et al., 2002b). Psychotherapy has the further advantage of demonstrated superiority to medications in long-term comparative studies (Antonuccio et al., 2002). Given these data, antidepressant medication might best be considered a last resort, restricted to patients who refuse or fail to respond to other treatments.
Dr. Kirsch is professor of psychology at University of Connecticut and former president of Division 30 of the American Psychological Association.
Dr. Antonuccio is professor of psychiatry and behavioral sciences at University of Nevada School of Medicine, and director of and staff psychologist for the stop smoking program at the Reno Veterans Affairs Medical Center.
References
Antonuccio DO, Burns DD, Danton WG (2002), Antidepressants: a triumph of marketing over science? Prevention & Treatment 5:Article 25. Available at: journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
Hollon SD, DeRubeis RJ, Shelton RC, Weiss B (2002), The emperor's new drugs: effect size and moderation effects. Prevention & Treatment 5:Article 28. Available at: journals.apa.org/ prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
Jacobson NS, Roberts LJ, Berns SB, McGlinchey JB (1999), Methods for defining and determining the clinical significance of treatment effects: description, application, and alternatives. J Consult Clin Psychol 67(3):300-307.
Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002a), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23. Available at: journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
Kirsch I, Sapirstein G (1998), Listening to Prozac but hearing placebo: a meta analysis of antidepressant medication. Prevention & Treatment 1: Article 0002a. Available at: journals.apa.org/prevention/volume-1/toc-jun26-98.html. Accessed Aug. 2, 2002.
Kirsch I, Scoboria A, Moore TJ (2002b), Antidepressants and placebos: secrets, revelations, and unanswered questions. Prevention & Treat-ment 5:Article 33. Available at: www.journals. apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
Klein DF (1998), Listening to meta-analysis but hearing bias. Prevention & Treatment 1:Article 0006c. Available at: www.journals.apa.org/prevention/volume 1/toc-jun26-98.html. Accessed Aug. 2, 2002.
Thase ME (2002), Antidepressant effects: the suit may be small, but the fabric is real. Prevention & Treatment 5:Article 32. Available at: journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 2.
Walach H, Maidhof C (1999), Is the placebo effect dependent on time? A meta-analysis. In: How Expectancies Shape Experience, Kirsch I, ed. Washington, D.C.: American Psychological Association, pp321-332.
Irving Kirsch, Ph.D., and David Antonuccio, Ph.D., point out that antidepressants have small specific effects in placebo-shielded, randomized, controlled trials (RCTs). Similar data from meta-analyses of related data sets have been out there for several years. Our perceptions about antidepressant efficacy have been inflated by the "file drawer" effect: the selective publication of positive studies and suppression of negative ones (Thase, 2002a). In order to properly evaluate efficacy, the meta-analyst must have access to all relevant trials. This became feasible when the Freedom of Information Act was used to obtain the New Drug Application (NDA) data sets from the U.S. Food and Drug Administration (Khan et al., 2000; Walsh et al., 2002). Using the NDA summary reports for six newer drugs (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], venlafaxine [Effexor], nefazodone [Serzone] and citalopram [Celexa]), Kirsch et al. (2002) found that antidepressants offer only about a 20% (two-point) greater reduction in Hamilton Rating Scale for Depression (HAM-D) scores than placebo.
There is now no doubt that nonspecific factors (i.e., placebo, expectancy, social support, spontaneous remission) account for a majority of the explainable variance in industry-funded RCTs of outpatients with depression. The same may be true for federally funded studies of similar patient groups (i.e., Elkin et al., 1989; Hypericum Depression Trial Study Group, 2002). To conclude from these data that antidepressants do not have clinically meaningful effects, however, requires overlooking a number of issues.
There are serious methodologic and analytic problems that compromise the design sensitivity of contemporary RCTs of antidepressants (Thase, 2002b). Briefly, the studies are underpowered (mean power50%), pay too little attention to reliability of assessment, are often overinclusive (i.e., investigators are paid by number enrolled, not number excluded) and are analyzed with outmoded approaches that do not accurately take into account the effects of attrition (Klein et al., 2002; Thase, 2002a). These studies, by and large, do not enroll patients with the subforms of depression that respond more favorably to antidepressants and are plagued by "inflation" of entry symptom severity thresholds (Klein et al., 2002). The problems persist largely because the standard methods still work well enough to accomplish the studies' primary aim of the sponsors: to obtain FDA approval of their medications (Thase, 2002b).
Kirsch and Antonuccio suggest that the "hidden moderators" argument also cannot account for much of an effect. However, if only 10% to 20% of a group of outpatients respond specifically to the drug, a mean two-point advantage would be explained by a 10- to 15-point average difference among the small subgroup's true drug responders. Thus, the one or two additional patients who respond to an active medication (per 10 treated) get substantial benefit. This is not a trivial effect from a public health perspective (Thase, 2002a).
The greater relative benefit of antidepressant therapy among more severely depressed patients (e.g., Elkin et al., 2002, or Thase et al., 1997a) is offhandedly rejected as an artifact or "regression to the mean." Most recently, Khan and colleagues (2002) reported a steady linear relationship between pretreatment severity and the probability of observing a significant drug-placebo difference. The well-replicated observation that milder depressions are more placebo-responsive is not mentioned. Nor is the futility of placebo treatment of psychotic depression.
Kirsch and Antonuccio also minimize the rapid loss of drug effect when antidepressants are withdrawn prematurely. The statement that placebo accounts for 71% of the benefits of continuation-phase therapy hides a difference of 20% in relapse rates (i.e., 50% versus 70% survival). This again is a significant effect. Moreover, although I was unable to review the study of Walach and Maidhof (1999), I believe that the direction of the described effect has been reversed. In the antidepressant continuation-therapy literature, most relapses on placebo occur during the first six months; the curve of an antidepressant-treated group has a flatter slope (Thase, 2000). In other words, a longer study length is more closely related to active drug failure (than is the case with placebo).
A final point of (largely) agreement: psychoeducation, exercise and proven, focused psychotherapies are underutilized as treatments of depression. I wish that all individuals with mild to moderate depression who wanted these interventions received them first, reserving pharmacotherapy for nonresponders (Thase et al., 1997a). But for patients with more severe or chronic depression, there is now good evidence that the combination of pharmacotherapy and psychotherapy is superior to either treatment alone (Keller et al., 2000; Thase et al., 1997b). I suggest that we work harder to ensure that more people with depression get adequate, evidence-based treatments and stop squabbling over the magnitude of specific and nonspecific elements of treatment.
Dr. Thase is professor of psychiatry at University of Pittsburgh Medical Center. He is also director of the depression treatment and research program and chief of adult academic psychiatry at Western Psychiatric Institute.
References
Elkin I, Shea MT, Watkins JT et al. (1989), National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Arch Gen Psychiatry 46(11):971-982; discussion, 983 [see comment].
Hypericum Depression Trial Study Group (2002), Effect of Hypericum perforatum (St John's Wort) in major depressive disorder: a randomized controlled trial. JAMA 287(14):1807-1814 [see comments].
Keller MB, McCullough JP, Klein DN et al. (2000), A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. [Published erratum N Engl J Med 345(3):232.] N Engl J Med 342(20):1462-1470 [see comments].
Khan A, Leventhal RM, Khan SR, Brown WA (2002), Severity of depression and response to antidepressants and placebo: an analysis of the Food and Drug Administration database. J Clin Psychopharmacol 22(1):40-45.
Khan A, Warner HA, Brown WA (2000), Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 57(4):311-317 [see comments].
Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23. Available at: www.journals.apa.org/prevention/volume5/toc-jul15-02.html. Accessed Aug. 5.
Klein DF, Thase ME, Endicott J et al. (2002), Improving clinical trials: American Society of Clinical Psychopharmacology recommendations. Arch Gen Psychiatry 59(3):272-278 [see comments].
Thase ME (2000), Relapse and recurrence of depression. An updated practical approach for prevention. In: Drug Treatment Issues in Depression, Palmer KJ, ed. Auckland, New Zealand: Adis International Limited, pp35-52.
Thase ME (2002a), Comparing the methods used to compare antidepressants. Psychopharmacol Bull 36(suppl 1):4-17.
Thase ME (2002b), Studying new antidepressants: if there was a light at the end of the tunnel could we see it? J Clin Psychiatry 63(suppl 2):24-28.
Thase ME, Buysse DJ, Frank E et al. (1997a), Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles. Am J Psychiatry 154(4):502-509.
Thase ME, Greenhouse JB, Frank E et al. (1997b), Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry 54(11):1009-1015.
Walach H, Maidhof C (1999), Is the placebo effect dependent on time? A meta-analysis. In: How Expectancies Shape Experience, Kirsch I, ed. Washington, D.C.: American Psychological Association, pp321-332.
Walsh BT, Seidman SN, Sysko R, Gould M (2002), Placebo response in studies of major depression: variable, substantial, and growing. JAMA 287(14):1840-1847 [see comment].
Almost 40 years ago I worked for the a NIMH early drug evaluation unit at a major university. I think I am still an expert as to study design and the "placebo effect." The problems are many, but the basic two are as follows. First, to do a proper study you need to have depressive illnesses with a biological component --Major Depression, Bipolar Disorder Depressed and so forth. Using reactive depressions or individuals with an adult situational reaction leads to faulty results since these are time limited disorders and often improve spontaneously. If these reactive disorders don't improve spontaneously, they usually require social treatments such as some form of psychotherapy.
The second problem is that do a a good study you should have more than clinical rating scales. Some form of self-rating scale as well as an MMPI or other instrument is a good check on your clinical judgement.
All told, the antidepressants probably are very helpful for the most seriously depressed individuals who have marked biological signs and symptoms of a depression. The antidepressants are of little value for Dysthymic Disorders (Neurotic Depressions) and adjustment disorders with a depressed mood. This seems to be true even though many patients and psychiatrists believe otherwise --the problem is the placebo effect in addition to spontaneous recovery or amelioration of symptoms by time alone.
Glad to hear that. Zoloft keeps my pistol out of my mouth.
I think you make a really good point--different people respond very differently to the various actions of the assorted AD's. You almost never get the correct one first time around and may even need to try several 'til you find the effective one for your 'chemistry'.
I think the result of this study is that:
"relying on the first choice of antidepressants, neglecting the patients feedback and an unwillingness to try other antidepressants leads to an outcome only slightly better than a placebo."
Do you have any more info on these "neurotic depressions", because I know an individual or two who fit the profile and I wish to hell they'd get over themselves... It would seem to me that these would be the most common-- what was once termed "hysterics" in women, for example... What's the current wisdom on effective treatment, or is it pretty much like a Southern snowstorm-- just wait for the sun to dry everything up?
Dysthymic Disorder is characterized by a chronic depressed mood for more days than not over a period of two years or more. Common symptoms are low energy, fatigue, sleep disorders, low self-esteem and feelings of hopelessness. Sometimes, the presenting complaint is indecisiveness and trouble making decisions. Generally, the point prevelence is 3% and the lifetime prevalence is 6%. The usual treatment is psychotherapy, individual,group or family: some individuals report response to one or more of the antidepressants to a greater or lesser degree. Generally, antidepressants are less effective in this disorder than in more acute and serious, biological depressions.
The only other tip I can give you is to find out not what an individual wants to do, but what they don't want to do. The answer will often lead you to the type and nature of the psychotherapy.
Excellent point. If I had my "comments" to do over again I would make point three the willingness to try more than one drug and listen to the patient's self-reports of efficacy or lack thereof.
Me being decidedly in the pull-up-yer-boot-straps-and-buckle-to-it camp, I have little patience for what I consider to be partly (I said partly, y'all) a self-induced character flaw. Y'all can start in now with "you don't understand! It's a disease! It's a chemical imbalance! You insensitive clod" but let me ask you this-- how does one really know how much of the behavior in question stems from genuine illness of sorts, and how much is, as I said above, manipulation on the part of the "affected" individual? One doesn't know. I admit that I tend to withhold benefit of doubt in this area...
I guess if they actually succeed in snuffing themselves you know they weren't faking it.
If I were a shrink, I would put all my patients on lithium or something to knock 'em out good so they can't go apesh!t. How much good does the couch do, anyway? Seems to me that they'd be better off being put to work, so they can't dwell on themselves so much... Volunteer for some charity or something...
Okay, I'm an impatient person, I guess... Haha... Wouldn't do too well in the headshrinking scene... But tell us the truth, doc, in your experience, how much good does "talking about it" actually do? Does it make folks quit going apesh!t?
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