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<DIV><SPAN class=609311815-23102005><FONT face=Arial color=#0000ff size=2>By the
way, does anyone have a source for</FONT></SPAN></DIV>
<DIV><SPAN class=609311815-23102005><FONT face=Arial color=#0000ff size=2>the
original science indicating a relationship</FONT></SPAN></DIV>
<DIV><SPAN class=609311815-23102005><FONT face=Arial color=#0000ff
size=2>between seratonin and depression?</FONT></SPAN></DIV>
<DIV><SPAN class=609311815-23102005></SPAN> </DIV>
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<DIV class=OutlookMessageHeader dir=ltr align=left><FONT face=Tahoma
[mailto:firstname.lastname@example.org]<B>On Behalf Of </B>Todd I.
Stark<BR><B>Sent:</B> Sunday, October 23, 2005 7:19 AM<BR><B>To:</B> The new
improved paleopsych list<BR><B>Subject:</B> Re: [Paleopsych] Prevention &
Treatment: Listening to ProzacbutHearing Placebo<BR><BR></FONT></DIV><FONT
face=Arial,sans-serif><FONT size=2>Kirsch and Sapirstein (1998) was actually
the lead article for a whole series of articles in Prevention and
Treatment. If you read the rest of the series, you'll see that there is
good evidence that the placebo effect and the drug effect are largely
independent. That is, the effect of SSRIs and the effect of expectancy
both contribute to the clinical outcome, but neither depends entirely upon the
other. The common interpretation that evidence of expectancy effects is
also evidence against the efficacy of SSRIs is inaccurate, or at least very
misleading. In my opinion, a more consistent interpretation would be
that expectancy effects and drug effects are both important factors in
clinical outcome for depression, and that the investigative goal should
probably focus on the conditions facilitating each, and the tradeoffs for
each.<BR><BR>kind regards,<BR><BR>Todd<BR><BR><SPAN type="cite">Lynn D.
Johnson, Ph.D. wrote on 10/22/2005, 9:35 PM:</SPAN> </FONT></FONT>
<P><FONT face=Arial,sans-serif size=2></FONT></P>
style="PADDING-LEFT: 10px; MARGIN-LEFT: 0pt; BORDER-LEFT: blue thin solid"
type="cite"><FONT face=Arial,sans-serif size=2>The interesting thing about
this is that the placebo effect for antidepressants has been consistently
increasing since the 1980s when Prozac came out, and Kramer wrote
<I>Listening to Prozac</I>.* This suggests that loss of hope is a key
ingredient in depression; how that interfaces with the Omega-3 evidence, I
wish someone would tell me.<BR>Lynn<BR>*The increasing placebo effect means
it is steadily harder to show a statistically significant treatment effect
for antidepressants. Discouraging for the drug houses.<BR><BR>Steve Hovland
type="cite"><FONT face=Arial,sans-serif size=2></FONT><PRE wrap="">There was a studyin Britain not so long ago<BR>where Zoloft, placebo, and St. John's Wort<BR>produced similar results. I have heard<BR>that St. Johns is the most common prescription<BR>for depression in Germany.<BR><BR>-----Original Message-----<BR>From: <A class=moz-txt-link-abbreviated href="mailto:email@example.com">firstname.lastname@example.org</A><BR>[<A class=moz-txt-link-freetext href="mailto:email@example.com">mailto:firstname.lastname@example.org</A>]On Behalf Of Lynn D. Johnson,<BR>Ph.D.<BR>Sent: Saturday, October 22, 2005 12:57 PM<BR>To: The new improved paleopsych list<BR>Subject: Re: [Paleopsych] Prevention & Treatment: Listening to Prozac<BR>butHearing Placebo<BR><BR><BR>Recent reviews of effect size of antidepresants is around 0.2, <BR>indicating 2/10s of a standard deviation difference between placebo and <BR>active drug. Active placebos (with side effects) have a bigger effect <BR>size. Not!
e than there is little placebo response seen in anti-psychotic <BR>and ADHD drugs, presumably because of the difference in the patient <BR>population.<BR>Lynn<BR><BR>Premise Checker wrote:<BR><BR> </PRE><FONT
<BLOCKQUOTE type="cite"><FONT face=Arial,sans-serif size=2></FONT><PRE wrap="">Listening to Prozac but Hearing Placebo: A Meta-Analysis of <BR>Antidepressant Medication<BR><A class=moz-txt-link-freetext href="http://www.journals.apa.org/prevention/volume1/pre0010002a.html">http://www.journals.apa.org/prevention/volume1/pre0010002a.html</A><BR>Prevention & Treatment, Volume 1, Article 0002a, posted June 26, 1998<BR><BR>[I read something similar in Science, maybe twenty years ago, about <BR>the placebo effect being proportionate to the medical effect, and I <BR>think it deal with a much larger categories of illnesses. Does anyone <BR>know anything further about these anomalies?]<BR><BR>by Irving Kirsch, Ph.D., University of Connecticut, Storrs, CT<BR>and Guy Sapirstein, Ph.D., Westwood Lodge Hospital, Needham, MA<BR><BR> ABSTRACT<BR><BR> Mean effect sizes for changes in depression were calculated for<BR> 2,318 patients who had been randomly assigned to either<BR> antidepressant medication or placebo in 19 double!
-blind clinical<BR> trials. As a proportion of the drug response, the placebo response<BR> was constant across different types of medication (75%), and the<BR> correlation between placebo effect and drug effect was .90. These<BR> data indicate that virtually all of the variation in drug effect<BR> size was due to the placebo characteristics of the studies. The<BR> effect size for active medications that are not regarded to be<BR> antidepressants was as large as that for those classified as<BR> antidepressants, and in both cases, the inactive placebos produced<BR> improvement that was 75% of the effect of the active drug. These<BR> data raise the possibility that the apparent drug effect (25% of<BR> the drug response) is actually an active placebo effect.<BR> Examination of pre-post effect sizes among depressed individuals<BR> assigned to no-treatment or wait-list control groups suggest that<BR> approximately one quarter!
of the drug response is due to the<BR> administration of an active medication, one half is a placebo<BR> effect, and the remaining quarter is due to other nonspecific<BR> factors.<BR> _________________________________________________________________<BR><BR> EDITORS' NOTE<BR><BR> The article that follows is a controversial one. It reaches a<BR> controversial conclusion--that much of the therapeutic benefit of<BR> antidepressant medications actually derives from placebo<BR> responding. The article reaches this conclusion by utilizing a<BR> controversial statistical approach--meta-analysis. And it employs<BR> meta-analysis controversially--by meta-analyzing studies that are<BR> very heterogeneous in subject selection criteria, treatments<BR> employed, and statistical methods used. Nonetheless, we have chosen<BR> to publish the article. We have done so because a number of the<BR> colleagues who originally reviewed the !
manuscript believed it had<BR> considerable merit, even while they recognized the clearly<BR> contentious conclusions it reached and the clearly arguable<BR> statistical methods it employed.<BR><BR> We are convinced that one of the principal aims of an electronic<BR> journal ought to be to bring our readers information on a variety<BR> of current topics in prevention and treatment, even though much of<BR> it will be subject to heated differences of opinion about worth and<BR> ultimate significance. This is to be expected, of course, when one<BR> is publishing material at the cutting-edge, in a cutting-edge<BR> medium.<BR><BR> We also believe, however, that soliciting expert commentary to<BR> accompany particularly controversial articles facilitates the<BR> fullest possible airing of the issues most germane to appreciating<BR> both the strengths and the weaknesses of target articles. In the<BR> same vein, we welcome !
comments on the article from readers as well,<BR> though for obvious reasons, we cannot promise to publish all of<BR> them.<BR><BR> Feel free to submit a comment by emailing <A class=moz-txt-link-abbreviated href="mailto:email@example.com">firstname.lastname@example.org</A>.<BR><BR> Peter Nathan, Associate Editor (Treatment)<BR> Martin E. P. Seligman, Editor<BR> _________________________________________________________________<BR><BR> We thank R. B. Lydiard and Smith-Kline Beecham Pharaceuticals for<BR> supplying additional data. We thank David Kenny for his assistance<BR> with the statistical analyses. We thank Roger P. Greenberg and<BR> Daniel E. Moerman for their helpful comments on earlier versions of<BR> this paper.<BR><BR> Correspondence concerning this article should be addressed to<BR> Irving Kirsch, Department of Psychology, U-20, University of<BR> Connecticut, 406 Babbidge Road Storrs, CT 06269-1020.<BR> E-mail: <A class="! moz-txt-link-abbreviated" href="mailto:Irvingk@uconnvm.uconn.edu">Irvingk@uconnvm.uconn.edu</A><BR> _________________________________________________________________<BR><BR> More placebos have been administered to research participants than any<BR> single experimental drug. Thus, one would expect sufficient data to<BR> have accumulated for the acquisition of substantial knowledge of the<BR> parameters of placebo effects. However, although almost everyone<BR> controls for placebo effects, almost no one evaluates them. With this<BR> in mind, we set about the task of using meta-analytic procedures for<BR> evaluating the magnitude of the placebo response to antidepressant<BR> medication.<BR><BR> Meta-analysis provides a means of mathematically combining results<BR> from different studies, even when these studies have used different<BR> measures to assess the dependent variable. Most often, this is done by<BR> using the statistic d, which is a standar!
dized difference score. This<BR> effect size is generally calculated as the mean of the experimental<BR> group minus the mean of the control group, divided by the pooled<BR> standard deviation. Less frequently, the mean difference is divided by<BR> standard deviation of the control group (Smith, Glass, & Miller,<BR> 1980).<BR><BR> Ideally, to calculate the effect size of placebos, we would want to<BR> subtract the effects of a no-placebo control group. However, placebos<BR> are used as controls against which the effects of physical<BR> interventions can be gauged. It is rare for an experimental condition<BR> to be included against which the effects of the placebo can be<BR> evaluated. To circumvent this problem, we decided to calculate<BR> within-cell or pre-post effect sizes, which are the posttreatment mean<BR> depression score minus the pretreatment mean depression score, divided<BR> by the pooled standard deviation (cf. Smith et al., 1980)!
. By doing<BR> this for both placebo groups and medication groups, we can estimate<BR> the proportion of the response to antidepressant medication that is<BR> duplicated by placebo administration, a response that would be due to<BR> such factors as expectancy for improvement and the natural course of<BR> the disorder (i.e., spontaneous remission). Later in this article, we<BR> also separate expectancy from natural history and provide estimates of<BR> each of these effects.<BR><BR> Although our approach is unusual, in most cases it should provide<BR> results that are comparable to conventional methods. If there are no<BR> significant pretreatment differences between the treatment and control<BR> groups, then the subtraction of mean standardized pre-post difference<BR> scores should result in a mean effect size that is just about the same<BR> as that produced by subtracting mean standardized posttreatment<BR> scores. Suppose, for example, we have a !
study with the data displayed<BR> in Table 1. The conventionally calculated effect size would be would<BR> be 1.00. The pre-post effect sizes would be 3.00 for the treatment<BR> group and 2.00 for the control group. The difference between them is<BR> 1.00, which is exactly the same effect calculated from posttreatment<BR> scores alone. However, calculating the effect size in this manner also<BR> provides us with the information that the effect of the control<BR> procedure was 2/3 that of the treatment procedure, information that we<BR> do not have when we only consider posttreatment scores. Of course, it<BR> is rare for two groups to have identical mean pretreatment scores, and<BR> to the extent that those scores are different, our two methods of<BR> calculation would provide different results. However, by controlling<BR> for baseline differences, our method should provide the more accurate<BR> estimate of differential outcome.<BR><BR> CAPTION: Ta!
ble 1<BR> Hypothetical Means and Standard Deviations for a Treatment Group and a<BR> Control Group<BR><BR> Treatment Control<BR> Pretreatment Posttreatment Pretreatment Posttreatment<BR> M 25.00 10.00 25.00 15.00<BR> SD 5.50 4.50 4.50 5.50<BR><BR> The Effects of Medication and Placebo<BR><BR>Study Characteristics<BR><BR> Studies assessing the efficacy of antidepressant medication were<BR> obtained through previous reviews (Davis, Janicak, & Bruninga, 1987;<BR> Free & Oei, 1989; Greenberg & Fisher, 1989; Greenberg, Bornstein,<BR> Greenberg, & Fisher, 1992; Workman & Short, 1993), supplemented by a<BR> computer search of PsycLit and MEDLINE databases from 1974 to 1995<BR> using the search terms drug-therapy or pharmacotherapy or<BR> psychotherapy or placebo and depression or affective disord!
ers.<BR> Psychotherapy was included as a search term for the purpose of<BR> obtaining articles that would allow estimation of changes occurring in<BR> no-treatment and wait-list control groups, a topic to which we return<BR> later in this article. Approximately 1,500 publications were produced<BR> by this literature search. These were examined by the second author,<BR> and those meeting the following criteria were included in the<BR> meta-analysis:<BR><BR> 1. The sample was restricted to patients with a primary diagnosis of<BR> depression. Studies were excluded if participants were selected<BR> because of other criteria (eating disorders, substance abuse,<BR> physical disabilities or chronic medical conditions), as were<BR> studies in which the description of the patient population was<BR> vague (e.g., "neurotic").<BR> 2. Sufficient data were reported or obtainable to calculate<BR> within-condition effect sizes. This re!
sulted in the exclusion of<BR> studies for which neither pre-post statistical tests nor<BR> pretreatment means were available.<BR> 3. Data were reported for a placebo control group.<BR> 4. Participants were assigned to experimental conditions randomly.<BR> 5. Participants were between the ages of 18 and 75.<BR><BR> Of the approximately 1,500 studies examined, 20 met the inclusion<BR> criteria. Of these, all but one were studies of the acute phase of<BR> therapy, with treatment durations ranging from 1 to 20 weeks (M =<BR> 4.82). The one exception (Doogan & Caillard, 1992) was a maintenance<BR> study, with a duration of treatment of 44 weeks. Because of this<BR> difference, Doogan and Caillard's study was excluded from the<BR> meta-analysis. Thus, the analysis was conducted on 19 studies<BR> containing 2,318 participants, of whom 1,460 received medication and<BR> 858 received placebo. Medications studied were amitriptyline,<BR> amy!
lobarbitone, fluoxetine, imipramine, paroxetine, isocarboxazid,<BR> trazodone, lithium, liothyronine, adinazolam, amoxapine, phenelzine,<BR> venlafaxine, maprotiline, tranylcypromine, and bupropion.<BR><BR> The Calculation of Effect Sizes<BR><BR> In most cases, effect sizes (d) were calculated for measures of<BR> depression as the mean posttreatment score minus the mean pretreatment<BR> score, divided by the pooled standard deviation (SD). Pretreatment SDs<BR> were used in place of pooled SDs in calculating effect sizes for four<BR> studies in which posttreatment SDs were not reported (Ravaris, Nies,<BR> Robinson, et al., 1976; Rickels & Case, 1982; Rickels, Case,<BR> Weberlowsky, et al., 1981; Robinson, Nies, & Ravaris, 1973). The<BR> methods described by Smith et al. (1980) were used to estimate effect<BR> sizes for two studies in which means and SDs were not reported. One of<BR> these studies (Goldberg, Rickels, & Finnerty, 1981) repor!
ted the t<BR> value for the pre-post comparisons. The effect size for this study was<BR> estimated using the formula:<BR><BR> d= t (2/n)^1/2<BR><BR> where t is the reported t value for the pre-post comparison, and n is<BR> the number of subjects in the condition. The other study (Kiev &<BR> Okerson, 1979) reported only that there was a significant difference<BR> between pre- and posttreatment scores. As suggested by Smith et al.<BR> (1980), the following formula for estimating the effect size was used:<BR><BR> d= 1.96 (2/n)^ 1/2 ,<BR><BR> where 1.96 is used as the most conservative estimation of the t value<BR> at the .05 significance level used by Kiev and Okerson. These two two<BR> effect sizes were also corrected for pre-post correlation by<BR> multiplying the estimated effect size by (1 - r)^ 1/2 , r being the<BR> estimate of the test-retest correlation (Hunter & Schmidt, 1990).<BR> Bailey and Coppen (1976) reported test-retest c!
orrelations of .65 for<BR> the Beck Depression Inventory (BDI; Beck, Ward, Mendelson, Mock, &<BR> Erbaugh, 1961) and .50 for the Hamilton Rating Scale for Depression<BR> (HRS-D; Hamilton, 1960) . Therefore, in order to arrive at an<BR> estimated effect size, corrected for the pre-post correlation, the<BR> estimated effect sizes of the HRS-D were multiplied by 0.707 and the<BR> effect sizes of the BDI were multiplied by 0.59.<BR><BR> In studies reporting multiple measures of depression, an effect size<BR> was calculated for each measure and these were then averaged. In<BR> studies reporting the effects of two drugs, a single mean effect size<BR> for both was calculated for the primary analysis. In a subsequent<BR> analysis, the effect for each drug was examined separately. In both<BR> analyses, we calculated mean effect sizes weighted for sample size (D;<BR> Hunter & Schmidt, 1990).<BR><BR> Effect Sizes<BR><BR> Sample sizes and effect size!
s for patients receiving medication or<BR> placebo are presented in Table 2. Mean effect sizes, weighted for<BR> sample size, were 1.55 SDs for the medication response and 1.16 for<BR> the placebo response. Because effect sizes are obtained by dividing<BR> both treatment means by a constant (i.e., the pooled SD), they can be<BR> treated mathematically like the scores from which they are derived. ^1<BR> In particular, we have shown that, barring pretreatment between-group<BR> differences, subtracting the mean pre-post effect size of the control<BR> groups from the mean pre-post effect size of the experimental groups<BR> is equivalent to calculating an effect size by conventional means.<BR> Subtracting mean placebo response rates from mean drug response rates<BR> reveals a mean medication effect of 0.39 SDs. This indicates that 75%<BR> of the response to the medications examined in these studies was a<BR> placebo response, and at most, 25% might be a !
true drug effect. This<BR> does not mean that only 25% of patients are likely to respond to the<BR> pharmacological properties of the drug. Rather, it means that for a<BR> typical patient, 75% of the benefit obtained from the active drug<BR> would also have obtained from an inactive placebo.<BR><BR> CAPTION: Table 2<BR> Studies Including Placebo Control Groups<BR><BR> Drug Placebo<BR> Study n d n d<BR> Blashki et al. (1971) 43 1.75 18 1.02<BR> Byerly et al. (1988) 44 2.30 16 1.37<BR> Claghorn et al. (1992) 113 1.91 95 1.49<BR> Davidson & Turnbull (1983) 11 4.77 8 2.28<BR> Elkin et al. (1989) 36 2.35 34 2.01<BR> Goldberg et al. (1981) 179 0.44 93 0.44<BR> Joffe et al. (1993) 34 1.43 16 0.61<BR> Kahn et al. (19!
91) 66 2.25 80 1.48<BR> Kiev & Okerson (1979) 39 0.44 22 0.42<BR> Lydiard (1989) 30 2.59 15 1.93<BR> Ravaris et al. (1976) 14 1.42 19 0.91<BR> Rickels et al. (1981) 75 1.86 23 1.45<BR> Rickels & Case (1982) 100 1.71 54 1.17<BR> Robinson et al. (1973) 33 1.13 27 0.76<BR> Schweizer et al. (1994) 87 3.13 57 2.13<BR> Stark & Hardison (1985) 370 1.40 169 1.03<BR> van der Velde (1981) 52 0.66 27 0.10<BR> White et al. (1984) 77 1.50 45 1.14<BR> Zung (1983) 57 .88 40 0.95<BR><BR> Inspection of Table 2 reveals considerable variability in drug and<BR> placebo response effect sizes. As a first step toward clarifying the<BR> reason for this variability, we calculated the correlation between<BR> drug respon!
se and placebo response, which was found to be<BR> exceptionally high, r = .90, p < .001 (see Figure 1). This indicates<BR> that the placebo response was proportionate to the drug response, with<BR> remaining variability most likely due to measurement error.<BR><BR> [pre0010002afig1a.gif]<BR><BR> Figure 1. The placebo response as a predictor of the drug response.<BR><BR> Our next question was the source of the common variability. One<BR> possibility is that the correlation between placebo and drug response<BR> rates are due to between-study differences in sample characteristics<BR> (e.g., inpatients vs. outpatients, volunteers vs. referrals, etc.).<BR> Our analysis of psychotherapy studies later in this article provides a<BR> test of this hypothesis. If the correlation is due to between-study<BR> differences in sample characteristics, a similar correlation should be<BR> found between the psychotherapy and no-treatment response rates. In<BR> !
fact, the correlation between the psychotherapy response and the<BR> no-treatment response was nonsignificant and in the opposite<BR> direction. This indicates that common sample characteristics account<BR> for little if any of the relation between treatment and control group<BR> response rates.<BR><BR> Another possibility is that the close correspondence between placebo<BR> and drug response is due to differences in so-called nonspecific<BR> variables (e.g., provision of a supportive relationship, color of the<BR> medication, patients' expectations for change, biases in clinician's<BR> ratings, etc.), which might vary from study to study, but which would<BR> be common to recipients of both treatments in a given study.<BR> Alternately, the correlation might be associated with differences in<BR> the effectiveness of the various medications included in the<BR> meta-analysis. This could happen if more effective medications<BR> inspired greater expec!
tations of improvement among patients or<BR> prescribing physicians (Frank, 1973; Kirsch, 1990). Evans (1974), for<BR> example, reported that placebo morphine was substantially more<BR> effective than placebo aspirin. Finally, both factors might be<BR> operative.<BR><BR> We further investigated this issue by examining the magnitude of drug<BR> and placebo responses as a function of type of medication. We<BR> subdivided medication into four types: (a) tricyclics and<BR> tetracyclics, (b) selective serotonin reuptake inhibitors (SSRI), (c)<BR> other antidepressants, and (d) other medications. This last category<BR> consisted of four medications (amylobarbitone, lithium, liothyronine,<BR> and adinazolam) that are not considered antidepressants.<BR><BR> Weighted (for sample size) mean effect sizes of the drug response as a<BR> function of type of medication are shown in Table 3, along with<BR> corresponding effect sizes of the placebo response and the!
mean effect<BR> sizes of placebo responses as a proportion of drug responses. These<BR> data reveal relatively little variability in drug response and even<BR> less variability in the ratio of placebo response to drug response, as<BR> a function of drug type. For each type of medication, the effect size<BR> for the active drug response was between 1.43 and 1.69, and the<BR> inactive placebo response was between 74% and 76% of the active drug<BR> response. These data suggest that the between-drug variability in drug<BR> and placebo response was due entirely to differences in the placebo<BR> component of the studies.<BR><BR> CAPTION: Table 3<BR> Effect Sizes as a Function of Drug Type<BR><BR> Statistic Type of drug<BR> Antidepressant Other<BR> drugs<BR> Tri- and<BR> tetracyclic SSRI Other<BR> N 1,353 626 683 203<BR> K 13 4 8 3<BR> D--Drug 1.52 1.68 1.43 1.69<BR> D--Placebo 1.15 1.24 1.08 1.29<BR> Placebo/drug .76 .74 .76 .76<BR> N =!
number of subjects; K = number of studies; D = mean weighted<BR> effect size; placebo/drug = placebo response as a proportion of active<BR> drug response.<BR><BR> Differences between active drug responses and inactive placebo<BR> responses are typically interpreted as indications of specific<BR> pharmacologic effects for the condition being treated. However, this<BR> conclusion is thrown into question by the data derived from active<BR> medications that are not considered effective for depression. It is<BR> possible that these drugs affect depression indirectly, perhaps by<BR> improving sleep or lowering anxiety. But if this were the case and if<BR> antidepressants have a specific effect on depression, then the effect<BR> of these other medications ought to have been less than the effect of<BR> antidepressants, whereas our data indicate that the response to these<BR> nonantidepressant drugs is at least as great as that to conventional<BR> antidep!
ressants.<BR><BR> A second possibility is that amylobarbitone, lithium, liothyronine,<BR> and adinazolam are in fact antidepressants. This conclusion is<BR> rendered plausible by the lack of understanding of the mechanism of<BR> clinical action of common antidepressants (e.g., tricyclics). If the<BR> classification of a drug as an antidepressant is established by its<BR> efficacy, rather than by knowledge of the mechanism underlying its<BR> effects, then amylobarbitone, lithium, liothyronine, and adinazolam<BR> might be considered specifics for depression.<BR><BR> A third possibility is that these medications function as active<BR> placebos (i.e., active medications without specific activity for the<BR> condition being treated). Greenberg and Fisher (1989) summarized data<BR> indicating that the effect of antidepressant medication is smaller<BR> when it is compared to an active placebo than when it is compared to<BR> an inert placebo (also see Gre!
enberg & Fisher, 1997). By definition,<BR> the only difference between active and inactive placebos is the<BR> presence of pharmacologically induced side effects. Therefore,<BR> differences in responses to active and inert placebos could be due to<BR> the presence of those side effects. Data from other studies indicate<BR> that most participants in studies of antidepressant medication are<BR> able to deduce whether they have been assigned to the drug condition<BR> or the placebo condition (Blashki, Mowbray, & Davies, 1971; Margraf,<BR> Ehlers, Roth, Clark, Sheikh, Agras, & Taylor, 1991; Ney, Collins, &<BR> Spensor, 1986).^ This is likely to be associated with their previous<BR> experience with antidepressant medication and with differences between<BR> drug and placebo in the magnitude of side effects. Experiencing more<BR> side effects, patients in active drug conditions conclude that they<BR> are in the drug group; experiencing fewe!
r side effects, patients in<BR> placebo groups conclude that they are in the placebo condition. This<BR> can be expected to produce an enhanced placebo effect in drug<BR> conditions and a diminished placebo effect in placebo groups. Thus,<BR> the apparent drug effect of antidepressants may in fact be a placebo<BR> effect, magnified by differences in experienced side effects and the<BR> patient's subsequent recognition of the condition to which he or she<BR> has been assigned. Support for this interpretation of data is provided<BR> by a meta-analysis of fluoxetine (Prozac), in which a correlation of<BR> .85 was reported between the therapeutic effect of the drug and the<BR> percentage of patients reporting side effects (Greenberg, Bornstein,<BR> Zborowski, Fisher, & Greenberg, 1994).<BR><BR> Natural History Effects<BR><BR> Just as it is important to distinguish between a drug response and a<BR> drug effect, so too is it w!
orthwhile to distinguish between a placebo<BR> response and a placebo effect (Fisher, Lipman, Uhlenhuth, Rickels, &<BR> Park, 1965). A drug response is the change that occurs after<BR> administration of the drug. The effect of the drug is that portion of<BR> the response that is due to the drug's chemical composition; it is the<BR> difference between the drug response and the response to placebo<BR> administration. A similar distinction can be made between placebo<BR> responses and placebo effects. The placebo response is the change that<BR> occurs following administration of a placebo. However, change might<BR> also occur without administration of a placebo. It may be due to<BR> spontaneous remission, regression toward the mean, life changes, the<BR> passage of time, or other factors. The placebo effect is the<BR> difference between the placebo response and changes that occur without<BR> the administration of a placebo (Kirsch, 1985, 1997).<BR>!
<BR> In the preceding section, we evaluated the placebo response as a<BR> proportion of the response to antidepressant medication. The data<BR> suggest that at least 75% of the drug response is a placebo response,<BR> but it does not tell us the magnitude of the placebo effect. What<BR> proportion of the placebo response is due to expectancies generated by<BR> placebo administration, and what proportion would have occurred even<BR> without placebo administration? That is a much more difficult question<BR> to answer. We have not been able to locate any studies in which pre-<BR> and posttreatment assessments of depression were reported for both a<BR> placebo group and a no-treatment or wait-list control group. For that<BR> reason, we turned to psychotherapy outcome studies, in which the<BR> inclusion of untreated control groups is much more common.<BR><BR> We acknowledge that the use of data from psychotherapy studies as a<BR> comparison with those !
from drug studies is far less than ideal.<BR> Participants in psychotherapy studies are likely to differ from those<BR> in drug studies on any number of variables. Furthermore, the<BR> assignment of participants to a no-treatment or wait-list control<BR> group might also effect the course of their disorder. For example,<BR> Frank (1973) has argued that the promise of future treatment is<BR> sufficient to trigger a placebo response, and a wait-list control<BR> group has been conceputalized as a placebo control group in at least<BR> one well-known outcome study (Sloane, Staples, Cristol, Yorkston, &<BR> Whipple, 1975). Conversely, one could argue that being assigned to a<BR> no-treatment control group might strengthen feelings of hopelessness<BR> and thereby increase depression. Despite these problems, the<BR> no-treatment and wait-list control data from psychotherapy outcome<BR> studies may be the best data currently available for estimating the<!
br> natural course of untreated depression. Furthermore, the presence of<BR> both types of untreated control groups permits evaluation of Frank's<BR> (1973) hypothesis about the curative effects of the promise of<BR> treatment.<BR><BR> Study Characteristics<BR><BR> Studies assessing changes in depression among participants assigned to<BR> wait-list or no-treatment control groups were obtained from the<BR> computer search described earlier, supplemented by an examination of<BR> previous reviews (Dobson, 1989; Free, & Oei, 1989; Robinson, Berman, &<BR> Neimeyer, 1990). The publications that were produced by this<BR> literature search were examined by the second author, and those<BR> meeting the following criteria were included in the meta-analysis:<BR><BR> 1. The sample was restricted to patients with a primary diagnosis of<BR> depression. Studies were excluded if participants were selected<BR> because of other criteria (eating dis!
orders, substance abuse,<BR> physical disabilities or chronic medical conditions), as were<BR> studies in which the description of the patient population was<BR> vague (e.g., "neurotic").<BR> 2. Sufficient data were reported or obtainable to calculate<BR> within-condition effect sizes.<BR> 3. Data were reported for a wait-list or no-treatment control group.<BR> 4. Participants were assigned to experimental conditions randomly.<BR> 5. Participants were between the ages of 18 and 75.<BR><BR> Nineteen studies were found to meet these inclusion criteria, and in<BR> all cases, sufficient data had been reported to allow direct<BR> calculation of effect sizes as the mean posttreatment score minus the<BR> mean pretreatment score, divided by the pooled SD. Although they are<BR> incidental to the main purposes of this review, we examined effect<BR> sizes for psychotherapy as well as those for no-treatment and<BR> wait-list control grou!
ps.<BR><BR> Effect Sizes<BR><BR> Sample sizes and effect sizes for patients assigned to psychotherapy,<BR> wait-list, and no-treatment are presented in Table 4. Mean pre-post<BR> effect sizes, weighted for sample size, were 1.60 for the<BR> psychotherapy response and 0.37 for wait-list and no-treatment control<BR> groups. Participants given the promise of subsequent treatment (i.e.,<BR> those in wait-list groups) did not improve more than those not<BR> promised treatment. Mean effect sizes for these two conditions were<BR> 0.36 and 0.39, respectively. The correlation between effect sizes (r =<BR> -.29) was not significant.<BR><BR> CAPTION: Table 4<BR> Studies Including Wait-List or No-Treatment<BR> Control Groups<BR><BR> Study Psychotherapy Control<BR> n d n d<BR> Beach & O'Leary (1992) 15 2.37 15 0.97<BR> Beck & Stro!
ng (1982) 20 2.87 10 -0.28<BR> Catanese et al. (1979) 99 1.39 21 0.16<BR> Comas-Diaz (1981) 16 1.87 10 -0.12<BR> Conoley & Garber (1985) 38 1.10 19 0.21<BR> Feldman et al. (1982) 38 2.00 10 0.42<BR> Graff et al. (1986) 24 2.03 11 -0.03<BR> Jarvinen & Gold (1981) 46 0.76 18 0.34<BR> Maynard (1993) 16 1.06 14 0.36<BR> Nezu (1986) 23 2.39 9 0.16<BR> Rehm et al. (1981) 42 1.23 15 0.48<BR> Rude (1986) 8 1.75 16 0.74<BR> Schmidt & Miller (1983) 34 1.25 10 0.11<BR> Shaw (1977) 16 2.17 8 0.41<BR> Shipley & Fazio (1973) 11 2.12 11 1.00<BR> Taylor & Marsh!
all (1977) 21 1.94 7 0.27<BR> Tyson & Range (1981) 22 0.67 11 1.45<BR> Wierzbicki & Bartlett (1987) 18 1.17 20 0.21<BR> Wilson et al. (1983) 16 2.17 9 -0.02<BR><BR> Comparison of Participants in the Two Groups of Studies<BR><BR> Comparisons of effect sizes from different sets of studies is common<BR> in meta-analysis. Nevertheless, we examined the characteristics of the<BR> samples in the two types of studies to assess their comparability.<BR> Eighty-six percent of the participants in the psychotherapy studies<BR> were women, as were 65% of participants in the drug studies. The age<BR> range of participants was 18 to 75 years (M = 30.1) in the<BR> psychotherapy studies and 18 to 70 years (M = 40.6) in the drug<BR> studies. Duration of treatment ranged from 1 to 20 weeks (M = 4.82) in<BR> psychotherapy studies and from 2 to 15 weeks (M = 5.95) in<BR> pharmac!
otherapy studies. The HRS-D was used in 15 drug studies<BR> involving 2,016 patients and 5 psychotherapy studies with 191<BR> participants. Analysis of variance weighted by sample size did not<BR> reveal any significant differences in pretreatment HRS-D scores<BR> between patients in the drug studies (M = 23.93, SD = 5.20) and<BR> participants in the psychotherapy studies (M = 21.34, SD = 5.03). The<BR> Beck Depression Inventory (BDI) was used in 4 drug studies involving<BR> 261 patients and in 17 psychotherapy studies with 677 participants.<BR> Analysis of variance weighted by sample size did not reveal any<BR> significant differences in pretreatment BDI scores between<BR> participants in drug studies (M = 21.58, SD = 8.23) and those in<BR> psychotherapy studies (M = 21.63, SD = 6.97). Thus, participants in<BR> the two types of studies were comparable in initial levels of<BR> depression. These analyses also failed to reveal any pretreatment<BR> d!
ifferences as a function of group assignment (treatment or control)<BR> or the interaction between type of study and group assignment.<BR><BR> Estimating the Placebo Effect<BR><BR> Just as drug effects can be estimated as the drug response minus the<BR> placebo response, placebo effects can be estimated as the placebo<BR> response minus the no-treatment response. Using the effect sizes<BR> obtained from the two meta-analyses reported above, this would be 0.79<BR> (1.16 - 0.37). Figure 2 displays the estimated drug, placebo, and<BR> no-treatment effect sizes as proportions of the drug response (i.e.,<BR> 1.55 SDs). These data indicate that approximately one quarter of the<BR> drug response is due to the administration of an active medication,<BR> one half is a placebo effect, and the remaining quarter is due to<BR> other nonspecific factors.<BR><BR> [pre0010002afig2a.gif]<BR><BR> Figure 2. Drug effect, placebo effect, and natural history effect<!
br> as proportions of the response to antidepressant medication.<BR><BR> Discussion<BR><BR> No-treatment effect sizes and effect sizes for the placebo response<BR> were calculated from different sets of studies. Comparison across<BR> different samples is common in meta-analyses. For example, effect<BR> sizes derived from studies of psychodynamic therapy are often compared<BR> to those derived from studies of behavior therapy (e.g., Andrews &<BR> Harvey, 1981; Smith et al., 1980). Nevertheless, comparisons of this<BR> sort should be interpreted cautiously. Participants volunteering for<BR> different treatments might come from a different populations, and when<BR> data for different conditions are drawn from different sets of<BR> studies, participants have not been assigned randomly to these<BR> conditions. Also, assignment to a no-treatment or wait-list control<BR> group is not the same as no intervention at all.!
Therefore, our<BR> estimates of the placebo effect and natural history component of the<BR> response to antidepressant medication should be considered tentative.<BR> Nevertheless, when direct comparisons are not available, these<BR> comparisons provide the best available estimates of comparative<BR> effectiveness. Furthermore, in at least some cases, these estimates<BR> have been found to yield results that are comparable to those derived<BR> from direct comparisons of groups that have been randomly assigned to<BR> condition (Kirsch, 1990; Shapiro & Shapiro, 1982).<BR><BR> Unlike our estimate of the effect of natural history as a component of<BR> the drug response, our estimate of the placebo response as a<BR> proportion of the drug response was derived from studies in which<BR> participants from the same population were assigned randomly to drug<BR> and placebo conditions. Therefore, the estimate that only 25% of the<BR> drug response is due!
to the administration of an active medication can<BR> be considered reliable. Confidence in the reliability of this estimate<BR> is enhanced by the exceptionally high correlation between the drug<BR> response and the placebo response. This association is high enough to<BR> suggest that any remaining variance in drug response is error variance<BR> associated with imperfect reliability of measurement. Examining<BR> estimates of active drug and inactive placebo responses as a function<BR> of drug type further enhances confidence in the reliability of these<BR> estimates. Regardless of drug type, the inactive placebo response was<BR> approximately 75% of the active drug response.<BR><BR> We used very stringent criteria in selecting studies for inclusion in<BR> this meta-analysis, and it is possible that data from a broader range<BR> of studies would have produced a different outcome. However, the<BR> effect size we have calculated for the medication ef!
fect (D = .39) is<BR> comparable to those reported in other meta-analyses of antidepressant<BR> medication (e.g., Greenberg et al., 1992, 1994; Joffe, Sokolov, &<BR> Streiner, 1996; Quality Assurance Project, 1983; Smith et al., 1980;<BR> Steinbrueck, Maxwell, & Howard, 1983). Comparison with the Joffe et<BR> al. (1996) meta-analysis is particularly instructive, because that<BR> study, like ours, included estimates of pre-post effect sizes for both<BR> drug and placebo. Although only two studies were included in both of<BR> these meta-analyses and somewhat different calculation methods were<BR> used, ^2 their results were remarkably similar to ours. They reported<BR> mean pre-post effect sizes of 1.57 for medication and 1.02 for placebo<BR> and a medication versus placebo effect size of .50.<BR><BR> Our results are in agreement with those of other meta-analyses in<BR> revealing a substantial placebo effect in antidepressant medication<BR> !
and also a considerable benefit of medication over placebo. They also<BR> indicate that the placebo component of the response to medication is<BR> considerably greater than the pharmacological effect. However, there<BR> are two aspects of the data that have not been examined in other<BR> meta-analyses of antidepressant medication. These are (a) the<BR> exceptionally high correlation between the placebo response and the<BR> drug response and (b) the effect on depression of active drugs that<BR> are not antidepressants. Taken together, these two findings suggest<BR> the possibility that antidepressants might function as active<BR> placebos, in which the side-effects amplify the placebo effect by<BR> convincing patients of that they are receiving a potent drug.<BR><BR> In summary, the data reviewed in this meta-analysis lead to a<BR> confident estimate that the response to inert placebos is<BR> approximately 75% of the response to active antidepressant!
medication.<BR> Whether the remaining 25% of the drug response is a true pharmacologic<BR> effect or an enhanced placebo effect cannot yet be determined, because<BR> of the relatively small number of studies in which active and inactive<BR> placebos have been compared (Fisher & Greenberg, 1993). Definitive<BR> estimates of placebo component of antidepressant medication will<BR> require four arm studies, in which the effects of active placebos,<BR> inactive placebos, active medication, and natural history (e.g.,<BR> wait-list controls) are examined. In addition, studies using the<BR> balanced placebo design would be of help, as these have been shown to<BR> diminish the ability of subjects to discover the condition to which<BR> they have been assigned (Kirsch & Rosadino, 1993).<BR><BR> References<BR><BR> Andrews, G., & Harvey, R. (1981). Does psychotherapy benefit neurotic<BR> patients? A reanalysis of the !
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meta-analysis of psychotherapy and drug therapy in the treatment of<BR> unipolar depression with adults. Journal of Consulting and Clinical<BR> Psychology, 51, 856-863.<BR> Taylor, F. G., & Marshall, W. L. (1977). Experimental analysis of a<BR> cognitive-behavioral therapy for depression. Cognitive Therapy and<BR> Research, 1(1), 59-72.<BR> Tyson, G. M., & Range, L. M. (1987). Gestalt dialogues as a treatment<BR> for depression: Time works just as well. Journal of Clinical<BR> Psychology, 43, 227-230.<BR> van der Velde, C. D. (1981). Maprotiline versus imipramine and placebo<BR> in neurotic depression. Journal of Clinical Psychiatry, 42, 138-141.<BR> White, K., Razani, J., Cadow, B., et al. (1984). Tranylcypromine vs.<BR> nortriptyline vs. placebo in depressed outpatients: a controlled<BR> trial. Psychopharmacology, 82, 258-262.<BR> Wierzbicki, M., & Bartlett, T. S. (1987). The efficacy of group and<BR> individual cognitive therap!
y for mild depression. Cognitive Therapy<BR> and Research, 11(3), 337-342.<BR> Wilson, P. H., Goldin, J. C., & Charboneau-Powis, M. (1983).<BR> Comparative efficacy of behavioral and cognitive treatments of<BR> depression. Cognitive Therapy and Research, 7(2), 111-124.<BR> Workman, E. A., & Short, D. D. (1993). Atypical antidepressants versus<BR> imipramine in the treatment of major depression: A meta-analysis.<BR> Journal of Clinical Psychiatry, 54(1), 5-12.<BR> Zung, W. W. K. (1983). Review of placebo-controlled trials with<BR> bupropion. Journal of Clinical Psychiatry, 44(5), 104-114.<BR> _________________________________________________________________<BR><BR> ^1 A reviewer suggested that because effect sizes are essentially<BR> z-scores in a hypothetically normal distribution, one might use<BR> percentile equivalents when examining the proportion of the drug<BR> response duplicated by the placebo response. As an example of why this<!
br> should not be done, consider a treatment that improves intelligence by<BR> 1.55 SDs (which is approximately at the 6^th percentile) and another<BR> that improves it by 1.16 SDs (which is approximately at the 12^th<BR> percentile). Our method indicates that the second is 75% as effective<BR> as the first. The reviewer's method suggests that it is only 50% as<BR> effective. Now let's convert this to actual IQ changes and see what<BR> happens. If the IQ estimates were done on conventional scales (SD =<BR> 15), this would be equivalent to a change of 23.25 points by the first<BR> treatment and 17.4 points by the second. Note that the percentage<BR> relation is identical whether using z-scores or raw scores, because<BR> the z-score method simply divides both numbers by a constant.<BR><BR> ^2 Instead of dividing mean differences by the pooled SDs, Joffe et<BR> al. (1996) used baseline SDs, when these were available, in<BR> calculating effect sizes. !
When baseline SDs were not available, which<BR> they reported to be the case for most of the studies they included,<BR> they used estimates taken from other studies. Also, they used a<BR> procedure derived from Hedges and Olkin (1995) to weight for<BR> differences in sample size, whereas we used the more straightforward<BR> method recommended by Hunter and Schmidt (1990).<BR>_______________________________________________<BR>paleopsych mailing list<BR><A class=moz-txt-link-abbreviated href="mailto:email@example.com">firstname.lastname@example.org</A><BR><A class=moz-txt-link-freetext href="http://lists.paleopsych.org/mailman/listinfo/paleopsych">http://lists.paleopsych.org/mailman/listinfo/paleopsych</A><BR><BR><BR> </PRE><FONT
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