{'fraction_non_alphanumeric': 0.030599491445071757, 'fraction_numerical': 0.018273499116493556, 'mean_word_length': 5.082306684141547, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 1, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Placebo Effect in Obsessive-Compulsive Disorder (OCD). Placebo Response and Placebo Responders in OCD: The Trend Over Time

Background Placebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials. Method We included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff. Results We included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017. Conclusion We observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatment-resistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.


INTRODUCTION
A common belief lasting until the early nineties was that obsessive-compulsive disorder (OCD) did not respond to placebo [1]. However, this view rapidly changed as reliable scales developed to measure OCD symptoms.
There are two ways to measure the response of a patient or of a group of patients to a given treatment, drug or placebo, i.e., to consider improvement with respect to a baseline on a predetermined rating scale in terms of points or percentage, hence providing a measure of the percent response of a group, and to define some criteria for responsiveness and provide the percentage of patients who reached or surpassed a given threshold to qualify as treatment responders. A further specification of the latter is the remitter status, based on even stricter criteria. We will call the former "placebo (or drug) effect" to differentiate it from the ambiguous term "placebo (or drug) response", and term the latter responder rate (to placebo or drug) so to hold the two concepts apart. In OCD, the most commonly used rating scale as a primary outcome measure is the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [2,3] and responses to treatments, or treatment effects, as we term them to avoid confusion with number of persons who are considered as treatment responders, are rated as percent variations of scores on the Y-BOCS from baseline at a given time-point. On the other hand, treatment responder rates are considered as the fraction of patients in the sample who are judged on the basis of established criteria, usually an at least 35% (or 25%, according to the study's author choice) drop of Y-BOCS scores from baseline or 1 or 2 (very much or much improved, respectively) on the Clinical Global Impressions scale, improvement version [4].
There is evidence for the growth of placebo effect (and responder rates) in clinical trials across the years for depression [5] and, less consistently, bipolar disorder [6], although some biases may have influenced the conclusions of this second study [7]. Other psychiatric disorders have not been investigated for this year-of-publication effect specifically, but a multivariate meta-analysis carried-out by Ackerman and Greenland [8] found an increase in the effect of placebo through the years, confirming the impressions of others [9]. This could be due to the host of factors, like trends in the type of patient recruited (regarding illness duration, severity, and comorbidity), type of drug used (the side effect profile of a drug like clomipramine increases the likelihood of drug identification by both clinician and patient and may affect outcome), study site characteristics (that may reflect the characteristics of participating physicians and principal investigators and contribute to large across-sites differences which are usually disregarded in most reports), outcome measures employed, publication bias-file drawer effect, and last, but not least, the fact that the more effective the drug in a study, the more effective the placebo [10]. In fact, a publication year effect has been shown for OCD treatment across the years [11]. However, Ackerman and Greenland [8], who used meta-regression to evaluate placebo-controlled drug trials in OCD, did not include in their remarkable paper, drug trials in paediatric populations did not consider surgical procedures versus sham surgery or psychotherapies versus sham psychological interventions, and failed to consider a considerable number of papers covering a quite long period of time. In fact, they analysed a restricted period of time of placebo-controlled drug trials of three SSRIs and clomipramine in a period spanning from 1989 to 1999 (i.e., after the introduction of the Yale-Brown Obsessive Compulsive Scale, Y-BOCS), with a consequent loss of more than ten years of literature.
Systematic investigations of treatment of OCD started at the dawn of the eighties, with the use of clomipramine [12,13]; clomipramine [14] and imipramine [15,16] dominated the scene during the mid-eighties, and it was only during the late eighties that SSRIs, primarily fluvoxamine, were introduced [17,18]. The first two studies comparing sertraline to placebo appeared in 1990 and yielded contrasting results [19,20]. The first published trials of fluoxetine versus placebo appeared in 1992 [21], but regarded data that started being gathered in the late eighties [22][23][24], therefore simultaneous with, if not preceding those of sertraline. It is noteworthy that fluoxetine had received extensive open trials in OCD since 1985 [25], whereas for sertraline, the two aforementioned double-blind studies were the first studies of sertraline in OCD to be published [19,20]. This publication lag may create a bias in the attempt to clarify whether the effect of a given treatment increased or decreased with time. Unfortunately, most studies do not provide the period during which they were conducted and render it difficult to correct for this bias. Hence, we will consider publication data as a factor despite realising that it does not exactly reflect the period during which the study has been carried out.
Our aim was to extend Ackerman and Greenland's [8] observations beyond 2002, including also studies that did not use drugs, but other methods as well that could ensure double-blinding. We did not use the same method, but rather a JoinPoint regression.

METHODS
We carried-out a general search in the PubMed-MedLine-Index Medicus and Embase-Excerpta Medica and PsycLit-Psychological Abstracts databases using the following strategy: (placebo OR sham) AND (obsessive* OR OCD) with no time, language or any other restriction, but animal studies were subsequently excluded. We did not use the PubMed "Animal studies" function to exclude such studies, because such function often produces unreliable results. Papers were individually searched for adherence to our inclusion criteria. Retrieved relevant papers, comprising reviews and meta-analyses, were searched in their reference lists for providing additional papers with adequate research data. Final inclusion criteria for data analysis comprised: single or double-blind design, clearly stated assessment of response (responder rate or percent response on rating scales), sufficient time of treatment administration for the expected response to be observed, absence or adequate addressing of confounders that could render response not attributable to specific treatments. Specifically, the second part of cross-over studies was discarded if switching from one treatment to another had not a sufficient treatment-free wash-out period to avoid carry-over effects; survival studies were excluded when tapering-off of a combined therapy involved a drug vs. placebo when another drug or treatment was continued; add-ons were given not to patients stabilised on a given drug, but on drug-free or drug naïve populations. In this first report on placebo response in OCD we concentrate on double-blind studies using drugs, hence we excluded studies with psychotherapy or comparing mechanical devices with sham, like deep brain stimulation, electroconvulsive therapy, or deep/repetitive transcranial magnetic stimulation, provided they did not have a placebo and a drug arm. Excluded were also studies focusing on other than clinical outcomes, those carried-out on mixed populations (e.g., OCD and Tourette's) without providing results specific for each subpopulation, and those with designs such that a placebo effect could not be calculated.

Statistical Analysis
We analysed temporal trends of placebo and drug response rates/responder proportions through log-linear joinpoint segmented regression models, which identify points corresponding to statistically significant changes over time in the linear slope of the occurring trend [26]. We used annual mean rates of placebo and drug effect (mean placebo and drug-induced improvements and mean placebo/drug responders) as independent variable assuming constant variance (homoscedasticity) without log transformation. We applied a grid search method to fit regression functions with unknown joinpoints assuming a Poisson distribution and uncorrelated errors. We set the minimum/maximum joinpoint number from 0 to 2, and used a permutation test with overall significance level set at p<0.05 and number of randomly permuted datasets of 4,499 to select the best fit. In the final model, each joinpoint indicates a trend change. We reported the estimated annual percent change (APC) for segmented analysis. Joinpoint analyses were performed using the Joinpoint Regression Program, version 3.5, from the US National Cancer Institute (https://surveillance.cancer.gov/joinpoint/).
Joinpoint regression analyses of the period 1979-2017 showed that placebo mean annual effect rates in OCD studies significantly increased (APC value significantly differing from zero to α = 0.05 level) from 1991 to 2017 with an APC of 0.66% (p=0.04) following a period without statistically significant APC changes (Fig. 2). Placebo mean annual responder rates also significantly increased from 2010 to 2017 with an APC of 5.45% (p=0.02) following a period without statistically significant APC changes (Fig. 3).
Drug mean annual effect rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72% (p=0.04) between two periods without statistically significant APC changes (Fig. 4). Drug mean annual responder rates did not    show statistically significant APC changes between 1984 and 2017 (Fig. 5).

DISCUSSION
In this study, using Joinpoint regression analyses, we found significant increases in the net effect of placebo from 1991 to 2017 and in placebo responder rates from 2010 to 2017. The effects of drug treatment of OCD increased from 1987 to 2012, between two periods of no significant changes (1979-1987 and 2012-2017), while responder rates to drug treatment showed no statistically significant annual changes between 1984 and 2017. We confirmed the finding of a trend towards an increase of placebo effects in OCD drug treatment studies, previously reported by Ackerman and Greenland for the decade 1989 to 1999 in their 2002 metaregression [8]. Surprisingly, we did not find drugs to increase their effect of responder rates in parallel with placebo. In fact, the increasing placebo effect that was found for other psychiatric (e.g., schizophrenia [129] and depression [130]) and non-psychiatric disorders (e.g., hypertension [131]), and placebo efficacy dragged drug efficacy to higher levels [130]. Here we found a trend towards increased placebo effects and responder rate, with a decrease in the difference between drug and placebo, to the point that the most recent response rates (effects) between placebo and drugs nearly overlap (Figs. 2 and 4), while responder rates differ little (Figs. 3 and 5); something similar has been described for schizophrenia [132], but not for depression [130]. Furthermore, we also found that effect/responder rates for OCD to both placebo and drugs are low compared to other psychiatric disorders, as recently reported using effect sizes as outcome measures [133]. Why OCD should be stiffer than other psychiatric disorders in responding to treatment may have a response to the pathophysiology of the disorder and to its related personality characteristics. That you can't teach an old dog new tricks may well apply to this disorder. A therapeutic response may be hampered by too often controlling one's health state, that prevents a patient from establishing an adequate clinical progress, and people with OCD often display pathological doubt, that prompts them to control for any change all too often and then to doubt for results.
It is not easy to explain the increase with time of placebo effects and responder rates we found here. One explanation that has been offered for similar results in depression is the "baseline inflation" [134], i.e., the tendency to inflate baseline scores of the scale chosen for subject inclusion in a randomised clinical trial (RCT) so to ensure more participants to the sponsor. This, combined with patient expectation and the Hawthorne-like effect of being closely observed, yields better results for drug and placebo alike. However, there has been no increase in baseline Y-BOCS scores of included samples.
Other possible explanations may involve historical factors. In fact, most early studies involved testing the efficacy of clomipramine and SSRIs in patients with OCD, or were survival studies focusing on Kaplan-Meyer curves after switching patients with a benefit on an antidepressant agent to placebo, measuring recurrence/relapse rates. In contrast, later studies increasingly focused on treatmentresistant populations and add-on drugs vs. placebo. It is highly probable that such populations are more resistant to the effects of both drugs and placebo. However, this should have been followed by a decrease in overall responsiveness, which we did not find; on the contrary, both effect and responder rates increased in later years, more so regarding placebo (Figs. 2-5).
Another issue may regard the principal sites involved in the various studies. In antipsychotic drug trials, the increase in placebo response has been observed for North Americabased studies, but not for those conducted in the rest of the world or for international studies including US sites [135], and the same phenomenon has been observed for painkiller trials, with sample size and study duration driving the placebo response increase [136]. Sample size in US studies correlated weakly with placebo response in our study (Pearson's r=0. 21). However, treatment duration did correlate strongly (Pearson's r=0.54). Here we observed a curious phenomenon, i.e., that in studies 1980-2008, USbased studies prevailed over the rest of the world (N=52 vs. N=24), whereas in studies conducted from 2009 on, the rest of the world studies reversed the ratio (N=13, USA vs. N=24, rest of the world). The reversal was driven by Iran (N=17), a country that was not present during the 1980-2009 period. In Iranian studies, the correlation between sample size was much weaker than in US-based studies (r=0.093), perhaps a consequence of the fact that sample sizes in these studies were about 20 each with a much lower standard deviation than in US studies ( Table 1). In contrast with US studies, there was a strong negative correlation between treatment duration and response to placebo (r=-0.471). Despite the entity of placebo effect did not differ between US-based and Iran-based studies (Student's t=1. 145; p=0.256, not significant), we feel that the recent upsurge of placebo responder rates and the constant increase of placebo response are linked to the results of Iranian studies. The samples in American studies varied widely, as did the number of sites, while the Iranian studies recruited middle samples and tended to be single-center (Table 1). It has been suggested in antidepressant trials for major depression that two factors that may be linked to reduced ability to detect a signal for an antidepressant are constituted by extremely large and extremely small samples and by multicentricity [137]; a reduced signal is usually linked to increasing placebo response that dampens the drug-placebo difference.
A possibility with longer-term treatment to associate with placebo response could reside in the exacerbating-remitting course that often characterizes OCD [138], especially in paediatric cases [139]. If the interpretation of the placebo effect as a regression to the mean holds true [140], it would ensure that by treating people for more time, there will be an increased probability of spontaneous remission of the disorder, that would be subsequently attributed to placebo. This matches the results of American studies, but is opposite to what Iranian studies tell us.
Still another possibility is a change in the characteristics of included patients. It has been speculated that RCTs tend to include patients repeatedly the same persons who participated in prior antidepressant trials, and this is usually addressed with excluding patients having participated recently in another RCT or having received psychotherapy in recent times. In fact, it was shown that patients with low income may be eager to participate in more than one antidepressant drug trial [141]. These patients would be expected to display a rather uniform behaviour in responding to treatment, thus favouring placebo response and their data tend to be increasingly included in databases, thus affecting results. In OCD, we do not have data at this regard, but the recent change in the classification of OCD spectrum disorders in the DSM-5 [142], which were previously classified amidst the anxiety disorders and included hoarding disorder [143], may have impacted the response of OCD to placebo. However, in this case, we should have expected a join point to occur about 2013, the year of introduction of DSM-5 [142]. In placebo effect, there was no such join point. Placebo effect showed a continuous growth from 1991 onwards, while placebo responder rate had a joinpoint at 2010, when the shift from DSM-IV-TR™ had still to occur. It should be said that DSM-IV-TR™ diagnoses in drug trials continued to be adopted along with DSM-5 diagnoses for some time. At any rate, it appears that in OCD, as in other mental and non-mental disorders, placebo effect and responder rates are puzzlingly increasing and appear to be out of control, and this depends on multiple factors [137,144], pointing to changing populations included in RCTs (independently from initial severity) and prompting to a revision of the RCT model. Given that this trend is not specifically bound to a single condition, it is possible that it reflects continuing human evolution.

Limitations and Strengths
Our study is not a meta-analysis and the overall placebo effect and placebo-responder rates are not weighted for sample size. Furthermore, we did not include studies not using drugs, i.e., somatic treatments vs. sham, and did not distinguish between adult and paediatric studies. Moreover, we did not select our studies based on their quality nor did we address possible sponsor bias. However, our study is the first considering such a wide time period and the first to consider both net placebo effects and responder rates based on clear-cut criteria. Future studies will have to address the above concerns. It has been suggested that mechanical devices [145] and surgery [146] are endowed with a superior placebo effect than drugs, although the evidence is still inconclusive [147], and placebo, despite displaying large effects in depression, was not superior in non-pharmacological than in pharmacological studies in a meta-analysis [148]. Comparison between drug and somatic treatment of OCD will show whether in this disorder there is a strong mechanical device component in placebo response and whether there is an increase of response with the year of publication with these treatments similar to what occurs with drugs.
The fact that the curves of effect and responder rates did not reciprocally correspond for both placebo and drugs may be explained by the fact that some studies did not report one of them ( Table 1). Investigators need to report their data more clearly in the future, so to allow other investigators to perform meta-analyses on their data.
The current situation with OCD treatment is that this disorder is either treated with drugs having the ability to block the reuptake of serotonin or with cognitive-behavioral therapy or both, or with attempts to add-on ongoing pharmacotherapy other pharmacological agents having antidopaminergic or antiglutamatergic properties or somatic treatments like deep brain stimulation or transcranial magnetic stimulation. The first studies focused on the efficacy of drugs used classical designs and were carried-out by prestigious institutions. Once the concept that first line treatments were represented by SSRIs/clomipramine, the treatment paradigms shifted towards add-on and somatic treatments, and this may have affected the figures we obtained. The closing gap between placebo and drug treatment must prompt investigators to formulate new hypotheses to test and industries to produce alternatively working drugs.

CONCLUSION
In this Joinpoint regression analysis, we observed an increase of the response to placebo (placebo effect) as well as an increase in responder rates in OCD studies with the year of publication. Changes in study types and sites are apparently related to the results obtained. The gap between response to drug and response to placebo appears to be reducing to an extent that current therapeutic approaches to OCD are becoming questionable and should prompt to seek newer approaches in facing this stubborn disorder.

CONSENT FOR PUBLICATION
Not applicable.

FUNDING
This work has not been supported by any funding. All authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with the subject matter or materials discussed in the manuscript.