BMC Psychiatry The consumption of Internet child pornography and violent and sex offending

Jérôme Endrass
Department of Justice
Psychiatric/Psychological Service
Canton of Zurich
Feldstrasse 428004ZurichSwitzerland

Frank Urbaniok firstname.lastname@example.com
Department of Justice
Psychiatric/Psychological Service
Canton of Zurich
Feldstrasse 428004ZurichSwitzerland

Lea C Hammermeister
Department of Justice
Psychiatric/Psychological Service
Canton of Zurich
Feldstrasse 428004ZurichSwitzerland

Christian Benz
Praxis Dr. Benz
Mühlebachstrasse 428008ZurichSwitzerland

Thomas Elbert email@example.com
University of Constance
78457ConstanceGermany

Arja Laubacher email@example.com
Department of Justice
Psychiatric/Psychological Service
Canton of Zurich
Feldstrasse 428004ZurichSwitzerland

Astrid Rossegger firstname.lastname@example.com
Department of Justice
Psychiatric/Psychological Service
Canton of Zurich
Feldstrasse 428004ZurichSwitzerland

BMC Psychiatry The consumption of Internet child pornography and violent and sex offending
10.1186/1471-244X-9-43BioMed Central Page 1 of 7 (page number not for citation purposes) Research article * Corresponding author
Background:There is an ongoing debate on whether consumers of child pornography pose a risk for hands-on sex offenses. Up until now, there have been very few studies which have analyzed the association between the consumption of child pornography and the subsequent perpetration of hands-on sex offenses. The aim of this study was to examine the recidivism rates for hands-on and hands-off sex offenses in a sample of child pornography users using a 6 year follow-up design.Methods:The current study population consisted of 231 men, who were subsequently charged with consumption of illegal pornographic material after being detected by a special operation against Internet child pornography, conducted by the Swiss police in 2002. Criminal history, as well as recidivism, was assessed using the criminal records from 2008.Results: 4.8% (n = 11) of the study sample had a prior conviction for a sexual and/or violent offense, 1% (n = 2) for a hands-on sex offense, involving child sexual abuse, 3.3% (n = 8) for a handsoff sex offense and one for a nonsexual violent offense. When applying a broad definition of recidivism, which included ongoing investigations, charges and convictions, 3% (n = 7) of the study sample recidivated with a violent and/or sex offense, 3.9% (n = 9) with a hands-off sex offense and 0.8% (n = 2) with a hands-on sex offense.Conclusion:Consuming child pornography alone is not a risk factor for committing hands-on sex offenses -at least not for those subjects who had never committed a hands-on sex offense. The majority of the investigated consumers had no previous convictions for hands-on sex offenses. For those offenders, the prognosis for hands-on sex offenses, as well as for recidivism with child pornography, is favorable.

Background

The legal definition of what constitutes child pornography, as well as the interpretation and enforcement of statutory provisions relating to child pornography, vary considerably from country to country. Not surprisingly, the definitions of child pornography to be found in the relevant research literature are equally heterogeneous [1][2][3]. The definitions differ regarding the age boundary of consenting adult vs. child and in respect to how explicit the sexual depiction of the material must be in order to be considered "illegal pornography". Furthermore, some criminal codes penalize only the production and distribution of illegal pornography, while others criminalize the possession as well.

In April 2002, a new article was introduced into Swiss penal law stating that the possession of pornographic material depicting sexual acts with children, excrement, animals, as well as violent sexual intercourse, is illegal (Art.197 Swiss Penal Code). Accordingly, the production, import, storage, marketing, making available, and presentation of illegal pornography is a punishable offense. Before April 2002, only the trade and production of child pornography was against the law, not its possession. Swiss penal law neither specifies the age which discriminates children from adults, nor does it specifically state the exact characteristics of pornography. However, judicial practice defines children younger than 16 as juveniles, which is also the appointed age of consent [4,5].

The high accessibility of the Internet has changed the consumption of child pornography. According to Cooper, Delmonico and Berg [6], three attributes of the Internet, called the "Triple A Engine", facilitate the consumption of child pornography: Accessibility (millions of websites are accessible 24 hours a day, 7 days a week), affordability (acquiring the material does not demand substantial financial resources), and anonymity (no personal contact with others is needed to consume child pornography). Quayle, Vaughan, and Taylor [7] also underline the importance of the ostensible anonymity of the Internet for the consumption of Internet child pornography, as it does not require contacting a dealer and the material can easily be acquired at home. Furthermore, virtual pornographic material can be stored easily and no strenuous effort is needed to keep the illegal material hidden [8].

One of the most consistent findings when trying to characterize the "typical" user of child pornography is -not surprisingly -that there are only male consumers [1,[9][10][11][12][13][14][15][16]. According to Quayle, Erooga, Wright, Taylor and Harbinson [2], it is safe to assume that female child pornography consumers are non-existent. Furthermore, there is evidence that consumers of child pornography have a relatively high educational background. According to Wolak, Finkelhor and Mitchell [16], 38% out of 1,713 convicted consumers of child pornography in the U.S. had a highschool diploma, 21% went to college at some point, 16% held a college diploma, and 4% finished their education at a doctoral level. This finding was corroborated by Riegel [13], who found that 77% of his sample of alleged pornography consumers consisted of college graduates. In the Swiss study of Frei, Erenay, Dittman and Graf [1], one out of three child pornography users reported working in an executive position or holding an academic degree. Burke, Sowerbutts, Blundell and Sherry [4], as well as O'Brien and Webster [17], found higher scores of intelligence, a better educational background, as well as a higher rate of employment for Internet child pornography consumers than for hands-on sex offenders.

When investigating the prevalence of Internet child pornography consumption, an important practical question is whether consumers of child pornography pose a risk for hands-on sex offenses. Empirical studies use different study designs and samples for answering this question. However, there are three main approaches to be found in the relevant research literature.

Firstly, there are studies that examine the role of child pornography consumption on offending in samples of hands-on sex offenders [10,15]. Following such an approach, Kingston, Fedoroff, Firestone, Curry and Bradford [10] examined convicted hands-on sex offenders and found that the consumption of illegal pornography was a relevant risk factor, namely that those offenders who had consumed illegal pornography were more likely to reoffend -irrespective of their risk-level of recidivism. Howitt [9] investigated convicted hands-on sex offenders, who reported that the source of sexual stimuli did not stem solely from child pornographic material, but also from the cognitive manipulation of legal adult pornography or from seeing arousing images in newspapers and magazines (usually not involving nudity). Unlike Kingston et al. [10], Howitt [9] concluded that it is not possible to establish an association between hands-on sex offenses and the consumption of child pornographic material. Since Kingston et al. [10] and Howitt [9] investigated samples containing only hands-on offenders, it is evident, that the conclusions of these authors cannot be generalized to hands-off offenders.

Secondly, there are studies that examine the prevalence of prior convictions for hands-on sex offenses in populations of child pornography consumers [1,14,15].

Webb, Craissati and Keen [15] compared 90 child pornography consumers with 120 offenders convicted of handson sex offenses. The number of offenders with prior convictions for sexual offenses was higher in the group of hands-on sex offenders than in the group of child pornography users. In an investigation by Frei, Erenay, Dittmann and Graf [1], none of the child pornography consumers had a criminal record.

This approach allows an initial conclusion to be drawn regarding the prevalence of hands-on sex offenses for child pornography consumers. However, due to the limitations of retrospective designs, it cannot answer the question of whether child pornography consumption represents a risk factor for committing hands-on sex offenses in the future.

Thirdly, research designs following up on a sample of offenders convicted of child pornography consumption would appear to be the best approach [14]. So far, there is only one study that has analyzed the association between child pornography consumption and the subsequent perpetration of hands-on sex offenses [14]. In their sample of convicted child pornography consumers, Seto and Eke [14] found a recidivism rate of 1.3% for hands-on sex offenses and 5.3% for hands-off sex offenses in a followup time of two and a half years. In this study, 24% of the study sample had been convicted for a hands-on sex offense against a minor. An Internet based survey by Riegel [13] found results pointing in the same direction as Seto and Eke's: Participants identifying themselves as "Boy-Attracted Pedosexual Males (BPM)" were asked whether the consumption of child pornographic material increased the desire to commit sexual acts with minors, 84.5% of the survey sample replied "rarely" or "never". The author interpreted this finding as an indication that the consumption of child pornography alone is not a sufficient risk factor for committing a hands-on sex offense.

Altogether, the empirical literature does not put forward any evidence that the consumers of child pornography pose a considerably increased risk for perpetrating handon sex offenses. Instead, the current research literature supports the assumption that the consumers of child pornography form a distinct group of sex offenders. Though some consumers do commit hands-on sex offenses as well -the majority of child pornography users do not. Previous hands-on sex offenses are a relevant risk factor for future hands-on sex offenses among child pornography users, just as they are among sex offenders in general. The consumption of child pornographic material alone does not seem to predict hands-on sex offenses.

The aim of this study was to analyze the characteristics of a sample of child pornography users and the proportion of those who subsequently re-offended with hands-on and hands-off sex offenses.

Methods

Ethical approval

Non-invasive studies and studies that do not examine patients directly are not investigated by the Ethics Commission of the Canton of Zurich, as their ethical soundness is generally assumed. Nonetheless, in order to ensure ethical and judicial approval, the entire research project was presented to the Justice Department of the Canton of Zurich. A second examination was conducted by the Federal Office of Justice in connection with the request for the criminal records. The study was approved and supported by both authorities.

Sample

On a website owned by the US company "Landslide Productions", illegal pornography was distributed over the Internet [2,18]. When the website was shut down by the US-Postal Service in 1999, it had approximately 75'000 customers worldwide. The user data was handed over to the judicial authorities in the respective countries, which led to well coordinated, international police operations [18]. Through a number of house searches in 2002, a Swiss police operation ("Operation Genesis") revealed over 400 persons suspected of having consumed illegal pornographic material via Landslide Productions Inc. Of these 400 people, only those suspected of child pornography consumption, were included in the study sample. This led to a sample size of N = 231.

Data collection

The Department of Public Prosecution provided the judicial files and all necessary information for assessing the socio-demographic and offense related characteristics.

2002 was the cut-off point, with any convictions prior to this date being 'previous convictions'. The follow-up was in 2008, therefore resulting in a six year follow-up period, during which time all new offenses were deemed to be reoffending.

The information on previous convictions was collected from the criminal records.

Recidivism was assessed based on two sources of information, namely the criminal records as well as the database of the Zurich criminal justice system. By using these two sources of information, it was possible to analyze two different definitions of recidivism.

According to a strict definition, recidivism was assumed only if new convictions subsequent to the index offense (child pornography consumption) were registered in the criminal records.

A broader definition of recidivism was introduced including convictions, as well as ongoing investigations and charges, as it is a well known fact that the use of criminal records frequently leads to an underestimation of especially sex and violent recidivism. Thus, in Switzerland, convictions of criminally non-responsible offenders, which often involve sex and violent offenses, are not registered in the official criminal records. Also, the registration of sex and violent offenses in the criminal records often takes several years due to longer investigation and appeal periods.

Statistical analysis

Descriptive statistical analyses were performed to examine the socio-demographic and offense related characteristics of the study sample. In order to investigate further, a stratified analysis was conducted: During the court proceedings, 95% (n = 217) of the sample confessed to having used child pornography, however, the evidence only led to convictions in 55% (n = 127) of the cases. Unlike current legal practice, saving illegal data in the temporary data cache of the computer was not enough for a conviction in 2002 -only if a permanent recording of the illegal material could be proven was it possible to convict the accused. Though only around half of the sample was actually convicted, there were sufficient grounds for assuming that all subjects in the study sample had consumed child pornography, seeing as they had registered with their personal credit cards and confessed to the allegations. Accordingly, the legal fees were also imposed on those offenders who were acquitted. However, this lead to two different subsamples which allowed a stratified analysis: the sample of convicted offenders and the sample of acquitted offenders. The aim of the stratified analysis was to determine whether a legal sanction led to a behavioral change regarding the consumption of illegal pornography. Significance was tested with the chi-square test.

All statistical analyses were carried out with STATA SE 10.1.

Results

Socio-demographic characteristics

At the time of offense, the average age of the subjects was 36 years (SD 10.0), with a range from 18 to 65. The majority of the subjects were Swiss nationals (94%, n = 217), 58% (n = 128) were single, 33% (n = 74) were married, 8% (n = 19) were divorced and 1% (n = 3) were widowed. 25% (n = 55) of the study sample had children.

Out of 226 subjects, 45% (n = 102) worked in a position that required a university level diploma, 50% (n = 112) held a job requiring formal vocational training and 5% (n = 12) were unskilled workers. Roughly one third (32%, n = 70) worked in a computer science or engineering-oriented profession, 26% (n = 56) held a blue collar job and 33% (n = 72) worked in the service industry. Nearly half of the study sample worked primarily with a computer at their place of work.

Offense characteristics

Location of pornography consumption (index offense) 95% (n = 218) of the sample had Internet access from home and 30% (n = 68) at work. Even so, child pornography was consumed at work in only four cases (2%) and only one subject actually saved child pornography onto a work computer.

Characteristics of the illegal material

Two subjects (1%) were in possession of pornographic material they had made themselves. 19% (n = 43) of the sample were in possession of more than 5'000 files of illegal pornography. Forty percent (n = 93) of the subjects consumed only child pornography, the rest consumed other types of illegal pornography, such as pornography depicting sexual acts with animals, excrement, or involving brutality. One out of three subjects (33%, n = 77) consumed at least three types of illegal pornography.

Criminal history

Before the police operation "Genesis" in 2002, 4.8% (n = 11) of the study sample had prior convictions for a sex and/or violent offense: Two subjects (1.0%) had prior convictions for hands-on sex offenses involving child sexual abuse, 3.5% (n = 8) subjects had prior convictions for hands-off sex offenses (possession/consumption of illegal pornography) and one subject had a prior conviction for a violent offense.

Recidivism

Applying the strict definition of recidivism, 3.0% (n = 7) of all subjects re-offended with a sex and/or violent offense during the six year follow-up. In detail, 2.6% (n = 6) of the study sample recidivated with a hands-off sex offense (consumption of illegal pornography) and 0.4% (n = 1) with a violent offense (bodily harm). No one in the study sample was convicted of a hands-on sex offense.

Applying the broader definition of recidivism (including reconvictions, ongoing investigations and charges), the rate of violent and/or sexual recidivism was 6% (n = 14). Nine (3.9%) of the subjects were investigated, charged or convicted for hands-off sex offenses, all of which were due to illegal pornography possession. Two subjects (0.8%) were being investigated, charged or convicted for a handson sex offense, namely child sexual abuse. Recidivism with a violent offense was documented in 1.3% (n = 3) of the cases.

Of the 9 subjects who had recidivated with a hands-off sex offense according to the broad definition, none had previously been convicted (before the index offense) for a hands-off sex offense. Of the two subjects who had reoffended with a hands-on sex offense according to the broad definition, one had previously been convicted for a hands-on sex offense. Table 1 shows the prevalence rates for prior convictions, as well as recidivism rates.

Convicted vs. acquitted consumers of illegal pornography

Stratified analyses of the data revealed several differences between subjects convicted of consuming illegal pornog-raphy (group: convicted) and those who were acquitted (group: acquitted).

Acquitted offenders were significantly more likely to be married (40% vs. 28%) but did not differ with respect to vocational education or job position.

More frequently, various forms of illegal pornography were found in the group of convicted consumers and these subjects were also more likely to own a collection of this material (30% vs. 5%). Furthermore, they held more subscriptions to commercial websites containing legal pornographic material (28% vs. 10%) and were more likely to be in the possession of commercial (legal) pornographic material recorded on VHS, CDs, and DVDs (19% vs. 4%).

Convicted and acquitted subjects did not differ with respect to prior convictions. However, the two subjects already convicted for a hands-on sex offense, along with the only person previously convicted for a violent offense, were not convicted for the possession of illegal pornography as result of the police operation.

According to the broad definition of recidivism, 7.3% (n = 9) of the convicted group re-offended with a hands-off sex offense while none of the acquitted group did. Viceversa, none of the convicted group re-offended with a hands-on sex offense while 1.9% (n = 2) of the acquitted group did. Table 2 shows the significant differences in the consumption pattern of convicted vs. acquitted users of illegal pornography.

Discussion

For the present study, the criminal records of all men charged with child pornography, as a result of the police operation "Genesis", were analyzed. This study is one of the few scientific reports covering a six year follow-up period of a sample of subjects charged with the consumption of child pornographic material. Descriptive analyses suggest that child pornography users are less likely to be married: While only one out of three subjects was married at the time of the police operations, the census data of the Canton of Zurich reported that 45% of the Swiss male population living in the Canton of Zurich was married. Moreover, the foreign nationals (6%) in the present study were underrepresented in comparison to the 31% of foreign male residents in the Canton of Zurich [19]. This finding is remarkable seeing as this underrepresentation cannot be found for hands-on sex offenses [20]. As in other studies [4,13,16,17], the finding that child pornography consumers are well educated was replicated in the present study: Only 5% of the investigated sample held an unqualified job position -a figure that is rather low compared to the 16% of unskilled workers in the permanent living population of the Canton of Zurich [21].

In summary, our results suggest that users of child pornography are probably well integrated in Swiss society, as the majority of subjects held a job requiring extensive training and were Swiss nationals.

The question of whether consumers of child pornography pose a risk for hands-on sex offenses has not yet been answered. In their sample of child pornography users, Seto und Eke [14] found that 24% of the study sample had a criminal record for a hands-on sex offense against a minor and 15% had a prior conviction for the possession of child pornography. Other studies however, have found low rates of previous convictions for hands-on sex offenses among child pornography consumers [4,15].

In our study, we were able to replicate the finding that the majority of child pornography consumers do not have a criminal record for a violent and/or sex offense. Before the police operation, 3.5% of the study sample had prior convictions for a hands-off sex offense and 1% (n = 2) for hands-on sex offenses involving child sexual abuse. We cannot explain the large difference of prior conviction rates in our sample compared to Seto and Eke [14] -further research would be necessary to find out if they differ Sex and/or violent offenses 4.8 (11) 3.0 (7) 6.0 (14) significantly in regard to socio-economic, educational and/or other variables.

Studies investigating hands-on sex offender populations support the assumption that the consumption of illegal pornography is a relevant risk factor for recidivism [10]. In contrast, Seto and Eke [14] found low recidivism rates for both hands-on (1.3%) and hands-off (5.3%) sex offenses in a follow-up time of two and a half years for their sample of child pornography consumers.

Similar to Seto and Eke [14], we found low rates of recidivism among our sample. When applying the broader definition of recidivism by taking investigations and charges into account, the recidivism rates were 0.8% for hands-on and 3.9% for hands-off sex offenses. These recidivism rates after a follow-up time of six years indicate that the risk of re-offending for child pornography consumers is quite low.

Limitations

The investigated population could be severely biased, seeing as the users needed a credit card and sufficient knowledge of a foreign language (English) in order to gain access to the pornographic material. This could explain the rather elevated proportion of well educated subjects in the study sample and indicates that the investigated sample is most probably not representative for consumers of illegal pornography in Switzerland.

Conclusion

Among the subjects of the present study, only 1% were known to have committed a past hands-on sex offense, and only 1% were charged with a subsequent hands-on sex offense in the 6 year follow-up. The consumption of child pornography alone does not seem to represent a risk factor for committing hands-on sex offenses in the present sample -at least not in those subjects without prior convictions for hands-on sex offenses.

Table 1 :
1Criminal history and recidivism divided into offense categoriesCriminal history (N = 231)
Recidivism (N = 231)

Strict definition
Broad definition

% (n)
% (n)
% (n)

Table 2 :
2Significant differences in the consumption pattern of convicted vs. acquitted users of illegal pornographyConvicted
Acquitted
χ 2

% (n)
% (n)

(page number not for citation purposes)
(4) 12.14* *p < .05Publish with Bio Med Central and every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours -you keep the copyright Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentral
AcknowledgementsWe would like to thank the Canton Zurich Department of Public Prosecution, as well as the Sex Offense Department of the Zurich Canton Police for supporting the study.Further thanks go to Nicole Wetli for proof reading and further manuscript layout.Competing interestsThe authors declare that they have no competing interests.Authors' contributionsJE has given substantial contributions to the conception, analysis, and interpretation of the data and helped draft the manuscript. FU and CB developed the idea for the study and developed the study design. LH was involved in the process of data collection and performed the statistical analysis. TE and AL have been involved in revising the manuscript critically. AR was substantially involved in interpreting the results and writing the manuscript. All authors read and approved the final manuscript.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/9/43/pre pub
Paedophilia on the Internet -a study of 33 convicted offenders in the Canton of Lucerne. A Frei, N Erenay, V Dittmann, M Graf, Swiss Medical Weekly. 135Frei A, Erenay N, Dittmann V, Graf M: Paedophilia on the Inter- net -a study of 33 convicted offenders in the Canton of Lucerne. Swiss Medical Weekly 2005, 135(33-34):488-494.

Abuse Images and the Internet. E Quayle, M Erooga, L Wright, M Taylor, D Harbinson, E Quayle, M Erooga, L Wright, M Taylor, D Harbinson, Lyme Regis, Only Pictures? Therapeutic work with Internet. Russell House Publishing LtdQuayle E, Erooga M, Wright L, Taylor M, Harbinson D: Abuse Images and the Internet. In Only Pictures? Therapeutic work with Internet sex offenders Edited by: Quayle E, Erooga M, Wright L, Taylor M, Harbinson D. Lyme Regis: Russell House Publishing Ltd; 2006:1-11.

Child Pornography, the Internet and offending. M Taylor, E Quayle, G Holland, The Canadian Journal of Policy Research. 2Taylor M, Quayle E, Holland G: Child Pornography, the Internet and offending. The Canadian Journal of Policy Research 2001, 2:94-100.

A Burke, S Sowerbutts, B Blundell, M Sherry, Child Pornography and the Internet: Policing and Treatment Issues. Psychiatry, Psychology and Law. 9Burke A, Sowerbutts S, Blundell B, Sherry M: Child Pornography and the Internet: Policing and Treatment Issues. Psychiatry, Psychology and Law 2002, 9(1):79-84.

Kinderpornographie und Internet; Child pornography in the Internet Goettingen: Hogrefe. K Kuhnen, Kuhnen K: Kinderpornographie und Internet; Child pornography in the Internet Goettingen: Hogrefe; 2007.

Cybersex: The dark side of the force A special issue of the. A Cooper, D L Delmonico, R Burg, Cybersex users, abusers, and compulsives: New findings and implications. 7Cooper A, Delmonico DL, Burg R: Cybersex users, abusers, and compulsives: New findings and implications. Cybersex: The dark side of the force A special issue of the Journal of Sexual Addiction & Com- pulsivity 2000, 7:5-27.

Sex offenders, internet child abuse images and emotional avoidance: The importance of values. Aggression and Violent Behavior. E Quayle, M Vaughan, M Taylor, 11Quayle E, Vaughan M, Taylor M: Sex offenders, internet child abuse images and emotional avoidance: The importance of values. Aggression and Violent Behavior 2006, 11(1):1-11.

Collecting Images. E Quayle, M Erooga, L Wright, M Taylor, D Harbinson, E Quayle, M Erooga, L Wright, M Taylor, D Harbinson, Lyme Regis, Only Pictures? Therapeutic work with Internet. Russell House Publishing LtdQuayle E, Erooga M, Wright L, Taylor M, Harbinson D: Collecting Images. In Only Pictures? Therapeutic work with Internet sex offenders Edited by: Quayle E, Erooga M, Wright L, Taylor M, Harbinson D. Lyme Regis: Russell House Publishing Ltd; 2006:119-129.

Pornography and the paedophile: Is it criminogenic?. D Howitt, Br J Med Psychol. 68Pt 1Howitt D: Pornography and the paedophile: Is it crimino- genic? Br J Med Psychol 1995, 68(Pt 1):15-27.

Pornography use and sexual aggression: the impact of frequency and type of pornography use on recidivism among sexual offenders. D A Kingston, P Fedoroff, P Firestone, S Curry, J M Bradford, Aggressive Behavior. 344Kingston DA, Fedoroff P, Firestone P, Curry S, Bradford JM: Pornog- raphy use and sexual aggression: the impact of frequency and type of pornography use on recidivism among sexual offenders. Aggressive Behavior 2008, 34(4):341-351.

Child seduction and self-representation on the Internet. E Quayle, M Taylor, Cyberpsychol Behav. 45Quayle E, Taylor M: Child seduction and self-representation on the Internet. Cyberpsychol Behav 2001, 4(5):597-608.

Child pornography and the Internet: Perpetuating a cycle of abuse. E Quayle, M Taylor, Deviant Behavior. 234Quayle E, Taylor M: Child pornography and the Internet: Per- petuating a cycle of abuse. Deviant Behavior 2002, 23(4):331-362.

Effects on boy-attracted pedosexual males of viewing boy erotica. D L Riegel, Arch Sex Behav. 334Riegel DL: Effects on boy-attracted pedosexual males of view- ing boy erotica. Arch Sex Behav 2004, 33(4):321-323.

The criminal histories and later offending of child pornography offenders. M C Seto, A W Eke, 17Seto MC, Eke AW: The criminal histories and later offending of child pornography offenders. Sexual abuse: a journal of research and treatment 2005, 17(2):201-210.

Characteristics of internet child pornography offenders: a comparison with child molesters. Sexual abuse: a journal of research and treatment. L Webb, J Craissati, S Keen, 19Webb L, Craissati J, Keen S: Characteristics of internet child pornography offenders: a comparison with child molesters. Sexual abuse: a journal of research and treatment 2007, 19(4):449-465.

Child-Pornography Possessors Arrested in Internet-Related Crimes: Findings From the National Juvenile Online Victimization Study. Alexandria: National Center for Missing & Exploited Children. J Wolak, D Finkelhor, K J Mitchell, Wolak J, Finkelhor D, Mitchell KJ: Child-Pornography Possessors Arrested in Internet-Related Crimes: Findings From the National Juvenile Online Victimization Study. Alexandria: National Center for Missing & Exploited Children; 2005.

The construction and preliminary validation of the Internet Behaviours and Attitudes Questionnaire (IBAQ). Sex Abuse. M D O'brien, S D Webster, 19O'Brien MD, Webster SD: The construction and preliminary validation of the Internet Behaviours and Attitudes Ques- tionnaire (IBAQ). Sex Abuse 2007, 19(3):237-256.

The Impact of Viewing on Offending Behaviour. E Quayle, Child Sexual Abuse And the Internet: Tackling the New Frontier Edited by: Calder MC. Lyme RegisRussell House Publishing LtdQuayle E: The Impact of Viewing on Offending Behaviour. In Child Sexual Abuse And the Internet: Tackling the New Frontier Edited by: Calder MC. Lyme Regis: Russell House Publishing Ltd; 2004:25-36.

Statistisches Amt des Kantons Zürich: Wohnbevölkerung nach Heimat und Geschlecht. Statistisches Amt des Kantons Zürich: Wohnbevölkerung nach Heimat und Geschlecht. 2008 [http://www.statistik.zh.ch/ themenportal/themen/daten_detail.php?id=572&tb=1&mt=2].

Abschlussbericht zum Modellversuch "Therapieevaluation undPrädiktorenforschung. J Endrass, A Rossegger, F Urbaniok, Zürcher Forensik StudieEndrass J, Rossegger A, Urbaniok F: Zürcher Forensik Studie. Abschlussbericht zum Modellversuch "Therapieevaluation undPrädiktorenforschung". 2007 [http://www.zurichforen sic.org].

. Statistisches Amt des Kantons Zürich: Erwerbsbevölkerung nach Ausbildung. Statistisches Amt des Kantons Zürich: Erwerbsbevölkerung nach Ausbildung, 2007. 2008 [http://www.statistik.zh.ch/themenportal/ themen/daten_detail.php?id=564&tb=2&mt=2].


Philosophy, Ethics, and Humanities in Medicine Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?

John Pa
Department of Hygiene and Epidemiology
Clinical Trials and Evidence-Based Medicine Unit
University of Ioannina School of Medicine and the Biomedical Research Institute
Foundation for Research and Technology-Hellas
IoanninaGreece

Institute for Clinical Research and Health Policy Studies
Department of Medicine
Tufts University School of Medicine
BostonUSA

Ioannidis
Philosophy, Ethics, and Humanities in Medicine Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?
10.1186/1747-5341-3-14BioMed Central Page 1 of 9 (page number not for citation purposes) Review
Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval). However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second metaanalysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted reporting of results has built and nourished a seemingly evidence-based myth on antidepressant effectiveness and how higher evidence standards, with very large long-term trials and careful prospective meta-analyses of individual-level data may reach closer to the truth and clinically useful evidence.

Background

Few drugs have been as successful blockbusters as the class of antidepressants. Cumulatively, hundreds of millions of patients have taken these medications, and the selective serotonin reuptake inhibitors (SSRIs) and newer generation drugs in particular have been immensely popular. Antidepressants reflect one of the major manifestations of medicalization of modern society [1]. In 2006, 5 of the 35 drugs with top sales in the USA were antidepressants, and each of them had sales of 1.08-2. 25 billion dollars in that year (Table 1) [2]. About 30% of the cost of depression in the USA (80 billion dollars per year) goes to drug expenditures [3]. This is not an epidemic that lacks evidence-based material to support it. Few drugs have had such a long chain of double-blind, placebo-controlled trials performed to demonstrate their effectiveness and to pass through seemingly strict regulatory approvals. The randomized literature of antidepressants is apparently one of the richest in evidence-based credentials. While for a large proportion of medical interventions, we have no or few clinical trials ever conducted, for antidepressants there are probably well over a thousand. PsiTri, an online library of clinical trials for mental health conditions [4], lists 4058 clinical trials for depression, and a large share of them (over a quarter of the total, exact count depends on eligibility criteria) pertain to randomized trials of antidepressants. A systematic review of SSRI trials for diverse indications until 2003 [5] found 702 trials (411 comparisons between SSRIs and placebo, 220 comparisons between SSRIs and tricyclic antidepressants, and 159 comparisons between SSRIs and active therapies other than placebos or tricyclic antidepressants). In another review [6] of 12 antidepressants where only double-blind, placebo-controlled trials for diverse indications in adults were involved, sponsors furnished data to the FDA on 406 trials with approximately 100,000 randomized patients.

Formally, statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials, both pre-approval and post-approval. In theory, this is a prototype of evidence-based medicine where treatments pass through rigorous randomized testing, and are vastly successful both in the clinical science arena as well as in the market.

This picture of bliss was questioned recently by two large, well-conducted meta-analyses [7,8]. In this review, I examine first what these meta-analyses have found and what are some possible limitations of these studies. Then I try to dissect what are the components that have con-structed the seemingly evidence-based picture that antidepressants are so effective and why this picture may be problematic on close scrutiny. I try to address eventually whether antidepressants are widely indicated to treat depression and whether it is unethical to kill a living myth. Finally, I make some suggestions about how we can get appropriate evidence on these drugs.

Upset by meta-analyses Selective reporting

The first meta-analysis used data that were submitted to the U.S. Food and Drug Administration (FDA) for 12 antidepressant drugs that were approved between 1987 and 2004 [7]. These were bupropion SR (Wellbutrin SR, Glax-oSmithKline), citalopram (Celexa, Forest), duloxetine (Cymbalta, Eli Lilly), escitalopram (Lexapro, Forest), fluoxetine (Prozac, Eli Lilly), mirtazapine (Remeron, Organon), nefazodone (Serzone, Bristol-Meyers Squibb), paroxetine (Paxil CR, GlaxoSmithKline), sertraline (Zoloft, Pfizer), venlafaxine (Effexor, Wyeth), and venlafaxine XR (Effexor XR, Wyeth). The major advantage of using data submitted to FDA is that this includes all the trials that each company had registered as evidence in support for marketing approval or change in labelling. This registration allows one to have knowledge of all these trials, regardless of whether they were eventually published or not. Moreover, the process of regulatory review is such that there is less room for manipulating analyses and distorting results in data entered in the FDA registry tables.

The meta-analysts found 74 eligible FDA-registered trials with 12,564 patients. Among them, a third (n = 26 trials [31%] with 3449 patients) had remained unpublished. The FDA had determined that half of the registered trials (38/74) had found statistically significant benefits for the antidepressant ("positive" trials). All but one of these trials had been published in journals. Conversely, of the other half trials (36/74) that were deemed to be "negative" by the FDA, one in three were published as "negative" results; another 11 trials were published, but the results were presented in such a way so as to seem "positive" and 22 "negative" trials were silenced and never appeared in the literature. The meta-analysts studied the estimated effectiveness of these drugs when data were combined from the FDA records and when data were combined from the published literature. For all drugs, the published literature inflated the effect sizes. The inflation varied from 11% to 69% and it was 32% on average. The FDA data would suggest that these agents had small, modest benefits (standardized effect size [ES] = 0.31 on average). Conversely, for 4 of the 12 agents, if one were to perform unawares only a meta-analysis of the published data, the summary result would suggest clinically important effectiveness (ES>0.5). This was not true for any agent based on more complete FDA data.

Treatment and placebo effect as a function of baseline severity

A second meta-analysis in PLoS Medicine used also data that were submitted to FDA on 6 new generation antidepressants and eventually used the information on four of them (5 trials on fluoxetine, 4 on venlafaxine, 8 on nefazodone, and 16 on paroxetine) [8]. For 2 other drugs (sertraline and citalopram), some trials were simply reported even in the FDA databases as having non-significant results. In contrast with the other meta-analysis, the investigators of this meta-analysis did not wish to impute data when there was such missing information.

The PLoS Medicine meta-analysis asked the question: is there a relationship between the baseline severity of depression and the difference in effectiveness between drug and placebo? Meta-regression analyses identified such a relationship. Drug-placebo differences were generally small, but they increased with increasing baseline severity. The meta-analysts used a previous consensus [9] to propose that a clinically important difference needs to be at least 3 points in the Hamilton scale or ES>0.50. The difference between drug and placebo became large enough to be clinically important only in the small minority of patient populations with severe depression (baseline score exceeding 28 in the study population). Even in these severely depressed patients, the difference between drug and placebo was due to the fact that placebo became less effective; there was no evidence that the antidepressants became more effective. The authors concluded that most of the benefit from antidepressants is duplicated by the placebo effect. This is a conclusion that had been proposed also based on earlier meta-analysis [9]. Moreover, the current meta-analysis added the insight that these agents may be of clinical use only in severely depressed people, a small minority compared with the vast populations who take antidepressants currently. Even in the few extremely depressed patients, the eventual benefit was due to lack of responsiveness of placebo, not due to increased responsiveness to antidepressants.

Limitations in the meta-analyses

Both meta-analyses have some limitations. Many more trials are conducted after approval or outside of the FDA approval process. Moreover, registries of approved agents do not include antidepressants that were possibly tested in clinical trials in the USA, but did not make it (presumably because of more "negative" results), although they made it and were approved in other countries, e.g. fluoxamine, milnacipran, or mianserin. Among antidepressive drugs tested in the USA, only the "luckier" ones, the ones with larger ES, went to the FDA and received approval. The lack of a comprehensive global database is a major deficit in that we may be missing trials done in countries where the overall results for a particular agent were not very promising or overtly negative. Figure 1 shows a simple simulation: suppose that a drug is tested in 40 countries and 5 small trials are preformed for licensing purposes in each country. Let us suppose that on average the drug has a true effect that is small (ES = 0.20). Each of the perfectly unbiased studies is expected to find on average ES = 0.20 and there can be some variability. We can examine situations with different levels of variability around this average, corresponding to standard deviations of 0.20, 0.40, and 0.60. The smaller the trials and the larger the diversity of the populations and drug response, the more variability is expected around the mean of ES = 0.20. Suppose the drug is approved only in countries where the 5 trials show average ES at least 0.20. This is expected to happen in about half the countries. Figure 1 shows what the average ES estimates are in the trials registered in countries where the drug was approved: ES is markedly inflated. Similar considerations apply, if we consider not only many countries, but also many drugs tested in many countries.

Even focusing on FDA-registered trials, their data are not necessarily totally unbiased. Inherent biases in the study design and analysis cannot be corrected by simple registration. Data collection, arbitration of measurements and outcomes and multiple analysis options leave room for selectivity and for presentation of more optimal conclusions -even in FDA-registered results. Second, even these data are eventually incomplete in important details. This is amply demonstrated by the considerable number of studies that were simply registered as having "negative" results without further details on effect sizes, and by the additional missing information that the meta-analysts had to impute even for FDA-registered data. Third, these trials did not have available individual-level information and the data collection and arbitration of outcomes and measurements remained out of reach of the meta-analysts. For the considerable proportion of patients who did not complete the trials, typically last observation carried forward (LOCF) methods were applied, but these have limitations and may lead to overestimation of treatment effects in some circumstances [10].

All these limitations are more likely to have resulted in inflation of the treatment benefit, although there is considerable uncertainty about the exact bias. Of note, the PLoS Medicine meta-analysis [8] noticed funnel plot asymmetry, i.e. smaller trials had larger effects than larger trials. Funnel plot asymmetry is typically considered a sign of publication bias (small "negative" trials remaining unpublished), but this is clearly a misleading simplification [11]. Here publication bias in theory is impossible for FDA-registered data. The authors attributed the asymmetry to confounding due to higher severity scores in smaller trials [8]. However, an alternative explanation is that even for FDA-registered trials, results may still be biased. Exclusion or inclusion of specific patients and data due to questionable eligibility criteria or grey measurements, selection of imputation techniques, use or not or adjustments, and selective reporting of outcomes allow for manipulation in effect size estimation. In small trials, the same amount of manipulation will inflate the effect size more than in large trials, in other words the vibration of the effect size is larger [12,13]. The FDA review process will of course decrease analytical flexibility, but evalua-tion of depression involves messy outcomes and analyses are not cut in stone. In all, if anything, expectation of these biases further reinforces the message about antidepressants being less effective than thought.

A more serious limitation is inherent in the use of metaregression techniques in the PLoS Medicine meta-analysis.

The main analysis used a fixed effects meta-regression, and only a secondary analysis used a mixed effects approach. The latter, which may be more appropriate than fixed effects [14], had less conclusive results. Metaregression modelling can be biased [15]. When the trials have only small differences in the average values of severity (as in this case), the slope of the regression terms can be affected by outliers and leverage problems. The most important limitation stems from the ecological fallacy [16,17]. The regression used as a moderator variable the average baseline severity of depression in each group of participants in each trial arm. However, this is a proxy that does not represent equally well all participants. For example, the average baseline score may be 28, but this may include patients with scores of 17, 27, 32, and 36. The relationship may not have been the same, if data could have been analyzed for individual patients. This is to say, while net effectiveness (difference of drug from placebo) seemed to increase with increasing average severity, within a specific trial it could be that the effectiveness decreased with increasing severity. Ecological fallacy is the main reason why meta-regression analyses with group average are viewed with scepticism [17].

Finally, the PLoS Medicine meta-analysis describes the end of the severity spectrum in the analyzed trials as containing patients who are "most extremely depressed" or alternatively "very severe" depression. In fact, "very severe" depression would correspond to patients with even worse depression status, primarily those hospitalized because of major depression. In fact, the analyzed regulatory trials have typically avoided including hospitalized patients with truly so extreme depression, because these newer agents had been shown early on to be ineffective -or at least less effective than older agents -in such patients.

Understanding the construction of the myth of antidepressant effectiveness

Acknowledging these caveats, the lessons we get from these meta-analyses and from the previous literature on antidepressants show us that there are many components that have helped to create the impression that antidepressants are very effective and worthy of being so popular in the general population.

Statistical versus clinical significance

The typical trial in the antidepressant field is a small investigation with anywhere between a few dozen and a few hundreds of participants. Nevertheless, these trials have used outcomes that can pick formally statistically significant differences between the compared arms even with such small sample sizes. The typical choice is depression scales such as the Hamilton Rating Scale of Depression. Such continuous outcomes can show formally statistically significant results (p < 0.05) even for differences that are small and trivial. Statistical significance is confused with clinical significance. A consensus by the National Institute for Clinical Excellence (NICE) has suggested that at least a 3 point difference is needed in the Hamilton scale or equivalently ES = 0.50 to claim a clinically important effect [9]. Nevertheless, the results of several single trials with statistically significant results and the results of practically all meta-analyses with statistically significant results exclude that and ES = 0.50 can be conferred by antidepressants, when we examine the 95% confidence intervals of the effects. Here one should acknowledge that there is nothing absolute about the cut-off of ES = 0.50 and some investigators may disagree with this cut-off. Typically proposed thresholds in the literature for small, moderate and large effects for continuous outcomes are 0.2, 0.5, and 0.8 standard deviations, but even this is arbitrary [18].

Study design and selection of study populations

The industry of randomized trials of antidepressants has generated over the years a long chain of practices and design "standards" that aims to maximize the chances of showing larger benefits from given drugs. These practices and standards include, but are not limited to, the use of placebo-controls, placebo lead-in periods, and a set of exclusion criteria for recruited participants.

Placebo-controls are of course dictated by regulatory agencies, and there is some considerable justification for them. Empirical data, even before the meta-analyses discussed above, have repeatedly shown that the placebo effect in depressive symptoms is large, variable, and seemingly increasing in magnitude in more recent trials [19]. However, this also generates the paradox that although we acknowledge, approve and massively sell drugs that we consider to be more effective than placebo, we continue to perform trials that require some of the participants to take what we consider to be ineffective treatments [20]. As a compromise, some trials randomize patients 2:1 or even 3:1, 4:1 and 5:1 to active drug versus placebo, a contradiction to the sense of equipoise that should permeate the ethics of running a clinical trial. Obviously, the placebocontrolled trials have a better chance of showing larger benefits in terms of absolute effects; head-to-head comparisons typically show no or very small differences in overall efficacy of one antidepressant over the other, regardless of whether old or new agents are involved [21][22][23]. For example, a meticulous systematic review of fluox-etine versus other antidepressants concluded than even if some nominally significant results were seen in some comparisons, "the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn" [21].

The use of placebo lead-in excludes patients who show a good response to placebo over a brief period of time, before participating in the proper trial. In theory, this may inflate the difference between drug and placebo in the patients who are eventually enrolled in the trial, if the good response to placebo in the lead-in period correlates with good response to placebo also during the longer follow-up of the trial. The presence and strength of this correlation is debatable [24].

Finally, the corpus of antidepressant trials has silently adopted a series of exclusion criteria. An empirical evaluation found that common exclusion criteria are short-episode duration, mild severity of illness, psychiatric comorbidities, long duration of illness, medical comorbidities, and prior non-response to treatment [24]. Actually, there is little empirical evidence that any of these criteria, perhaps with the exception of short-episode duration, does affect the magnitude of the net treatment effect. Conversely, they all diminish the generalizability of the trial findings. Based on their extensive sales, we have to infer that antidepressants are used far more widely in clinical practice compared with the narrow clinical trial setting defined by such restrictive eligibility criteria.

Overall, we know little about how design features can influence results. For example, even the dosing schedule (flexible versus fixed), the number of treatment arms, and the percentage of female patients have been reported to be associated with the magnitude of the treatment effect in trials [25].

Short follow-up

Most antidepressant trials have limited duration of follow-up, typically 6 weeks, and rarely exceeding 8 weeks. Some trials even last only 3-4 weeks. Even with such short follow-up, attrition (losses to follow-up, and/or discontinuation of study medication) is very common in these trials [26]. Imputing outcomes when information is missing due to attrition is not easy and leaves room for bias.

It is mostly differences in long-term, hard clinical outcomes that would matter (suicide, loss of job, other major personal or social events), because these drugs are sometimes used by patients in the community on a far more long-term basis. The evidence on long-term maintenance has been reviewed by a meta-analysis of trials where patients responding at the acute phase have been randomized to maintenance versus placebo [27]. While large reduction in the odds of relapse has been demonstrated, these 31 trials are still small (total n = 4410), most do not exceed 12 months of follow-up, they focus on those who responded acutely, and have not been able to address other hard outcomes of depression.

Selective and distorted reporting

As demonstrated by the New England Journal of Medicine meta-analysis [7], selective and distorted reporting of results is a major problem in the antidepressant literature. Even with all the manipulations listed above and with potentially selective analyses, only half of the trials of antidepressants reach conventional statistical significance. The other half either disappear or are further distorted so as to be published with the impression that they also have found "positive" results. Meta-analyses of the published literature are thus likely to give misleading impressions about the effectiveness of these drugs.

Unknown harms

Antidepressant trials are not geared towards demonstrating the possible harms of these medications. The imbalance of emphasis between effectiveness and harms in the design and reporting of randomized trials has been repeatedly demonstrated in various medical specialties [28], including mental health interventions [29]. Small trials are unlikely to pick any major harms, even relatively common ones, let alone uncommon harms that are lifethreatening and may lead to death. Antidepressants are thus licensed in almost perfect vacuum on harms information. Harms may be detected subsequently from metaanalyses, large registries, or other means of post-marketing surveillance, but all of these methods have limitations and imperfect sensitivity and specificity. The large debate about the unrecognized suicide risk for children taking antidepressants is one example about how very important harms can go unrecognized [30][31][32]. The late addition of black box warnings increases the sense of uncertainty about these drugs [33]. Uncertainty about harms does not help anyone, even the industry. The reputation of the industry can be ruined even by postulated harms that may not exist, e.g. as in the debate about increase in suicides in adults.

Extension of the market As described above, clinical trials of antidepressants enrol highly restricted types of patient populations, and typically employ short-term administration. However, once licensed, the antidepressant drugs are used widely in the general population and are often prescribed for very longterm use [1][2][3]. Antidepressants are a prime example of the over-medicalization of our society [1]. Direct to consumer advertisement probably contributes extensively to this diffusion of use. A pharmacoeconomic evaluation found that direct to consumer advertisement of antidepressants may result in treating people so widely that 94% of antidepressant use due to direct-to-consumer advertising is from non-depressed individuals [34]. The same evaluation concluded that this is more than counterbalanced by the accumulated societal benefits conferred by the treatment of truly depressed patients who would not have been treated otherwise [34]. However, this inference is based on an assumption of large effectiveness of antidepressants that is probably not commensurate with the current evidence.

Building the supporting scientific myth Besides randomized trials, the industry has used biological arguments to promote the idea in the wider community that antidepressants have mechanisms of action that correct major chemical imbalances in the brain [1]. The typical example is SSRI marketing based on the serotonin hypothesis. It is unfair or even wrong to summarize decades of neuroscience research as showing that depression is caused by the imbalance of one or another neurotransmitter (serotonin, norepinephrine, or other) in the brain. If anything, evolving knowledge of biology shows that depression is an extremely complex behavioural phenotype regulated by a large number of biological pathways, external exposures, and genetic factors, each one contributing a small effect [1,35]. Drugs that supposedly impact on a single pathway are expected to have small impact on the overall biology of depression and would be equilibrated by balancing changes. Clinical effects would thus also be expected to be small on average.

Answering the main practical questions Are antidepressants indicated in depression?

Based on the above considerations, antidepressants are probably indicated only in select patients with major depression, probably preferentially in those who have severe symptoms and have not responded to anything else. For most patients with some depressive symptoms who are currently taking antidepressants, using these drugs would not have been the preferred option, placebo would be practically as good, if not better, and would save toxicities and cost.

Current approval of specific antidepressants by regulatory agencies means that some specific criteria have been met that demonstrate some nominally statistically significant results in some trials and for some scales, but this is not equivalent to proof of major clinical benefit, effectiveness in the wider population level. The trials that are undertaken are not necessarily scientific exercises but rather exercises that are designed to produce a demonstration of a particular effect for regulatory/legal purposes.

Some other meta-analysts have found even more gloomy results than the two meta-analyses reviewed above. For example, after including both published and unpublished data (29 and 11 trials, respectively), one meta-analysis recently found absolutely no benefit from paroxetine over placebo when focusing on the "hard" clinical outcome of treatment discontinuation [36]. Some treatment effect probably exists in "softer" scale-based outcomes, but it is likely to be small, and possibly the effect estimates are inflated compared to the truth. Cumulative meta-analyses suggest that for drug treatments in mental health indications in general, treatment effects tend to decrease over time, as more studies are conducted [37]. Empirical evidence suggests also that much of the placebo effect in antidepressant trials is related simply to the number of patient visits during a trial [38]. Trials where patients are scheduled to visit physicians more often for evaluation during the study improve more, regardless of whether they are given drug or placebo. There is a 0.6-0.9 point improvement in the Hamilton scale for each additional visit performed during the trial.

Perhaps most people given antidepressants for depressive symptoms would just need some attention from their physician and people to talk to and take some care of them. Antidepressants may be covering largely the lost placebo of human interaction and patient-physician interaction that has become so sparse in modern society. However, I will not comment here whether formal psychotherapies are as or more effective than antidepressants. The evidence base of psychotherapies is not any better, it pertains to similarly small trials, affected by most of the same problems (and more), and it would need a whole separate review on its own [39].

Is it unethical to kill a living myth?

If most of the antidepressant efficacy reflects simply the placebo effect, and if most people just benefit as much as the placebo effect allows, is it unethical to kill a living myth? One might argue that if the general population is informed that antidepressants are not really effective, this might demolish the benefits that we get from the placebo effect when we administer these drugs. However, is it not unethical to lie to patients that an intervention is effective when it is not? Moreover, if we want to utilize this placebo effect, why is it justified that this should cost cumulatively more billion dollars to society than almost any other (truly effective) pharmaceutical intervention for any other condition? It would be weird for our society to compromise with a view that someone should make fortunes by selling official placebos.

The pharmaceutical industry is going through rough times [40]. As the exclusive licenses of most major blockbusters are expiring currently, the fear is that unless the big pharma manages to keep up in its profits, then its R&D effort will be stalled. An even more cynical view is that since our society aims at making profit, if we don't allow the pharmaceutical industry to make large profits, even by selling largely ineffective drugs to the population at-large, then some other industry will attract capital investments and will flourish instead. This may be in an entrepreneurial domain that is less useful or even very harmful for society, e.g. the weapons industry. My reply is that the pharmaceutical industry should be encouraged and supported to conduct high-quality research in antidepressant drugs and beyond. Serious investigation in the life sciences by corporate, government and academic investigators should be given priority as societal goals, but expectations should be realistic: most major promises do not materialize [41], major discoveries are rare, drugs are not miraculous, and we should be honest about how much has been achieved and how much we can achieve. Telling lies to compete against more unscrupulous producers of lies in our society is not the way to make scientific progress.

Conclusion

After the publication of the PLoS Medicine meta-analysis, Eli Lilly, the producers of fluoxetine made a statement pointing attention to the fact that "more than 40 million people suffering from depression have been treated with fluoxetine in over 100 countries" [42]. Fluoxetine received approval from FDA based on 5 registered trials where a total of 817 patients with depression took fluoxetine [4]. A simple calculation shows that for each randomized patient receiving fluoxetine in the FDA application package, approximately 50,000 patients have been treated subsequently in everyday practice. Even if we consider all the other trials of fluoxetine (pre-and post-approval and with various indications), the ratio is likely to remain way above 1,000 to 1. Similar considerations apply practically to all antidepressants. While we have a large number of trials, they are all small. Typically these trials do not provide sufficient evidence to determine the exact benefit with any accuracy in specific types of patients, e.g. as a function of the baseline risk of depression [43]. Moreover, they say little about hard clinical outcomes and the longterm benefit-harm ratio.

No matter how careful the efforts to collate small trials, the interpretation of the available fragmented evidence will remain largely subjective. For example, the authors of the New England Journal of Medicine meta-analysis wrote an editorial in the BMJ where they said that compared to the more negative stance of the PLoS Medicine meta-analysis, their stance was more critical rather than dismissive [44]. To settle this important matter with robust evidence, we need large trials with 100-fold more patients than what has been the norm to-date. These trials should be linked to long-term follow-up registries with thorough recording of long-term outcomes for both efficacy and harms. Efficacy outcomes should include long-term management and evolution of depression, suicide and major life events. These trials should be designed in a way that they do not simply have power to show a nominally statistically significant benefit (of debatable clinical importance), but for demonstrating whether the benefit is conclusively within the range of clinical importance and has a long-term portend. These trials should also have sufficient power to answer this question not only in the overall study population, but also in specific risk strata and as a function of the baseline risk of severity. When hundreds of millions have been treated with these drugs with such a suboptimal evidence base, asking to conduct mega-trials of 50,000 participants for each antidepressant agent is not an exaggerated wish. If there are concerns that different agents or different classes thereof may have different effects, then large-scale evidence should be collected for each of them and for head-to-head comparisons thereof. The general public should be sensitized not to compromise with suboptimal evidence for drugs that are used by hundreds of millions of people.

Antidepressant trials should be pre-registered before their conduct [45], but this alone does not suffice. Their protocols need to be entirely transparent and their analysis plans explicit in detail upfront. There should be no room for flexibility in the collected data and performed analyses. The full data should be available in public, for scrutiny and use by all interested scientists. Finally, the complete agenda of these trials should be co-ordinated in a way that they will eventually be part of an overarching global prospective meta-analysis of individual-level data. Simply waiting to perform meta-analyses after the fact with data that are selectively analyzed, presented, submitted, and published is an invitation to confusion. Under such circumstances, meta-analyses end up being mostly detective tools that struggle to unearth problems under dark circumstances. Conversely, full registration of largescale transparent trials with full detailed availability of data and prospective meta-analyses would show that we are serious about finding the true merits and risk-benefit of antidepressants or any other type of medical intervention.

Clinical trial registration has made major progress [45], but details of protocols are still missing and flexibility and selective analyses and reporting are probably still prevalent. This does not mean that this vision is utopian. In fact, it may be the only way to avoid running into vicious circles of pseudo-evidence-based medicine where we are blinded by a blizzard of small, selectively designed, analyzed and reported trials. This may sound depressing for the current state of clinical trials research on antidepressants and beyond. Nevertheless, even if one feels a bit depressed by this state of affairs, there is no reason to take antidepressants, they probably won't work.

Anticipated mean and range of average effect size (ES) for tri-als in countries where a drug is approved, when the true average effectiveness is ES = 0.20 and the standard deviation (SD) of the estimated ES across trials is 0.20, 0.40, and 0.60Figure 1 Anticipated mean and range of average effect size (ES) for trials in countries where a drug is approved, when the true average effectiveness is ES = 0.20 and the standard deviation (SD) of the estimated ES across trials is 0.20, 0.40, and 0.60. Trials are assumed to be of similar size and similar weight in the calculations. Forty approval packages with 5 trials each have been simulated in each of the three settings and the data show the ES in the successful packages (those where the average ES is at least 0.20). Anticipated effect sizes in approved settings (average and range)

Table 1 :
1Top-selling antidepressants in the USA, 2006Drug (brand name)
Rank across all drugs
Sales (billions $)

Venlafaxine XR (Effexor XR)
6
2.25
Escitalopram (Lexapro)
10
2.10
Sertraline (Zoloft)
15
1.77
Bupropion XL (Wellbutrin XL)
16
1.67
Duloxetine (Cymbalta)
35
1.08

Information is derived from [2]

(page number not for citation purposes)
AcknowledgementsI am grateful to Professor Toshi Furukawa for his very interesting comments.Competing interestsThe author declares that he has no competing interests.Authors' contributionsJI conceived this article, carried out the included analyses, and wrote the paper.
Serotonin and depression: a disconnect between the advertisements and the scientific literature. J R Lacasse, J Leo, PLoS Med. 212e392. 2. Drugs.com. last accessed MarchLacasse JR, Leo J: Serotonin and depression: a disconnect between the advertisements and the scientific literature. PLoS Med 2005, 2(12):e392. 2. Drugs.com [http://www.drugs.com/top200.html]. last accessed March 8, 2007

The economic burden of depression in the United States: how did it change between 1990 and. P E Greenberg, R C Kessler, H G Birnbaum, S A Leong, S W Lowe, P A Berglund, P K Corey-Lisle, J Clin Psychiatry. 6412Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe SW, Ber- glund PA, Corey-Lisle PK: The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry 2003, 64(12):1465-75.

. Psi-Tri, Psi-Tri database [http://psitri.stakes.fi/EN/psitri.htm]. last accessed March 8, 2007

Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. D Fergusson, S Doucette, K C Glass, S Shapiro, D Healy, P Hebert, B Hutton, BMJ. 3307488396Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B: Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of ran- domised controlled trials. BMJ 2005, 330(7488):396.

FDA briefing document for Dec. 13, 2006, meeting of Psychopharmacologic Drugs Advisory Committee. FDA briefing document for Dec. 13, 2006, meeting of Psychopharmacologic Drugs Advisory Committee 2006 [http://www.fda.gov/ohrms/dockets/ ac/06/briefing/2006-4272b1-index.htm].

US FDA. Rockville (MDRockville (MD): US FDA, Center for Drug Evaluation and Research last accessed March 8, 2007

Selective publication of antidepressant trials and its influence on apparent efficacy. E H Turner, A M Matthews, E Linardatos, R A Tell, R Rosenthal, N Engl J Med. 3583Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R: Selec- tive publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008, 358(3):252-60.

Johnson BT: Initial severity and antidepressant benefits: a metaanalysis of data submitted to the Food and Drug Administration. I Kirsch, B J Deacon, T B Huedo-Medina, A Scoboria, T J Moore, PLoS Med. 5245Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, John- son BT: Initial severity and antidepressant benefits: a meta- analysis of data submitted to the Food and Drug Administra- tion. PLoS Med 2008, 5(2):e45.

Depression: management of depression in primary and secondary care. London: NICENational Institute for Clinical ExcellenceClinical practice guideline No 23National Institute for Clinical Excellence: Depression: manage- ment of depression in primary and secondary care. Clinical practice guideline No 23. London: NICE; 2004.

Direct likelihood analysis versus simple forms of imputation for missing data in randomized clinical trials. C Beunckens, G Molenberghs, M G Kenward, Clin Trials. 25Beunckens C, Molenberghs G, Kenward MG: Direct likelihood analysis versus simple forms of imputation for missing data in randomized clinical trials. Clin Trials 2005, 2(5):379-86.

The case of the misleading funnel plot. J Lau, J P Ioannidis, N Terrin, C H Schmid, I Olkin, BMJ. 3337568Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I: The case of the misleading funnel plot. BMJ 2006, 333(7568):597-600.

Why most published research findings are false. J P Ioannidis, PLoS Med. 28124Ioannidis JP: Why most published research findings are false. PLoS Med 2005, 2(8):e124.

Why most discovered true associations are inflated. J P Ioannidis, Epidemiology. in pressIoannidis JP: Why most discovered true associations are inflated. Epidemiology 2008 in press.

Controlling the risk of spurious findings from meta-regression. J P Higgins, S G Thompson, Stat Med. 2311Higgins JP, Thompson SG: Controlling the risk of spurious find- ings from meta-regression. Stat Med 2004, 23(11):1663-82.

. Ethics, and Humanities in Medicine. 3Submit your manuscript hereSubmit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp BioMedcentral Philosophy, Ethics, and Humanities in Medicine 2008, 3:14 http://www.peh-med.com/content/3/1/14

How should meta-regression analyses be undertaken and interpreted. S G Thompson, J P Higgins, Stat Med. 2111Thompson SG, Higgins JP: How should meta-regression analyses be undertaken and interpreted? Stat Med 2002, 21(11):1559-73.

Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors. C H Schmid, P C Stark, J A Berlin, P Landais, J Lau, J Clin Epidemiol. 577Schmid CH, Stark PC, Berlin JA, Landais P, Lau J: Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors. J Clin Epidemiol 2004, 57(7):683-97.

Anti-Lymphocyte Antibody Induction Therapy Study Group: Individual patient-versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. J A Berlin, J Santanna, C H Schmid, L A Szczech, H I Feldman, Stat Med. 213Berlin JA, Santanna J, Schmid CH, Szczech LA, Feldman HI, Anti-Lym- phocyte Antibody Induction Therapy Study Group: Individual patient-versus group-level data meta-regressions for the investigation of treatment effect modifiers: ecological bias rears its ugly head. Stat Med 2002, 21(3):371-87.

Statistical power analysis for the behavioral sciences. J Cohen, Lawrence Erlbaum AssociatesNew York2nd editionCohen J: Statistical power analysis for the behavioral sciences. 2nd edition. New York: Lawrence Erlbaum Associates; 1988.

Placebo response in studies of major depression: variable, substantial, and growing. B T Walsh, S N Seidman, R Sysko, M Gould, JAMA. 28714Walsh BT, Seidman SN, Sysko R, Gould M: Placebo response in studies of major depression: variable, substantial, and grow- ing. JAMA 2002, 287(14):1840-7.

Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway?. R J Lilford, BMJ. 326Lilford RJ: Ethics of clinical trials from a bayesian and decision analytic perspective: whose equipoise is it anyway? BMJ 2003, 326:980-1.

Fluoxetine versus other types of pharmacotherapy for depression. A Cipriani, P Brambilla, T Furukawa, J Geddes, M Gregis, M Hotopf, L Malvini, C Barbui, Cochrane Database Syst Rev. 4185Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M, Hotopf M, Malvini L, Barbui C: Fluoxetine versus other types of pharma- cotherapy for depression. Cochrane Database Syst Rev 2005:CD004185.

Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. S Macgillivray, B Arroll, S Hatcher, S Ogston, I Reid, F Sullivan, B Williams, I Crombie, BMJ. 32673971014MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, Wil- liams B, Crombie I: Efficacy and tolerability of selective serot- onin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: sys- tematic review and meta-analysis. BMJ 2003, 326(7397):1014.

Comparative effectiveness of second-generation antidepressants in the pharmacologic treatment of adult depression. G Gartlehner, R A Hansen, P Thieda, A M Deveaugh-Geiss, B N Gaynes, E E Krebs, L J Lux, L C Morgan, J A Shumate, L G Monroe, K N Lohr, AHRQ PublicationRockville, MDGartlehner G, Hansen RA, Thieda P, DeVeaugh-Geiss AM, Gaynes BN, Krebs EE, Lux LJ, Morgan LC, Shumate JA, Monroe LG, Lohr KN: Comparative effectiveness of second-generation antidepres- sants in the pharmacologic treatment of adult depression. Rockville, MD: AHRQ Publication No. 07-EHC007-EF; 2007.

A reevaluation of the exclusion criteria used in antidepressant efficacy trials. M A Posternak, M Zimmerman, G I Keitner, I W Miller, Am J Psychiatry. 1592Posternak MA, Zimmerman M, Keitner GI, Miller IW: A reevalua- tion of the exclusion criteria used in antidepressant efficacy trials. Am J Psychiatry 2002, 159(2):191-200.

Research design features and patient characteristics associated with the outcome of antidepressant clinical trials. A Khan, R L Kolts, M E Thase, K R Krishnan, W Brown, Am J Psychiatry. 16111Khan A, Kolts RL, Thase ME, Krishnan KR, Brown W: Research design features and patient characteristics associated with the outcome of antidepressant clinical trials. Am J Psychiatry 2004, 161(11):2045-9.

Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs). C Barbui, M Hotopf, N Freemantle, J Boynton, R Churchill, M P Eccles, J R Geddes, R Hardy, G Lewis, J M Mason, 2791Cochrane Database Syst RevBarbui C, Hotopf M, Freemantle N, Boynton J, Churchill R, Eccles MP, Geddes JR, Hardy R, Lewis G, Mason JM: Treatment discontinua- tion with selective serotonin reuptake inhibitors (SSRIs) ver- sus tricyclic antidepressants (TCAs). Cochrane Database Syst Rev 2007:CD002791.

Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. J R Geddes, S M Carney, C Davies, T A Furukawa, D J Kupfer, E Frank, G M Goodwin, Lancet. 3619358Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM: Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lan- cet 2003, 361(9358):653-61.

Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. J P Ioannidis, J Lau, JAMA. 2854Ioannidis JP, Lau J: Completeness of safety reporting in rand- omized trials: an evaluation of 7 medical areas. JAMA 2001, 285(4):437-43.

Safety reporting in randomized trials of mental health interventions. P N Papanikolaou, R Churchill, K Wahlbeck, J P Ioannidis, Am J Psychiatry. 1619Papanikolaou PN, Churchill R, Wahlbeck K, Ioannidis JP: Safety reporting in randomized trials of mental health interven- tions. Am J Psychiatry 2004, 161(9):1692-7.

Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. S Hetrick, S Merry, J Mckenzie, P Sindahl, M Proctor, Cochrane Database Syst Rev. 4851Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M: Selective serotonin reuptake inhibitors (SSRIs) for depressive disor- ders in children and adolescents. Cochrane Database Syst Rev 2007:CD004851.

Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. J A Bridge, S Iyengar, C B Salary, R P Barbe, B Birmaher, H A Pincus, L Ren, D A Brent, JAMA. 297Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA: Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007, 297:1683-96.

Suicidal behaviour in youths with depression treated with new-generation antidepressants: meta-analysis. B Dubicka, S Hadley, C Roberts, Br J Psychiatry. 189Dubicka B, Hadley S, Roberts C: Suicidal behaviour in youths with depression treated with new-generation antidepres- sants: meta-analysis. Br J Psychiatry 2006, 189:393-8.

Expanding the black box -depression, antidepressants, and the risk of suicide. R A Friedman, A C Leon, N Engl J Med. 35623Friedman RA, Leon AC: Expanding the black box -depression, antidepressants, and the risk of suicide. N Engl J Med 2007, 356(23):2343-6.

Costs and benefits of direct-to-consumer advertising: the case of depression. A E Block, Pharmacoeconomics. 256Block AE: Costs and benefits of direct-to-consumer advertis- ing: the case of depression. Pharmacoeconomics 2007, 25(6):511-21.

Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry in press. S López-León, A C Janssens, González-Zuloeta Ladd, A M Del-Favero, J Claes, S J Oostra, B A Van Duijn, C M , López-León S, Janssens AC, González-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, van Duijn CM: Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry in press. 2007 Oct 16

Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials. C Barbui, T A Furukawa, A Cipriani, CMAJ. 178Barbui C, Furukawa TA, Cipriani A: Effectiveness of paroxetine in the treatment of acute major depression in adults: a system- atic re-examination of published and unpublished data from randomized trials. CMAJ 2008, 178:296-305.

Effect sizes in cumulative metaanalyses of mental health randomized trials evolved over time. T A Trikalinos, R Churchill, M Ferri, S Leucht, A Tuunainen, K Wahlbeck, J P Ioannidis, Eu-Psi, Project, J Clin Epidemiol. 5711Trikalinos TA, Churchill R, Ferri M, Leucht S, Tuunainen A, Wahlbeck K, Ioannidis JP, EU-PSI project: Effect sizes in cumulative meta- analyses of mental health randomized trials evolved over time. J Clin Epidemiol 2004, 57(11):1124-30.

Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis. M A Posternak, M Zimmerman, Br J Psychiatry. 190Posternak MA, Zimmerman M: Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials: meta-analysis. Br J Psychiatry 2007, 190:287-92.

Psychotherapy for depression among children and adolescents: a systematic review. N Watanabe, V Hunot, I M Omori, R Churchill, T A Furukawa, Acta Psychiatr Scand. 1162Watanabe N, Hunot V, Omori IM, Churchill R, Furukawa TA: Psy- chotherapy for depression among children and adolescents: a systematic review. Acta Psychiatr Scand 2007, 116(2):84-95.

Drug discovery in jeopardy. P Cuatrecasas, J Clin Invest. 11611Cuatrecasas P: Drug discovery in jeopardy. J Clin Invest 2006, 116(11):2837-42.

Translation of highly promising basic science research into clinical applications. D G Contopoulos-Ioannidis, E Ntzani, J P Ioannidis, Am J Med. 1146Contopoulos-Ioannidis DG, Ntzani E, Ioannidis JP: Translation of highly promising basic science research into clinical applica- tions. Am J Med 2003, 114(6):477-84.

Study shows difference between antidepressants and placebo is significant only in severe depression. S Mayor, BMJ. 336466Mayor S: Study shows difference between antidepressants and placebo is significant only in severe depression. BMJ 2008, 336:466.

Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. D M Kent, R A Hayward, JAMA. 29810Kent DM, Hayward RA: Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA 2007, 298(10):1209-12.

Efficacy of antidepressants. E H Turner, R Rosenthal, BMJ. 3367643Turner EH, Rosenthal R: Efficacy of antidepressants. BMJ 2008, 336(7643):516-7.

Trial registration: a great idea switches from ignored to irresistible. D Rennie, JAMA. 29211Rennie D: Trial registration: a great idea switches from ignored to irresistible. JAMA 2004, 292(11):1359-62.