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Professor Ian Hickie – Visionary Mental Health Reformer or Paid Pharmaceutical Industry Opinion Leader?

by Martin Whitely

Originally posted on February 12, 2012 at

“The bias in this paper is very disturbing…It is this kind of complicity that damages any hopes of a positive partnership between medicine and [the pharmaceutical] industry.” – Lancet Editor tweet on recent Hickie research


Along with his colleague Professor Patrick McGorry, Professor Ian Hickie is one of the most high profile and powerful psychiatrists in Australia. Feted by both the Gillard Government the Abbott Opposition and frequently quoted in the media as ‘independent mental health experts’; Professor’s Hickie and McGorry have made their priorities for reforming Australia’s mental health system, national priorities.


However critics are growing in strength and number. In 2011 Professor McGorry was embroiled in controversy about the details of his ‘early intervention’ approach to preventing psychosis. Critics, including me, were concerned with Professor McGorry’s history of experimenting with and advocating the use of antipsychotics as a means of preventing adolescents having a first psychotic episode.[1]

After considerable public debate McGorry stopped advocating or experimenting with antipsychotics as a preventative measure. While many critics remain suspicious that the national roll out of EPPIC services driven by Professor McGorry is based on flimsy evidence[2] at least Professor McGorry has modified his position to a less drug dominant approach.

Critical attention is now turning to Professor Hickie, who originally rose to prominence as the inaugural CEO of beyondblue: the national depression initiative. In May 2011, an article in the Lancet which Professor Hickie and Naomi Rogers co-authored, evaluated the use of melatonin analogs, commonly used to treat sleep disorders, for combating major depression.[3] The literature review based article extolled the virtues of agomelatine (brand name Valdoxan), an antidepressant that is sold in Europe and Australia by French pharmaceutical company Servier.

Both Hickie and Rogers have significant financial links to Servier.[4] Professor Hickie has been a high-profile key opinion leader appearing at a Servier Valdoxan briefing in April 2011, and presenting at Servier funded master-classes and symposia.[5] While he declared some of his earlier research ties to Sevier, he did not declare his appearances at Servier events in the original Lancet article, or in the authors’ response to criticism. He has a track record of not always disclosing his substantial links to pharmaceutical companies and other conflicts of interest.[6]

Their article claimed that the published research demonstrated that Valdoxan had advantages “over other antidepressants, including Prozac and Paxil, such as improved sleeping, reduced waking after onset, fewer relapses and the potential for fewer side effects.”[7]

It also claimed that less than a quarter (23.9%) of patients on Valdoxan relapse with depression compared to half (50%) of patients who were given a placebo. Compared to other melatonin analogs, the authors claimed that only Valdoxan, “has been reported to have clinically significant antidepressant effects… This drug might occupy a unique place in the management of some patients with severe depression and other major mood disorders.”[8]

The latest edition (21 January, 2012) of the Lancet published six letters from experts in America, Britain, France, Italy and Australia scathing in their criticism of Hickie and Rogers’ article. Among the problems identified were, exaggeration of the efficacy of agomelatine, downplaying of potential harms, including liver toxicity, misrepresentation of the cited literature, and conflicts of interest. An ‘Authors Reply’ from Hickie and Rogers was published in the same edition. Extracts from the critical letters and the full author’s response follow.

Extract from letter to the Lancet from Psychiatrist Jon Jureidini of the University of Adelaide and Psychiatric Epidemiologist Melissa Raven of Flinders University.[9]

‘Ian Hickie and Naomi Rogers’s paper illustrates substantial problems prevalent in reviews of psychotropic drugs: unjustified and misleading conclusions in the summary (abstract), withholding of information about serious adverse effects, citation misrepresentation, and possible conflicts of interest.

First, there is a serious discrepancy between the summary and the body of the paper. The summary claims that “fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%)”. But that was only one trial. The body of the paper admits that two other trials did not find lower relapse with agomelatine. Unfortunately, many will only read the summary, and will be misled.

Second, Hickie and Rogers selectively emphasise agomelatine’s lower risk of common side-effects but do not cite authoritative sources that raise concerns about the safety of agomelatine, including potential adverse hepatic reactions.

Third, there are several examples of citation misrepresentation, including the claim that depression treatment leads to increased workforce participation. The ultimate source is a study that found that “recovery from depression [not treatment per se] is associated with significant reductions in work disability”. Hickie also promoted Serzone (nefazodone)—another novel antidepressant—when his SPHERE project was funded by its manufacturer. Serzone was eventually withdrawn from the market because of hepatotoxicity.Now Hickie and colleagues are supported by Servier, appear at their media briefings promoting Valdoxan (agomelatine), and again lack rigour in data analysis…’

Extract from letter to the Lancet from Italian psychiatrists Corrado Barbui and Andrea Cipriani of the Department of Public Health and Community at the University of Verona.[10]

‘Hickie and Naomi Rogers, in their review of the pharmacology and clinical profile of novel melatonin-based therapies report that agomelatine has clinically significant antidepressant properties. However, this claim is not based on a systematic review of available evidence nor supported by the efficacy data that Hickie and Rogers themselves present.

…In terms of tolerability, Hickie and Rogers do not mention the potential relation between agomelatine and hepatic problems. For long-term data, they included three studies, two negative and one positive comparison between agomelatine and placebo, but in the text of the article and in the summary only the positive study is mentioned…’

Extract from letter to the Lancet from Robert Howland of the Department of Psychiatry at the University of Pittsburgh Medical Center.[11]

‘In their New Drug Class review Ian Hickie and Naomi Rogers overstate the efficacy, tolerability, and safety of agomelatine. Their assertion that agomelatine has similar efficacy to venlafaxine, fluoxetine, and sertraline is based on studies not designed a priori to test the antidepressant efficacy of these drugs…Clinical studies of agomelatine show a clear pattern of publication and outcome-reporting bias. The risk of liver toxicity also is not prominently highlighted in published studies.’

Extract from letter to the Lancet from Celia Lloret-Linares, Jean-François Bergmann and Stéphane Mouly, who work in a variety of hospitals in Paris.[12]

‘…We have several concerns about Hickie and Rogers’s statements about the efficacy and safety of agomelatine. Of the ten placebo-controlled trials involving various doses (1—25 mg/day) of agomelatine, half of them were negative and one (NCT00411242) gave inconclusive results with respect to the primary endpoints. Additionally, none of the active comparator trials presented in Hickie and Rogers’s table 4 was significantly in favour of agomelatine with respect to the two primary endpoints. Considering the small sample size of the various trials presented, these trials were too weak to allow a non-inferiority statement with respect to the effect of agomelatine (25—50 mg/day) with at least 80% statistical power.

Melatonin analogues, including agomelatine, are being developed with a view to achieving a better safety profile than the currently available antidepressant strategies. However, despite agomelatine producing no increase in serotonin concentrations, it did not seem to have a better safety profile than sertraline, venlafaxine, and fluoxetine, as shown in Hickie and Rogers’s table 4. These results do not support the statement that agomelatine is “unique” and displays a “significant antidepressant effect” and a “favourable safety profile”.

Readers should be aware of Hickie and Rogers’s numerous conflicts of interest with Servier. Clinical trials and audit sponsored by Servier, unrestricted educational grants, consultancy fees, and honoraria for lectures might explain the subjective nature and inappropriateness of Hickie and Rogers’s conclusions.’

Letter to the Lancet from Bernard Carroll of the Pacific Behavioral Research Foundation in California.[13]

‘The New Drug Class paper by Ian Hickie and Naomi Rogers does not adequately address the weak efficacy of agomelatine in depression and seems biased for promotional effect.

Where is a pooled analysis of all the listed placebo-controlled trials? Listing the negative studies but then excluding those data from analyses is disingenuous. Where are the data for categorical outcome (response vs non-response) in all the trials, not just the three registration trials? The hidden data are needed to estimate the composite number needed to treat. And where are categorical outcomes (relapse vs non-relapse) to support the claim of prevention (table 4)? Why are these data hidden?

The financial arrangements are not transparent. Was this review commissioned? Was it proposed by Hickie and Rogers to Servier? Was the “unrestricted educational grant” from Servier Laboratories to Rogers effectively an honorarium to them? Who paid how much to whom, and where did the money go? Who paid the three acknowledged assistants?

Was the paper drafted by the assistants? Did the corporation supply content? Hickie and Rogers declare that “Both authors participated in the conception and writing of this article and have seen and approved the final version.” That careful parsing leaves a lot unsaid and might be viewed as dissembling. Did employees of Servier Laboratories participate in shaping the misleading manner of reporting the clinical trials data? Did they review the manuscript or request changes?

This paper seems to break new ground for sponsored writing in medical journals, with conflicts of interest hidden in plain sight while bias continues.’

Extract from letter to the Lancet from Mark Serfaty & Peter Raven of the Mental Health Sciences Unit, University College London.[14]

‘Ian Hickie and Naomi Rogers suggest that agomelatine, a synthetic (and therefore copyrightable) melatonin-based therapy, has promising antidepressant properties with minimal side-effects. However, they suggest that the naturally occurring hormone melatonin does not seem to be an effective antidepressant in human beings and cite Carman and colleagues’ seriously flawed workas evidence…Melatonin is probably safeand not subject to copyright. Unfortunately, the funding for drug trials that do not generate financial returns is limited. In this case, we propose that there would be substantial benefit in doing a larger trial in the use of melatonin as an antidepressant on the basis of the potential cost savings alone.’

Professor Ian Hickie & Naomi Rogers Authors Reply.[15]

‘Your correspondents focus rather narrowly on four issues surrounding our review of novel melatonin-based treatments: the efficacy of agomelatine, the clinical significance of agomelatine for managing depression, the comparative side-effect profile of this compound, and our professional relationships with its manufacturer (Servier Laboratories).

First, the basic issues related to the efficacy of agomelatine have been dealt with by regulatory agencies within countries. Indeed, these are based on the long-standing regulatory requirement of submission of positive studies, the agent is now licensed for use as a treatment for major depression in many nations. The generation of more short-term, longer-term, and comparative studies will result in the types of meta-analysis presented by Corrado Barbui and Andrea Cipriani.

Second, what is much more contentious about all antidepressants, and this now includes agomelatine, is whether any of these treatments have a clinically significant benefit when used in those who meet broad criteria for major depression. Interestingly, while criticising our use of the term, Barbui and Cipriani state that “No research evidence or consensus is available about what constitutes a clinically meaningful difference in Hamilton scores”. For most new antidepressants, any consistent separation from placebo (short-term or longer-term) has proved challenging.

Our use of the term “clinically significant” was in no way restricted in its implications. As shown by Cipriani and colleaguesin their previous publication in The Lancet, a broader measure of risk-to-benefit ratio is required. In our own work we have argued that depression treatments need to relate to other important outcomes such as reductions in suicide, reductions in co-prescribing (particularly for night time sedation, concurrent anxiety, or agitation), and enhanced economic and social participation. These issues represent a major challenge to the current ways in which the “efficacy” and “clinical significance” of antidepressant interventions are assessed.

Third, there can be little doubt that, owing to the very different pharmacological profile of agomelatine, it does not share many of the major serotonin-based adverse effects of most of the other commonly prescribed antidepressants. In clinical practice, sleep disturbance, sexual dysfunction, periodic agitation, nausea, headache, and gastrointestinal disturbance represent major barriers to either initiation or continuation of care. The rate of significant side-effects with the use of agomelatine, particularly of the type that overlaps with the other new serotonin or noradrenergic agents, has been low. The potential benefits for sleep variables has been explored further and supports our assertion that the need for co-prescribing of hypnotics or sedatives (particularly compared with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) should be much reduced.

New issues with regard to other safety concerns, including potential changes in liver function tests have been recognised in clinical trials of agomelatine. This recognition has already led to recommendations regarding appropriate forms of clinical monitoring. However, wider use of agomelatine has not yet been associated with evidence of a major signal for hepatotoxicity (reported as a non-significant 1·1% for agomelatine vs 0·7% for placebo in trial data and being comparable with that noted for other commonly prescribed agents). Specifically, in a study in a real-world setting, abnormal liver function tests were very common before exposure to agomelatine (12% for raised alanine aminotransferase and 9% for raised aspartate aminotransferase) and only increased marginally during the treatment phase (15% and 11%, respectively). Co-prescribing of other psychotropics (which are also likely to have adverse effects on liver function tests) was also high (about 31%). Consequently, there is a great need to keep these issues in perspective. Recently, IBH has participated in the development of guidelines for medical monitoring of all available antidepressant compounds. The consensus recommendation is for screening of liver function tests in all patients starting antidepressants—owing to the high comorbidity with alcohol misuse, frequent co-prescribing of other agents, and reports of altered liver function tests with a wider range of other antidepressants.

Importantly, the open European study of 3317 patients from 665 medical practices managed over 12 weeks (and now extended into a 9-month follow-up phase) re-emphasises these key clinical considerations. Of the participants, 58% had been treated previously with antidepressants, 38% had other psychiatric comorbidity, and 8% reported previous suicide attempts. During the assessment, about 10% of patients had significant side-effects, with 97% of those rated as “not severe”. Entirely consistent with the earlier registration trials, notable side-effects were headache (1·7%), nausea (1·4%), and dizziness (0·9%). There were 16 serious side-effects in only nine patients and six of these cases were related to thoughts of suicide. Only one patient developed mania, 5 months after start of therapy and some weeks after cessation of his agomelatine treatment. There was no reported change in bodyweight or body-mass index.

Fourth, the paper was commissioned by The Lancet and developed solely by us. It was not initiated or supported financially by Servier Laboratories. The additional research assistants who assisted with the paper’s preparation are long-standing employees of our institution who have worked previously on many similar datasets via our own financial resources. After initial submission (July 31, 2009), the paper progressed through a lengthy process of external peer review, revision, and consultation with the editorial staff of The Lancet. As outlined previously, issues of fact with regard to clinical trials of agomelatine were checked against international trial registers and with representatives of the manufacturer, Servier Laboratories. The opinions expressed and the conclusions drawn are those of the authors.

In most research in clinical psychiatry, the debate has shifted from simply searching for treatments that are equally efficacious in all patients to identification of treatments that are based on specific pathophysiologies, are useful in specific subgroups of patients, or are potentially useful in clinical practice (owing to better or different risk-to-benefit ratios or enhancement of some other aspect of practice—eg, better adherence or reduced co-prescribing). In that context, we prepared a balanced and independent report of the potential role of new melatonin-based strategies that target the circadian system. Our other academic, educational, public, research, and financial relationships with Servier Laboratories (and other government and industry-related entities) were disclosed exhaustively at the time of publication.’



Many of the detailed criticisms in the six letters, most notably the ignored negative studies and the misquoted research, are not addressed in the authors reply; at least not to the satisfaction of the Lancet’s editor Dr Richard Horton. The day before the six letters and authors reply was published Horton began a series of tweets which stated:

Tomorrow, we are very heavily criticised for publishing a review on melatonin-based drugs for depression. Biased and overstated, say many… The bias in this paper is very disturbing – it might be fine to argue your case in a Viewpoint or letter. But… this paper purported to be an unbiased review of a new drug class. Peer review improved it, yet not enough… As troubling is the fact that one author took part in speaking engagements for the company making one of these drugs… It is this kind of complicity that damages any hopes of a positive partnership between medicine and industry.[16]


The Lancet and in particular Richard Horton deserve praise for acknowledging the shortcomings of their editorial process. It appears the Lancet is considering changing its’ editorial policy to preclude drug literature reviews being promoted as original research. If published they would instead be identified as opinion pieces.


In the meantime Professor Hickie remains the darling of the mainstream Australian media (particularly the ABC), the Gillard Government, the Abbot Opposition and the Greens. ‘In October 2006, the Australian Financial Review included Professor Hickie in its list of the top 10 cultural influences. The specific comments noted his role as a “long-term campaigner”, “the person who orchestrated the campaign” that led to the COAG announcements ($4 billion dollars over five years).’[17]


In December 2011 Gillard Government Mental Health Minister Mark Butler nominated Professor Hickie as one of eight National Mental Health Commissioners and he has appeared in the media on a number of occasions in that capacity. The job of the Commissioners is to ‘provide expert and independent advice to the Government on the performance of our mental health system and will monitor whether services are delivering lasting outcomes for people living with a mental illness, their carers and their families.’[18]Previously Professor Hickie was appointed to the Mental Health Expert Working Group, the National Advisory Council on Mental Health, and he has been on numerous other government advisory bodies.


He and organisations he leads or has led, received millions of dollars in research funds mainly from government but also from pharmaceutical companies and health insurance giant Bupa.[19] Professor Hickie has conducted research focusing on mental health services, using it to push his agenda for mental health reform.


Other research has included a pharmaceutical industry funded clinical audit that has been criticised for exaggerating the prevalence of mental disorders in the Australian community and promoting inappropriate antidepressant prescribing.[20] Another review co-authored and frequently cited by Hickie was strongly criticised for exaggerating the benefits of antidepressants in suicide reduction.[21] Some of the research he is currently undertaking includes investigating the use of psychotropic drugs as a means of preventing disorders in people who do not have the disorder.

Hickie on ADHD


My only experience with Professor Hickie in the area of ADHD left me wondering about the depth of his understanding of research he was prepared to critique. In February 2010 results of the MICADHD Raine Study Review were published. The Review studied ADHD relevant data provided by the Raine Study, a long-term, large-scale, generalised study into children’s health and wellbeing conducted at Perth’s King Edward Memorial Hospital.[22] Published in February 2010 it provided unique independent data on the long-term effects (nine years) of psycho-stimulant medication on children diagnosed with ADHD in comparison to an un-medicated ADHD group.


One of the most significant findings of the review related to school failure, it found, ‘In children with ADHD, ever receiving stimulant medication was found to increase the odds of being identified as performing below age-level by a classroom teacher by a factor of 10.5 times.’[23] This finding that past stimulant use increased the probability of an ADHD child falling behind at school by a massive 950 per cent undermines the hypothetical basis of medicating for ADHD.


Initially, the medication proponents on committee that commissioned the research tried to claim that the outcomes for the medicated children were most probably worse than those for un-medicated children, because the medicated children had more severe ADHD. As a member of the committee, however, I insisted on a comparison of the groups at age five, which was prior to any of the children having been medicated. This analysis established that there were no statistically significant differences in developmental, behavioural and health measures before the children were medicated.


This did not prevent Professor Hickie, who had no involvement in the research, explaining away this research in national media using the unsupported hypothesis that differences in educational performance were due to pre-existing differences. He dismissed the poor educational outcomes saying, ‘typically those kids who go on the medication are considerably worse to start with’.[24] Even supposing Hickie’s criticisms had been valid, and the children who had been medicated were ‘considerably worse to start with’, if stimulants worked long term, they should have been performing at least as well at school as those with moderate, un-medicated ADHD.


Hickie on non-drug therapies for mental health


Subsequent to this experience I have observed Hickie’s comments on a range of issues. In my experience he speaks on anything and everything related to mental health and usually takes a position that maximises the potential benefits and minimises the potential risks of medical (read pharmaceutical) over behavioural interventions.


He superficially supports psychotherapy, but this appears to be largely lip-service, as he is a frequent critic of the role of talking therapies and psychologists.[25] A recent example was his response to the Gillard Government’s back-down on cuts to the Better Access program. The January 28, 2012 decision by Australian Government Mental Health Minister Mark Butler to suspend proposed cuts to the Better Access program from a maximum of 16 visits to counselling services to 10 per year appears to be a welcome and rare (if temporary) win for talking therapies over drug therapies. (see )


Professor Hickie was not impressed by the back-down commenting, “The Government realised it had to make this concession to keep the Greens onside, otherwise it wouldn’t get any of its other changes to mental health through the senate. We simply don’t know who was and wasn’t getting the proper care through Better Access. All we can hope is that the money being directed back to the program isn’t taken away from other more advanced packages to be introduced in coming years.”[26] Talking therapies are obviously less technologically ‘advanced’ than pharmacological therapies but despite Professor Hickie’s clear implication that does not mean they are inferior.


As previously stated all of the Australian political parties have to date bent over backwards to placate Professor Hickie. In my view this is largely because the mainstream media have persistently portrayed him as a visionary mental health leader. But it is also because mental health is such a mysterious policy area for non-experts that the certainty offered by seemingly ‘authoritative voices’ like Hickie, is attractive to time pressured and confused journalists and politicians.


Will some of the gloss come off Professor Hickie now that significant international players seem to regard him, in part at least, as a paid pharmaceutical industry opinion leader? Will the Gillard Government, the Abbott Opposition or perhaps the Greens abandon the herd and begin to question the substance of advice proffered by the likes of Hickie (et al)?

Maybe, but don’t hold your breath.




The Australian (Monday 13 February 2012) ‘Campaign Targets Deprerssion Guru’ Sue Dunleavy


ABC Radio (Monday 13 February 2012) The World Today ‘Psychiatrist claims campaign to discredit him’ Meredith Griffiths

[1] For details see

[2] Raven, M (2011) The EPPIC study: methodology, results, and misrepresentation. Alliance for Better Access. and Frances. A

[3] Novel melatonin-based therapies: potential advances in the treatment of major depression Ian B Hickie, Naomi L Rogers Lancet 2011; 378: 621–31

[4] Novel melatonin-based therapies: potential advances in the treatment of major depression Ian B Hickie, Naomi L Rogers Lancet 2011; 378: 621–31 (Conflict of Interest section)]

[5] See and  Mayze, T. (2010, November) Servier Depression Masterclass Conference Review


[7] Silverman, Ed. (2012, January 24). A Servier drug and a flawed paper in The Lancet. Pharmalot.]

[8] Hickie, I. B., & Rogers, N. L. (2011, August 13). Novel melatonin-based therapies: Potential advances in the treatment of major depression. Lancet, 378(9791), 621-631.]

[9] Complete referenced original available at

[10] Complete referenced original available at ]

[11] Complete referenced original available at ]

[12] Complete referenced original available at

[13] Complete referenced original available at

[14] Complete referenced original available at ]

[15] Referenced original available at ]

[16] 20-21 January 2012

[17] ]



[20] Phillips, N., Oldmeadow, M. J., & Krapivensky, N. (2002, February 18). SPHERE: A National Depression Project. Medical Journal of Australia, 176(4), 193-194.]


[22] The Raine Study started in 1989, when 2900 pregnant women were recruited into a comprehensive health and wellbeing research study at King Edward Memorial Hospital to examine ultrasound imaging. The mothers were assessed during pregnancy and after the children were born, and at one year, then two, three and five years of age. Information on their height, weight, eating, walking, talking, eating, behaviour, any medical conditions or illness etc. was collected. Further follow ups of the cohort have been conducted at eight, ten, fourteen, and seventeen years of age. At each follow-up information is collected from the parents and the child. The current follow up is being done at twenty years of age. By age fourteen ‘of the 1785 adolescents (remaining) in the sample, 131 (7.3 per cent) had received a diagnosis of ADHD’. At age five none of the 131 had taken ADHD stimulants. By age fourteen, twenty-nine had never taken stimulants, forty-one had been on prescription stimulants in the past but were not taking them, and sixty-one were on ADHD stimulants. This gave three groups for comparison, the ‘never medicated’, ‘previously medicated’ and the ‘currently medicated’ groups. In addition analysis of the effect of the duration of stimulant treatment was undertaken. Available at 7 May 2010). The statistically significant differences that existed at age fourteen occurred between age five and fourteen, after some of the children were medicated. To the extent that (non-statistically significant differences) existed at age five these were ‘controlled for by using the “propensity for medication” score, the symptom severity before commencement of medication treatment, and a number of sociodemographic measures’.

[23] Government of Western Australia, Department of Health, Raine ADHD Study: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, Department of Health, Perth, 2010, p. 6. See or for full report see

[24] Interview with Professor Ian Hickie on ABC PM program with Mark Colvin, ‘New Research Reignites Debate over ADHD’, 17 February 2002. Available at  (accessed 15 March 2010).

[25] Sweet, M. (2011, May 11) Mental health: PM, Butler get credit – are professions up to implementation? Crikey. Skinner, S. (2006, March 27). Ian Hickie urges psychiatry rebate rethink. ABC Radio National. PM. Hickie, IB. (2000). An approach to managing depression in general practice. MJA, 173, 106-110.]

[26] Norrie, J. (2012, February 1) Backdown on cuts to mental health counselling. The Conversation.]

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