Published and unpublished comments on the PANDA trial

In September 2019 the following paper was published in the Lancet Psychiatry [the full open-access paper can be accessed here):


Alongside the publication of the PANDA Trial in the Lancet the following was published in the “NEWS” section of the BMJ:


Alongside the publication of the PANDA Trial in the Lancet the Science Media Centre shared a summary of a briefing that the authors of the Lancet paper had with Journalists:


The Science Media Centre also provided the following “Expert reactions” to the PANDA Trial:


In the Correspondence section of the current edition of Lancet Psychiatry are two letters providing comments on the PANDA Trial, alongside this letter of reply from the authors.

The first letter providing comments is by Asger Sand Paludan-Müller and Klaus Munkholm of the Nordic Cochrane Centre:

 


The second letter providing comments on the PANDA Trial by Michael P Hengartner, Martin Plöderl, Alain Braillon, Janus C Jakobsen and Christian Gluud:


The following Rapid response was submitted to the BMJ on 10 October 2019 but the BMJ did not publish it:

PANDA trial: falling asleep despite loud and obvious spin is depressing

Alain Braillon (1), Joel Lexchin (2), Jon Jureidini (3), Florian Naudet (4), Peter J Gordon (5), John H Noble Jr (6), Iona Heath (7), Lassaâd M’Sahli (8) Ian Hamilton (9), Peter Kinderman (10).

(1) Senior consultant, University Hospital, 80000 Amiens, France. braillon.alain@gmail.com
(2) School of Health Policy and Management, Faculty of Health York University, Toronto, Canada M3J 1P3.
(3) Robinson Research Institute, University of Adelaide, Adelaide, Australia.
(4) University Hospital and Inserm, Rennes, France.
(5) Bridge of Allan FK9 4AX, UK.
(6) State University of New York at Buffalo, Buffalo, Texas, USA.
(7) UK Royal College of General Practitioners, London, UK.
(8) Council of INLUCC (National Anti-Corruption Agency), Tunisia.
(9) University of York, York, UK.
(10) Institute of Psychology Health and Society, University of Liverpool, Liverpool, UK.

CoI: AB and FN are among industry independent experts from Jeanne Lenzer’s list; PJG petitioned the Scottish Parliament for a Sunshine Act for Scotland, IA is associated with Alcohol Change UK 

Acknowledgements: We thank Michael Pascal Hengartner for comments.

The PANDA trial was negative on its primary outcome, namely depression symptoms, as measured with the Patient Health Questionnaire PHQ-9: the effect sizes (Cohen’s d) for drug-placebo differences were negligible both at week 6 (d = 0.09) and at week 12 (d = 0.19), and did not significantly interact with baseline severity.(1)

Accordingly, the reporting about this trial in the BMJ News section is problematic.(2) The BMJ has been an early crusader against spin (3) and has repeatedly warned against flawed reports about antidepressants.(4-6) In the spirit of helping to correct misleading information, we put forward the following questions about the KOLs quoted in the BMJ story.

Why does the title highlight one positive result among many secondary endpoints (which also included quality of life, economic costs and emotional processing tasks) when the difference is small and not clinically meaningful and, when the primary endpoint is negative?

Why was spin about this trial from Key Opinion Leaders (KOL) cited without: a) providing the link where they spoke; b) disclosing their conflict of interests (either personally or through organisations they chair) c) without disclosing that, sciencemediacentre, the media where they spoke is funded by Diageo (“one of the world’s largest producers of spirits and beers“, alcohol being an extremely potent depressant), Bayer Plc, AstraZeneca, GlaxoSmithKline or previously by Coca-Cola and Eli Lilly?

Why did KOLs accept the implausible statement that only seven of 655 patients experienced adverse events? Why concur with recommendations to use antidepressants where indications are weak in spite of rare but severe adverse events (e.g. brain haemorrhage or hepatotoxicity) or frequent ones that occur over the long term (e.g. sexual dysfunction, withdrawal reactions (5) …), which cannot be investigated by small and short term trials such as PANDA?

In addition, we also question why did the Lancet peer review process did not preclude the major spin in the abstract, where it was inappropriately concluded that “Our findings support the prescription of SSRI antidepressants in a wider group of participants …including those with mild to moderate symptoms who do not meet diagnostic criteria for depression or generalised anxiety disorder.”(1) Furthermore, while the conflict of interest section mentioned that the authors received grants from Pfizer, the article and various disclaimers failed to mention that sertraline is marketed by Pfizer.(1)

Treating patients with depression for 12 weeks with only a placebo is a breach of the Declaration of Helsinki which states that “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention.”(7) Why was the National Institute for Health Research willing funded, University College London sponsor and investigators recruit patients into a trial that violated this principle of the Declaration of Helsinki.

Finally, most cases of depression or anxiety, even major or persisting, are often successfully treated with psychosocial interventions which are robustly evidence-based in the real-life setting over the long term. This type of treatment is often preferred by patients, beneficial for self-esteem and social functioning and without adverse effects.(8)

“Do not tell my future mother in law I’m a healthcare professional … she believes I’m a used car salesman.”

References
1 Lewis G, Duffy L, Ades A et al. The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial. Lancet 2019.
2 Mahase E. Sertraline is better at reducing anxiety than depressive symptoms. BMJ 2019;366:l5655.
3 Tiwari L, Puliyel JM, Upadhyay P. Truth and evidence based medicine: spin is everything. BMJ 2004;329:1043
4 Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, Abi-Jaoude E. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320.
5 Davies J, Read J, Hengartner MP, et al. Clinical guidelines on antidepressant withdrawal urgently need updating. BMJ 2019;365:l2238.
6 Braillon A, Bewley S. Paucity of data on the safety of drugs for treating depression in pregnancy. BMJ. 2016 May 11;353:i2582.
7 World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects, July 9, 2018.
8 Braillon A, Lexchin J, Blumsohn A, Hengartner MP. The “pharmaceuticalisation” of life. BMJ 2019;365:l1972.


The following Rapid response was submitted to the BMJ on 25 October 2019 but the BMJ did not publish it:

The Royal College of Psychiatrists and antidepressants: It is a long way to Tipperary

Alain Braillon (1), Florian Naudet (2), Peter J Gordon (3), John H Noble Jr (4), Iona Heath (5), Lassaâd M’Sahli (6).

(1) Senior consultant, University Hospital, 80000 Amiens, France. braillon.alain@gmail.com
(2)  University Hospital and Inserm, Rennes, France.
(3) Bridge of Allan FK9 4AX, UK.
(4) State University of New York at Buffalo, Buffalo, Texas, USA.
(5) UK Royal College of General Practitioners, London, UK.
(6) Council of INLUCC (National Anti-Corruption Agency), Tunisia.

The Royal College of Psychiatrists deserved congratulations for accepting that it has not paid enough attention to severe withdrawal symptoms when patients stop antidepressants.(1)

This is a step forward after its 2018 statement when Burn and Baldwin, president of the College and Chair of the College Psychopharmacology Committee respectively, claimed “In the vast majority of patients, any unpleasant symptoms experienced on discontinuing antidepressants have resolved within two weeks of stopping treatment.”(2) This was in response to serial publications showing evidence of alarming numbers of people suffering disabling symptoms for multiple years following withdrawal from antidepressants.(3,4) Burn, aware of the turmoil surrounding this debate promise a “debate … conducted in an informed, professional, and respectful manner” when expressing her regret at Baldwin’s resignation from Public Health England in 2018 considering his links of interest.(2)

Will the College make a new U-turn after its recent claim“This trial (PANDA) is an interesting and important addition to the evidence base underpinning the use of antidepressants for patients suffering from depression and anxiety… These data are important because they confirm the benefits of treatment with an antidepressant in a group of patients in NHS general practice and will be reassuring for both doctors and patients.”(5) In reality, the trial was negative on its primary outcome, namely depression symptoms, as measured with the Patient Health Questionnaire PHQ-9: the effect sizes (Cohen’s d) for drug-placebo differences were negligible both at week 6 (d = 0.09) and at week 12 (d = 0.19), and did not significantly interact with baseline severity. Sadly, sciencemediacentre (a media funded by Diageo “one of the world’s largest producers of spirits and beers“, potent depressants, Bayer Plc, AstraZeneca, GlaxoSmithKline or previously by Coca-Cola and Eli Lilly) put the spin on the College’s claim with one-sided statements from Key Opinion Leaders including people who denied the reality of the withdrawal syndrome.

The next step forward should be avoiding organisational conflict of interest, as well as personal ones, with the pharmaceutical industry. Lundbeck ranked first (Platinum level) among exhibitors (and therefore was a major funder) for the 2019 Royal College of Psychiatrists International Congress. In 2016 the European Union upheld its decision to fine (€93.8 million) Lundbeck for violating competition law, Lundbeck having paid generics makers to delay cheaper versions of its anti-depressant citalopram, its best-selling drug , from entering the market. Last, citalopram and the escitalopram (therapeutically active (S)-enantiomer of citalopram) offer no advantages vs others antidepressants, their sole characteristic is robustly documented serious cardio-vascular adverse effects: they rank first for QTc-prolongation responsible for deadly torsades de pointe.(6)  For long, years after years, these drugs have been on the yearly list published by the independent drug bulletin Prescire International  which calls for market withdrawal of drugs more dangerous than beneficial or that have been superseded by drugs with a better harm-benefit balance.(7)

1 Iacobucci G. NICE updates antidepressant guidelines to reflect severity and length of withdrawal symptoms. BMJ 2019;367:l6103.
2 Iacobucci G. Antidepressant adviser to government quits after conflict of interest row. BMJ 2018;362:k4063.
3 Timimi S, Thomas P, Davies J, Kinderman P. Antipsychiatry and the antidepressants debate. Lancet Psychiatry2014;1:174.
4 Kinderman P, Davies J, Moore J, Guy A, Read J, Timimi S, Double D. Purpose, humility, civility, and science. Lancet Psychiatry 2018;5:964-965.
5 Mahase E. Sertraline is better at reducing anxiety than depressive symptoms. BMJ 2019;366:l5655.
6 A comparative study of QT prolongation with serotonin reuptake inhibitors.  Ojero-Senard A, Benevent J, Bondon-Guitton E, Durrieu G, Chebane L, Araujo M, Montastruc F, Montastruc JL.  Psychopharmacology (Berl) 2017;234:3075-3081.
7 Anonymous. Towards better patient care: drugs to avoid in 2018. Prescrire Int 2018;27:107.1-9

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