Skip to main content

Main menu

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors & Reviewers
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
    • Patient engagement
  • Members & Subscribers
    • Benefits for CMA Members
    • CPD Credits for Members
    • Subscribe to CMAJ Print
    • Subscription Prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2023
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN

User menu

Search

  • Advanced search
CMAJ
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN
CMAJ

Advanced Search

  • Home
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • COVID-19 Articles
  • Authors & Reviewers
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
    • Open access
    • Patient engagement
  • Members & Subscribers
    • Benefits for CMA Members
    • CPD Credits for Members
    • Subscribe to CMAJ Print
    • Subscription Prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2023
  • Visit CMAJ on Facebook
  • Follow CMAJ on Twitter
  • Follow CMAJ on Pinterest
  • Follow CMAJ on Youtube
  • Follow CMAJ on Instagram
Commentary

Antidepressants and adverse effects in young patients: uncovering the evidence

Andrew Herxheimer and Barbara Mintzes
CMAJ February 17, 2004 170 (4) 487-489;
Andrew Herxheimer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Barbara Mintzes
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Responses
  • Metrics
  • PDF
Loading
  • © 2004 Canadian Medical Association or its licensors

Family physicians are repeatedly told that depression is underrecognized in patients of all ages and that lack of treatment can lead to serious harm. Selective serotonin reuptake inhibitors (SSRIs) and other, newer, antidepressants have been regarded as the treatment of choice in primary care, and inadequate reimbursement for non-drug alternatives such as cognitive and behavioural therapy has left little room for alternatives. It is understandable, then, that prescribers and parents in the United Kingdom were dismayed by a recent warning1 from their national regulatory body (the Medicines and Healthcare products Regulatory Agency) that SSRIs are largely ineffective in the treatment of major depression in children and adolescents and can cause suicidal behaviour and self-harm. This warning is disturbing it itself, but it also leads to the question, Why did it take so long to discover this lack of benefit and potential for harm?

Part of the answer lies in the gap that exists between the quality of evidence needed to get a drug to market and the actual treatment needs of patients. A first episode of major depressive disorder typically lasts 7 to 9 months, and recurrence is common. However, the duration of most randomized controlled trials of antidepressants before marketing is only 6 to 8 weeks. One key measured outcome is a change in the patient's score on a physician-administered questionnaire such as the Hamilton Depression Rating Scale (HAM-D).2 Such scales combine many different outcomes, and it is rarely clear from trial reports in exactly what ways patients felt better or worse. The HAM-D scale uses a single question to assess suicide risk, a measure that David Healy has roundly criticized as inadequate.3 Further, in published studies, adverse drug reaction (ADR) reporting is often cursory.4

Premarket trials are often carried out in restricted patient populations that inadequately represent the users of a drug once it is on the market. For example, Zimmerman and colleagues found that 54% of a series of 293 adult patients diagnosed with major depression at a hospital outpatient psychiatric service had HAM-D scores below the threshold commonly used for trials of antidepressants.5 Additionally, as Jane Garland describes in this issue (see page 489),6 pharmaceutical companies are not required to disclose the results of negative trials (i.e., trials that show no efficacy or are inconclusive). Study data submitted by manufacturers to Health Canada during an approvals process are considered proprietary and thus are kept confidential unless a company chooses to publish or otherwise disclose them.7 Also confidential are any rejected applications for drug approval in a specific indication or for the extension of an indication to another patient group, such as children. The secrecy that surrounds the drug approvals process means that physicians and their patients may be unaware that they are using a medication in a manner for which the evidence of effectiveness and safety is inadequate. Such policies value commercial interest above that of patients.

The postmarketing surveillance of safety and effectiveness also leaves much to be desired. Most countries, including Canada, rely primarily on voluntary reports of suspected ADRs in order to monitor drugs once they are on the market. The UK's Yellow Card system is regarded as one of the best systems for adverse reaction surveillance in the world, and has a much higher reporting rate than we achieve in Canada.8 But even this system is inadequate. Medawar and Herxheimer evaluated 1555 anonymized Yellow Cards reporting withdrawal symptoms (1370), suicidal behaviour (91) or injury and poisoning (94) during paroxetine therapy between 1990 and 2002.9 This study compared the quality of the information in the Yellow Card reports to that obtained directly from patients in 862 messages that had been sent to a Web site discussion forum from 2000 to 2002, and in 1374 emails sent to the BBC after a television documentary on paroxetine was aired. An analysis of these patient reports uncovered previously unrecognized patterns of experiences coinciding with dosage increases and withdrawal of therapy.10

Patient reports of ADRs are commonly dismissed as anecdotal or unscientific. However, the collective weight of the patient accounts of experiences with paroxetine therapy was profound. Reports from users and relatives — especially with respect to behavioural effects — communicated information that professional reporters can never be expected to provide. They were far richer, and described suicidality and withdrawal symptoms much more clearly and intelligibly than the Yellow Card reports. The analysis of over a decade's worth of Yellow Card reports suggests that miscoding and flawed analyses by regulators led to an underestimation of the risk of suicidal behaviour during paroxetine therapy.9 In some cases, depending on the word the reporter had used in submitting a Yellow Card, different terms were used to classify indistinguishable phenomena (e.g., “withdrawal,” “discontinuation” and “dependence”). Most Yellow Cards lacked important information, such as the patient's history, the drug dosage and the outcome of the adverse reaction. Many reports of suicidal behaviour were very brief, and there was minimal evidence of follow-up. Indeed, scientists at the UK agency consider that its standard procedure for following up reports of serious adverse drug reactions11 is in an important respect incomplete. Poor reporting and data processing have impeded the recognition of what seems to be a close relation between suicidal behaviour and changes in drug concentration (after dosage increase or decrease). But, quite apart from this, the data also suggest that SSRI dosages are far too high for some users.

Drug manufacturers had submitted 70% of the Yellow Card reports of “injury and poisoning” and 37% of the reports of suicidal behaviours on behalf of doctors. In contrast, companies submit only 17% of ADR reports in the UK overall. Reports sent by manufacturers tended to be euphemistic (e.g., by describing suicide attempts as “nonaccidental overdose”). The value of the Yellow Card scheme is seriously limited by its emphasis on numbers rather than precision with words, by bureaucratic secrecy that obstructs wider access to anonymized data and by a lack of input from patients themselves.

The Yellow Card reports and the emails from patients included few reports about children and adolescents, but other accounts indicate that their reactions are qualitatively similar.12 Thorough reviews are needed to clarify whether there are important differences between adults and younger patients. We must also look at conditions other than depression: SSRIs are widely used to treat, for example, obsessive–compulsive disorder, social phobia and generalized anxiety. The adverse effects in people with these problems seem likely to be the same as in depression — but we need the evidence.

The current voluntary system for reporting suspected ADRs is inadequate not only for SSRIs but for all medications. Neither the problems in the quality of Yellow Card reports for paroxetine, nor the value of patients' descriptions of their own experiences, are limited to this drug or class. Direct reporting of suspected adverse effects by patients is necessary in addition to reporting by physicians, pharmacists and nurses. In the UK, only health professionals may report suspected adverse drug reactions to the Medicines and Healthcare products Regulatory Agency. In Canada, reports from patients are accepted but not encouraged, and few people know of this option. A nonprofit organization, PharmaWatch, was launched in Canada in November 2003 with the aim of raising public awareness of drug safety and supporting consumer adverse drug reaction reporting.13 Since no country has developed specific methods to handle patient reports, various pilot schemes need to be tried and evaluated.

The central recording, follow-up and analysis of ADR reports after a drug is marketed require a thorough overhaul. The focus should be on describing and understanding the reactions as clinical phenomena, their epidemiology and dose-relatedness, and on discovering the pharmacologic mechanisms. Other methods of adverse event monitoring using large databases, as suggested recently by Laupacis,14 should be implemented and evaluated.

It is critical that anonymized reports be made available to the scientific and medical community: they come from the public and are needed for the public good. Publication should be encouraged, and the Internet offers excellent opportunities for doing so. Regulatory decisions based on adverse reaction data should be accompanied by publication of those data.

Regulatory requirements for evidence of efficacy should adequately reflect the key outcomes of importance to patients. The acceptance of broad exclusion criteria for pre-market phase III trials also needs rethinking. Most important, we need to broaden our understanding of informed consent in clinical trials. Can a patient be a truly informed participant in a trial if he or she is barred from knowing its outcome? All trial participants — and the broader public — should have access to the results of clinical trials.

𝛃 See related articles pages 455 and 489

Footnotes

  • Contributors: Both authors drafted the article, critically revised it and approved the final version.

    Acknowledgement: We thank Charles Medawar and David Healy for valuable comments.

    Competing interests: None declared for Dr. Herxheimer. Dr. Mintzes is a member of the board of PharmaWatch.

References

  1. 1.↵
    Medicines and Healthcare products Regulatory Agency. Selective serotonin reuptake inhibitors — use in children and adolescents with major depressive disorder. 2003 Dec 10. Available: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/cemssri_101203.pdf (accessed 2004 Jan 22).
  2. 2.↵
    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
  3. 3.↵
    Healy D. Let them eat Prozac. Toronto: James Lorimer; 2003. p. 111-3.
  4. 4.↵
    Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of 7 medical areas. JAMA 2001;285(4):437-43.
    OpenUrlCrossRefPubMed
  5. 5.↵
    Zimmerman M, Mattia JI, Posternak MA. Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? Am J Psychiatry 2002;159:469-73.
    OpenUrlCrossRefPubMed
  6. 6.↵
    Garland EJ. Facing the evidence: antidepressant treatment in children and adolescents.CMAJ 2004;170(4):489-91.
    OpenUrlFREE Full Text
  7. 7.↵
    Lexchin J. Secrecy and the Health Protection Branch. CMAJ 1998;159(5): 481-3.
    OpenUrlFREE Full Text
  8. 8.↵
    Barnes DG, Campbell K. Post-market surveillance of biotherapeutics for late health effects: a systematic review and recommendations on active surveillance in Canada. Thomas Chalmers Centre for Systematic Reviews. Report to the Centre for Surveillance Coordination. Ottawa: Health Canada; 2002 Sept 19. Available: www.hc-sc.gc.ca/pphb-dgspsp/csc-ccs/docs/biology/Pharma-Systematic-Review-English-Final.pdf (accessed 2004 Jan 27).
  9. 9.↵
    Medawar C, Herxheimer A. A comparison of adverse drug reaction reports from professionals and users, relating to risk of dependence and suicidal behaviour with paroxetine. Int J Risk Safety Medicine 2003/2004;16:5-19. Available: www.socialaudit.org.uk/YELLOW%20CARD%20REVIEW.pdf (accessed 2004 Jan 26).
  10. 10.↵
    Medawar C, Herxheimer A, Bell A, Jofre S. Paroxetine, Panorama and user reporting of ADRs: consumer intelligence matters in clinical practice and post-marketing drug surveillance. Int J Risk Safety Medicine 2002;15:161-9. Available: www.socialaudit.org.uk/IJRSM-161-169.pdf (accessed 2004 Jan 26).
    OpenUrl
  11. 11.↵
    Medicines and Healthcare products Regulatory Agency internal document, Standard Operating Procedure PLCL 009, Follow up of ADR reports, 2003.
  12. 12.↵
    King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30:179-86.
    OpenUrlPubMed
  13. 13.↵
    Priest A. Group Prescribes Info to Ease Drug Problems. Georgia Straight 2003;37(1875):41.
    OpenUrl
  14. 14.↵
    Laupacis A, Paterson JM, Mamdani M, Rostom A, Anderson GM. Gaps in the evaluation and monitoring of new pharmaceuticals: proposal for a different approach CMAJ 2003;169(11):1167-70.
    OpenUrlFREE Full Text
PreviousNext
Back to top

In this issue

Canadian Medical Association Journal: 170 (4)
CMAJ
Vol. 170, Issue 4
17 Feb 2004
  • Table of Contents
  • Index by author

Article tools

Respond to this article
Print
Download PDF
Article Alerts
To sign up for email alerts or to access your current email alerts, enter your email address below:
Email Article

Thank you for your interest in spreading the word on CMAJ.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Antidepressants and adverse effects in young patients: uncovering the evidence
(Your Name) has sent you a message from CMAJ
(Your Name) thought you would like to see the CMAJ web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Antidepressants and adverse effects in young patients: uncovering the evidence
Andrew Herxheimer, Barbara Mintzes
CMAJ Feb 2004, 170 (4) 487-489;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
‍ Request Permissions
Share
Antidepressants and adverse effects in young patients: uncovering the evidence
Andrew Herxheimer, Barbara Mintzes
CMAJ Feb 2004, 170 (4) 487-489;
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Footnotes
    • References
  • Responses
  • Metrics
  • PDF

Related Articles

  • Highlights of this issue
  • UK psychiatrists question SSRI warnings for under-18s
  • Facing the evidence: antidepressant treatment in children and adolescents
  • PubMed
  • Google Scholar

Cited By...

  • Unlocking Health Canadas cache of trade secrets: mandatory disclosure of clinical trial results
  • Should paediatricians support the European Paediatric Clinical Trials Register?
  • SSRI treatment for under-18s
  • SSRI treatment for under-18s
  • Efficacy and safety of antidepressants for children and adolescents
  • Google Scholar

More in this TOC Section

  • Antiracism as a foundational competency: reimagining CanMEDS through an antiracist lens
  • Keeping the front door open: ensuring access to primary care for all in Canada
  • Improving post-tuberculosis care in Canada
Show more Commentary

Similar Articles

Collections

  • Topics
    • Drugs: psychotherapeutic
    • Psychiatry & mental health: child & adolescent

 

View Latest Classified Ads

Content

  • Current issue
  • Past issues
  • Collections
  • Sections
  • Blog
  • Podcasts
  • Alerts
  • RSS
  • Early releases

Information for

  • Advertisers
  • Authors
  • Reviewers
  • CMA Members
  • CPD credits
  • Media
  • Reprint requests
  • Subscribers

About

  • General Information
  • Journal staff
  • Editorial Board
  • Advisory Panels
  • Governance Council
  • Journal Oversight
  • Careers
  • Contact
  • Copyright and Permissions
  • Accessibiity
  • CMA Civility Standards
CMAJ Group

Copyright 2023, CMA Impact Inc. or its licensors. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p)

All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association or its subsidiaries.

To receive any of these resources in an accessible format, please contact us at CMAJ Group, 500-1410 Blair Towers Place, Ottawa ON, K1J 9B9; p: 1-888-855-2555; e: cmajgroup@cmaj.ca

Powered by HighWire