Study of depression from prostate drugs loses the signal by including past users

Response to: Hagberg KW, Divan HA, Nickel JC, Jick SS. Risk of incident antidepressant-treated depression associated with use of 5α-reductase inhibitors compared with use of α-blockers in men with benign prostatic hyperplasia: a population-based study using the Clinical Practice Research Datalink. Pharmacotherapy. 2017. doi:10.1002/phar.1925

SUMMARY: Hagberg et al, 2017 fails to assess the risk of depression associated with using finasteride or dutasteride (5-ARIs), because past users of 5-ARIs were counted as cases. 37% of cases in the 5-ARI group had stopped taking the drug 181 days or more prior to initial diagnosis or treatment for depression. Only slightly more than half of cases (52%) were current users of 5-ARIs at the time of initial diagnosis or treatment for depression.

This study assesses the risk of depression associated with 5-alpha reductase inhibitors (5-ARIs), alpha-blockers, or both drugs in combination based on records from the UK Clinical Practice Research Datalink [1]. The signal of depression was based on a diagnosis of depression and treatment with an antidepressant.

The 5-ARI group includes a substantial number of patients who were no longer using a 5-ARI at the time of treatment with antidepressants. As shown in tables below, 172 (39.6%) of the 434 cases of depression in the 5-ARI group were past or distant past users. Past users means they discontinued 5-ARI treatment 90 to 180 days prior to treatment with an antidepressant. Distant past users means they discontinued 5-ARI treatment 181 days or more prior to treatment with an antidepressant. Some 37% of this group had discontinued 5-ARI treatment 181 days or more prior to treatment with an antidepressant.

Timing of drug exposureCases%
Current22752.3%
Recent (0-90 days ago)358.1%
Past (91-180 days ago)102.3%
Distant past (181+ days ago)16237.3%
Table 2 from Hagberg et al, 2017. 37% of depression cases stopped taking a 5-ARI 181 days or more before initial diagnosis or treatment for depression. A little over half (52%) were current users of a 5-ARI at the time of initial diagnosis or treatment for depression.

Counting past users as cases dilutes drug-related risk. Consider a patient who began finasteride two years ago, developed drug-related depression, and stopped taking it one year ago. The depression resolved a month later. In this study, he is counted as a non-case, even though he experienced depression related to finasteride. Moreover, men who experience an adverse effect of a 5-ARI such as depression might be more likely to discontinue the drug. If so, actual cases are disproportionately converted to non-cases, biasing the results towards a null finding.

The inclusion of past users can also produce false alarms. A patient might have stopped using dutasteride two years ago. If he develops new depression unrelated to prior use of dutasteride and receives treatment for it, he is incorrectly counted as a case of 5-ARI-related depression because he is a past user of dutasteride.

A co-author of this study, J. Curtis Nickel, had prior affiliations with Merck, the sponsor of finasteride, and GlaxoSmithKline, the sponsor of dutasteride. These affiliations were not disclosed in this paper. In the 1990s, Dr. Nickel participated in the PROSPECT Study Group and PLESS Study Group, both supporting Merck’s development of Proscar (finasteride 5 mg) for the treatment of benign prostatic hyperplasia (BPH) [2,3]. Dr. Nickel was a co-inventor of U.S. Patent No. 6,403,640 with Merck researcher Elizabeth Stoner, who was involved in research on finasteride, and two others. The patent, which is not related to finasteride, is assigned to Merck and Temple University. In 2016 Dr. Nickel disclosed a financial relationship with GlaxoSmithKline on a patent lawsuit [4]. Dr. Nickel was an investigator for GlaxoSmithKline’s ARIA studies of dutasteride for the treatment of BPH [5]. In 2011, Dr. Nickel disclosed roles as a consultant and investigator for GlaxoSmithKline’s EPICS trial comparing finasteride and dutasteride for treating BPH [6].

This paper is one of three using a similar methodology to assess, respectively the risk of depression, erectile dysfunction (ED) and gynecomastia associated with 5-ARIs [1,4,7]. The study of ED risk has a similar limitation: past users of finasteride (1 mg) are included in ED cases, diluting the signal of drug-related risk of ED. Its limitations are discussed in this post: Study of ED risk loses the signal by including past users of finasteride.

This response has been posted to PubPeer. An notification was sent to the corresponding author who has the opportunity to respond there.


REFERENCES

  1. Hagberg KW, Divan HA, Nickel JC, Jick SS. Risk of incident antidepressant-treated depression associated with use of 5α-reductase inhibitors compared with use of α-blockers in men with benign prostatic hyperplasia: a population-based study using the Clinical Practice Research Datalink. Pharmacotherapy. 2017. doi:10.1002/phar.1925
  2. Nickel JC, Fradet Y, Boake RC, et al. Efficacy and safety of finasteride therapy for benign prostatic hyperplasia: results of a 2-year randomized controlled trial (the PROSPECT study). CMAJ. 1996. PMCID:PMC1335066
  3. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med. 1998. doi:10.1056/NEJM199802263380901
  4. Hagberg KW, Divan HA, Persson R, Nickel JC, Jick SS. Risk of erectile dysfunction associated with use of 5-α reductase inhibitors for benign prostatic hyperplasia or alopecia: population based studies using the Clinical Practice Research Datalink. BMJ. 2016;354:i4823. doi:10.1136/bmj.i4823
  5. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G; ARIA3001 ARIA3002 and ARIA3003 Study Investigators. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002. doi:10.1016/s0090-4295(02)01905-2
  6. Nickel JC, Gilling P, Tammela TL, Morrill B, Wilson TH, Rittmaster RS. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the Enlarged Prostate International Comparator Study (EPICS). BJU Int. 2011. doi:10.1111/j.1464-410X.2011.10195.x
  7. Hagberg KW, Divan HA, Fang SC, Nickel JC, Jick SS. Risk of gynecomastia and breast cancer associated with the use of 5-alpha reductase inhibitors for benign prostatic hyperplasia. Clin Epidemiol. 2017. doi:10.2147/CLEP.S124674