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Study Authors: David-Dan Nguyen, Maya Marchese, et al.; Roger Ho

Target Audience and Goal Statement: Dermatologists, endocrinologists, nurses, primary care physicians, psychiatrists

The goal was to determine the possible associations between finasteride use and an increase in spontaneous reports of suicidality, depression, and anxiety.

Question Addressed:

• Is finasteride use associated with more spontaneous reports of suicidality, depression, and anxiety?

Study Synopsis and Perspective:

Despite considerable research over more than 20 years, controversy continues to surround adverse events associated with oral finasteride (Propecia), a 5α-reductase inhibitor (5-ARI) used to treat male pattern baldness (androgenetic alopecia) and benign prostatic hyperplasia (BPH).

In 2011, reports of finasteride-related depression and suicidality led to an . Depression was added to the adverse reactions section of , which already listed several sexual dysfunction-related adverse events, including erectile dysfunction and libido, ejaculation, and orgasm disorders.

Now new research has linked finasteride with a significant reporting odds ratio (ROR) for suicidality, depression, and anxiety, particularly in those younger than 45 and those with alopecia, as opposed to older men with BPH.

Quoc-Dien Trinh, MD, of Brigham and Women's Hospital in Boston, and colleagues found that among 3,282 treated patients, there were 2,926 reports of psychological adverse events -- defined as cases of depression and anxiety -- associated with use of finasteride.

As the team noted in the study online in , this equated to a more than four times higher risk of experiencing depression and anxiety while using finasteride (ROR 4.33, 95% CI 4.17-4.49).

Psychological adverse events associated with finasteride also included 356 reports of suicidality, including suicidal ideation, attempted suicides, and completed suicides among these patients. The associations between finasteride and adverse mental health effects were not dose dependent.

Trinh and co-authors found that the odds of experiencing suicidality were 63% higher (ROR 1.63, 95% CI 1.47-1.81), with more than a four-fold higher chance of experiencing suicidal ideation (ROR 4.39, 95% CI 3.90-4.95). When the researchers looked at the data for attempted and completed suicides separately, however, the association was not significant.

For this "pharmacovigilance case-noncase" study, the researchers drew upon data from the World Health Organization's 153-country VigiBase database. Nearly all reports of suicidality, depression, and anxiety were from either American or European patients.

In sensitivity analyses stratified by indication and age, certain patients had greater odds of experiencing these adverse mental health effects while on finasteride. For instance, patients 45 years of age and younger were more likely to experience suicidality compared with users over 45 (ROR 3.47, 95% CI 2.90-4.15).

Additionally, finasteride use for the indication of androgenetic alopecia had significantly higher chances of suicidality compared with use for an unknown or ambiguous indication or for the indication of BPH (ROR 2.06, 95% CI 1.81-2.34).

Another sensitivity analysis found that similar treatment options on the market -- i.e., tamsulosin (Flomax) and dutasteride (Avodart) both indicated for BPH, or minoxidil (Rogaine) indicated for alopecia areata -- were not associated with the same safety signals as finasteride.

Looking at data from 1992-2019, the team found that reports of depression, anxiety, and suicidality increased significantly among users after 2012 (ROR 2.13, 95% CI 1.91-2.39).

Writing in an , Roger Ho, MD, MPH, of New York University Grossman School of Medicine, pointed out that this uptick in reports in 2012 is not much of a surprise since it coincided with the publication of the originally linking suicidality and finasteride, as well as the establishment of , all leading to the

Ho also suggested that the findings "should be considered as exploratory" and be the impetus for future large-scale prospective pharmacoepidemiologic studies specifically designed to assess these outcomes.

"Health care professionals should keep themselves abreast of these potential signals and, accordingly, conduct a full evaluation and a detailed, personalized risk-benefit assessment for patients before each prescription of finasteride," he recommended.

Source Reference: 2020; DOI: 10.1001/jamadermatol.2020.3385

Editorial: 2020; DOI: 10.1001/jamadermatol.2020.3384

Study Highlights and Explanation of Findings

Androgenetic alopecia -- which affects up to 80% of Caucasian males -- may, and as a 1999 review noted, the condition has been associated with potentially adverse psychosocial effects, if untreated.

The author explained that the deleterious effects of alopecia on self-esteem and some aspects of psychological adjustment are more apparent among women than men and among patients seeking treatment, with medical treatments -- specifically, minoxidil and finasteride -- yielding psychological benefits.

The timing of the marked increase in adverse effects reports following creation of the Post-Finasteride Syndrome Foundation has raised public awareness, and early treatment-related concerns helped generate further research.

Indeed, in 2007, prior to the spike in media attention, (i.e., an adverse side effect that is not a direct result of the specific pharmacological action of the drug) was reported in a study of 107 men with BPH who were receiving blinded administration of finasteride. Those researchers found that sexual dysfunction was significantly more likely to be noted by patients counseled about possible "but uncommon" sexual side effects compared with those not informed of these side effects, and while the findings in this small cohort should be interpreted with caution, clinicians should be aware of this potential effect, the researchers stated.

A of 34 clinical trials of finasteride in men with androgenetic alopecia concluded that the information available to date about toxicity is of poor quality and seems to be "systematically biased," and that most men prescribed finasteride for routine treatment of the condition would have been excluded from the pivotal studies that supported FDA approval of finasteride for that indication.

In the new study, Trinh and co-authors wrote: "There is a plausible biological basis linking finasteride ... with depression and anxiety. suggest that men with depression have lower levels of the neurosteroid allopregnanolone, which is produced by the 5α-reductase enzyme and has antidepressant and anxiolytic effects."

Indeed, one of the quantitative risk of depression in patients using 5-ARI for BPH reported a pooled overall hazard ratio of 1.23 (95% confidence interval [CI] 0.99-1.54) and a pooled overall OR of 1.19 (95% CI 0.95–1.49) in random effects models.

have been noted in men reporting persistent sexual symptoms after finasteride treatment for hair loss, compared with both those who did not report such symptoms and healthy men who had never used finasteride.

None of the men, however, had evidence of androgen deficiency, decreased peripheral androgen action, or persistent peripheral inhibition of steroid 5α-reductase in the men with depression; all participants were under age 50, with no pre-existing depression.

Those authors also noted that symptomatic finasteride users had functional magnetic resonance imaging findings consistent with those observed in depression, and evidence of depressed mood – with average scores in the range associated with moderately severe depression on three different depression scales. Depressed finasteride users also had higher levels of negative affect and lower levels of positive affect compared with healthy controls.

The group suggested that these symptomatic finasteride users are unlikely to benefit from treatment with testosterone, dihydrotestosterone, or any other androgen, and said that clinicians should focus instead on the treatment of depression and sexual symptoms.

Furthermore, the researchers said, because men seeking treatment for alopecia have a higher prevalence of depression and sexual dysfunction than the general population, it would be appropriate to ask about patients' history of depression or sexual dysfunction before starting treatment.