Mental Health Concerns in Treatment of Benign Prostatic Hyperplasia

Dakota Thaxton Craft, Mercer University College of Pharmacy

Benign prostatic hyperplasia (BPH) is an enlarged prostate that may lead to lower urinary tract symptoms, such as increased urinary frequency and urgency, weak urine flow, and trouble with urine initiation. [1]  The incidence and symptoms of BPH were stated to most commonly begin in men over the age of 40 and increase with age.  If left untreated, BPH can lead to more serious complications, including urinary tract infections and kidney or bladder damage.  Treatment options for BPH are based on the severity of symptoms may include watchful waiting, medication, and surgery. [2]

Finasteride and dutasteride are 5𝛼-reductase inhibitors that act to shrink the size of the prostate and relieve BPH symptoms by inhibiting the conversion of testosterone to dihydrotestosterone. [3]  In 2010, the Food and Drug Administration added new safety information for finasteride regarding the risk of suicide and depression-related adverse events. [4]  The association between 5𝛼-reductase inhibitors and depression may be explained by decreased levels of neurosteroids produced by 5𝛼-reductase [5] and lower levels of type I 5𝛼-reductase in the prefrontal cortex. [6]

Association of Suicidality and Depression with 5𝛼-Reductase Inhibitors [7]
Design Population-based, retrospective, matched cohort; N= 186,394
Objective To determine if there is an increased risk of suicide, self-harm, or depression among men starting 5𝛼-reductase inhibitors for treatment of prostatic enlargement
Study Groups Unexposed (n= 93,197); exposed (n= 93,197)
Methods Population-based data was obtained from Canadian administrative data sources for men aged 66 and older.  The prescription fill date for finasteride (n= 44,692) or dutasteride (n= 48,505) represented the index date for exposed patients, while unexposed men were assigned a random index date.  Exposed men were matched with unexposed men based on index date, history of depression or self-harm in the last 5 years, and evidence of antidepressant medication use in the last 6 months.  Self-harm included emergency department visits for a suicide attempt or parasuicide behavior and psychiatric hospital admission for recent self-harm or thoughts of self-harm.  Patients with history of depression in the 5 years prior to the index date were excluded for the analysis of depression outcome.  Study outcomes were observed during an at-risk period, defined as continuous medication usage plus 12 months beginning on the day the prescription was filled.  
Duration January 2003 to December 2013
Primary Outcome Measure Incidence of suicide
Secondary Outcome Measure Incidence of self-harm and depression
Baseline Characteristics
Unexposed Exposed Standardized difference, %
Median age, years (range) 75 (70- 81) 75 (70- 80) 5
Medical History, n (%)
Acute urinary retention 9,683 (10.4) 9,397 (10.1) 1
Benign prostatic hyperplasia 62,977 (67.6) 59,474 (63.8) 8
Cancer 6,480 (7) 5,977 (63.8) 8
Alcoholism 739 (0.8) 723 (0.8) 0
Anxiety 426 (0.5) 445 (0.5) 0
Bipolar disorder 115 (0.1) 98 (0.1) 0
Depression 3,353 (3.6) 3,353 (3.6) 0
Schizophrenia and/or delusional disorder 178 (0.2) 163 (0.2) 0
Self-harm 191 (0.2) 191 (0.2) 0
Substance abuse 144 (0.2) 142 (0.2) 0
Use of antidepressants, n (%)
SSRI and/or SNRI 7,306 (7.8) 7,057 (7.6) 1
Other 5,909 (6.3) 6,229 (6.7) 2
Use of antipsychotics, n (%)
Typical 2,277 (2.4) 2,127 (2.3) 1
Atypical 712 (0.8) 687 (0.7) 1
Use of mood stabilizers, n (%) 957 (1.0) 943 (1.0) 0
Psychiatric hospitalizations, n (%)
0 92,589 (99.3) 92,536 (99.3) 0
1 or more 608 (0.7) 661 (0.7) 0
Family physician mental health visits, n (%)
0 81,428 (87.4) 81,312 (87.2) 1
1 or more 11,769 (12.6) 11,885 (12.8) 1
Psychiatry visits, n (%)
0 90,417 (97) 90,316 (96.9) 1
1 or more 2,780 (3.0) 2,881 (3.1) 1
Results
Suicide
Exposed Unexposed p-value
Events, n (%) 38 (0.04) 36 (0.04)
Hazard ratio (95% CI) 0.88 (0.53- 1.45) ≥ 0.10
Change in absolute risk, % (IQR) 0 (-0.02 to +0.02)
Self-harm Depression
Exposed Unexposed (reference) p-

value

Exposed Unexposed (reference) p-

value

Events, n (%) 169 (0.18) 130 (0.14) 1,750 (1.95) 1,231 (1.37)
Stratified hazard ratio (95% CI)
0- 1.5 years 1.88 (1.34- 2.64) < 0.01 1.94 (1.73- 2.16) < 0.01
1.5- 3 years 0.63 (0.36- 1.09) ≥ 0.10 1.22 (1.08- 1.37) < 0.01
More than 3 years 1.07 (0.64- 1.77) ≥ 0.10 1.22 (1.08- 1.37) < 0.01
Change in absolute risk, % (IQR) +0.04 (+0.01 to +0.08) +0.58 (+0.46 to +0.70)
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions There was not an increased risk of suicide associated with 5𝛼-reductase inhibitors; however, there was an increased risk of self-harm and depression.

Although the risk of suicide was not found to be statistically significant, the threat of such a  severe side effect warrants consideration of depression or self-harm risk prior to initiation of 5𝛼-reductase inhibitors.  The incidence of suicide could have been underestimated due to the lack of sensitivity in identifying suicide as a cause of death.  Confounding variables, such as family history of depression or suicide and undisclosed life events, could have altered the incidence of outcomes.

 

References

[1] Urology Care Foundation: What is Benign Prostatic Hyperplasia (BPH)? http://www.urologyhealth.org/urologic-conditions/benign-prostatic-hyperplasia-(bph). Accessed April 10, 2017.

[2] National Institute of Diabetes and Digestive and Kidney Diseases: Prostate Enlargement (Benign Prostatic Hyperplasia). https://www.niddk.nih.gov/health-information/urologic-diseases/prostate-problems/prostate-enlargement-benign-prostatic-hyperplasia. Accessed April 10, 2017.

[3] Johns Hopkins Medicine: Benign Prostatic Hyperplasia. http://urology.jhu.edu/prostate/treatment_BPH.php. Accessed April 11, 2017.

[4] U.S. Food and Drug Administration: FDA Adverse Events Reporting System. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm471019.htm. Accessed April 11, 2016.

[5] Traish AM.  5α-reductases in human physiology: an unfolding story.  Endocr Pract. 2012;18(6):965-975.

[6] Hammond GL, Hirvonen J, Vihko R. Progesterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone and androsterone concentrations in specific regions of the human brain. J Steroid Biochem. 1983;18(2):185-189.

[7] Welk B, Mcarthur E, Ordon M, Anderson KK, Hayward J, Dixon S. Association of Suicidality and Depression With 5α-Reductase Inhibitors. JAMA Intern Med. 2017.

 

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