Clinical trial NCT03038867
Conditions: Infertility, Male Depression
Sponsor: Weill Medical College of Cornell University
Start date: 2016-12-12; Completion date: 2018-08-31
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators are conducting a placebo-controlled, randomized control trial with duloxetine in healthy, fertile men not previously on any antidepressants. Participants will be randomized to either the duloxetine or placebo groups for 6 weeks. The investigators will assess changes in sperm DNA fragmentation at 0, 2, 6, 8, and 10 weeks. Other outcomes measured will include semen parameters (sperm concentration, motility, morphology), hormone levels (testosterone, estrogen, prolactin, LH, FSH), and sexual function (IIEF and MSHQ) surveys.

Detailed description:
Antidepressant medications are commonly prescribed in the USA not only for depression, but also for anxiety disorders such as generalized anxiety disorder and obsessive-compulsive disorder, premature ejaculation, post-traumatic stress disorder, and neuropathic pain. Despite being widely prescribed in the United States in men of reproductive age, the impact of antidepressants on fertility has not been extensively studied.

After noticing worsened semen parameters in men on anti-depressants, the investigators performed the first prospective study to demonstrate a deleterious impact of selective serotonin reuptake inhibitors (SSRI) on sperm DNA integrity, which has been linked to reproductive outcomes. Further small studies have corroborated the negative impact of SSRIs on male fertility, as assessed by semen parameters and/or sperm DNA integrity.

No studies have examined the impact of a newer, but similar, class of antidepressant - the serotonin-norepinephrine reuptake inhibitor (SNRI). Like SSRIs, SNRIs inhibit the reuptake of serotonin, but also act on norepinephrine. The use of SNRIs has increased recently due to their slightly improved efficacy profile when compared to SSRIs. Duloxetine is an SNRI and is one of the most commonly prescribed anti-depressants in the United States.

The investigators are conducting this trial to determine whether or not the administration of duloxetine will result in a deterioration in sperm DNA fragmentation in healthy, fertile men.

Arms: arm 1: Duloxetine orally 60mg daily for 5 weeks, then taper to 30mg daily for 1 week arm 2: Placebo
Interventions: intervention 1: Duloxetine intervention 2: Placebo
Intervention descriptions: intervention 1: Duloxetine orally 60mg daily for 5 weeks, then taper to 30mg daily for 1 week intervention 2: Placebo orally 2 tabs daily for 5 weeks, then taper to 1 tab daily for 1 week

Protocol documents:
Prot_SAP_000.pdf: 
Impact of Duloxetine on Male Fertility  
NCT03038867 
Protocol Approval Date: 10/25/2016 
 
Protocol version 
Date of Approval  
Description 
Protocol 001 
10/25/2016 
Protocol was submitted to IRB for review and eventually approved. Please 
refer to protocol summary below. Subsequent amendments submitted to 
IRB do not reflect changes in protocol background, study design, methods, 
or statistical analysis.  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Background and Clinical Significance 
Antidepressant medications are commonly prescribed in the USA not only for depression, but also for 
anxiety disorders such as generalized anxiety disorder and obsessive-compulsive disorder, premature 
ejaculation, post-traumatic stress disorder, and neuropathic pain. In fact, prescriptions for antidepressants 
in American men increased by 28% between 2000 and 2010 (Medco, 2010). Despite being widely 
prescribed in the United States in men of reproductive age, the impact of antidepressants on fertility has 
not been extensively studied. After noticing worsened semen parameters in men on anti-depressants 
(Tanrikut and Schlegel 2007), the investigators performed the first prospective study to demonstrate a 
deleterious impact of selective serotonin reuptake inhibitors (SSRI) on sperm DNA integrity, which has 
been linked to reproductive outcomes (Tanrikut and Schlegel, 2010). Further small studies have 
corroborated the negative impact of SSRIs on male fertility, as assessed by semen parameters and/or 
sperm DNA integrity (Safarinejad, 2008 and Koyuncu et al, 2011). While the exact mechanism for the 
negative impact of SSRIs on male fertility is not yet known, animal studies have suggested the potential 
spermicidal action of SSRIs mediated through the binding of SSRIs to sulfhydryl groups on spermatozoa 
(Wolf et al, 1992; De Lamirande et al., 1998, and Kumar et al., 2006). Tanrikut and Schlegel suggested 
an impact on post-testicular sperm transport as the mechanism for sperm DNA damage (Tanrikut and 
Schlegel, 2010). An increase in sperm DNA fragmentation commonly occurs in men with delayed sperm 
transport, as has been shown in those with ejaculatory dysfunction or obstructive azoospermia. No 
studies have examined the impact of a newer, but similar, class of antidepressant - the serotonin-
norepinephrine reuptake inhibitor (SNRI). Like SSRIs, SNRIs inhibit the reuptake of serotonin, but also 
act on norepinephrine. The use of SNRIs has increased recently due to their slightly improved efficacy 
profile when compared to SSRIs. Duloxetine (trade name Cymbalta) is an SNRI and is one of the most 
commonly prescribed anti-depressants in the United States. The most common side effects for duloxetine 
at its optimal treatment dose of 60mg daily include nausea (23-25%), dry mouth (13-15%), headache (13-
14%), somnolence (10-12%), and fatigue (10-11%). Significant side effects include the activation of 
mania/hypomania in those with bipolar disorder and the potential for serotonin syndrome in those 
concurrently taking SNRIs with other serotonergic medications. 
 
Primary and Secondary Objectives 
The primary objective of the research study is to determine the administration of duloxetine on sperm 
DNA fragmentation, and the secondary objective is to determine the impact of duloxetine administration 
on semen parameters such as serum hormone levels, and sexual function.   
 
Study Design  
The hypothesis is that administration of duloxetine will result in a deterioration in sperm DNA 
fragmentation in healthy, fertile men. To evaluate the hypothesis, the investigators conducted a placebo-
controlled, randomized control trial with duloxetine in healthy, fertile men not previously on any 
antidepressants. Patients will be randomized to either the duloxetine (60mg PO daily) or placebo groups 
for 6 weeks. In the sixth and last week of therapy, the drug dosage will be halved to 30mg PO daily as a 
taper. Changes in sperm DNA fragmentation were assessed at numerous time points before, during, and 
after drug administration (semen analyses at baseline before administration, at 2-weeks, 6-weeks, and 
then at 2-weeks and 4-weeks after drug cessation). Other outcomes measured include semen 
parameters (sperm concentration, motility, morphology), hormone levels (testosterone, estrogen, 
prolactin, LH, FSH collected at baseline, at 2-weeks, 6-weeks, and at 2-weeks and 4-weeks after 
discontinuation of medication), and sexual function (IIEF and MSHQ) surveys (collected at baseline, at 6-
weeks, and at 4-weeks after discontinuation of medication). 
 


Methods  
Selective serotonin reuptake inhibitors (SSRI) are known to affect post-testicular sperm transport and 
adversely impact male fertility, but no studies have examined the impact of a newer, but similar, class of 
antidepressant - the serotonin-norepinephrine reuptake inhibitor (SNRI). Duloxetine (trade name 
Cymbalta) is an SNRI and is one of the most commonly prescribed anti-depressants in the United States. 
An increase in sperm DNA fragmentation commonly occurs in men with delayed sperm transport, as has 
been shown in those with ejaculatory dysfunction or obstructive azoospermia. The research hypothesis is 
that administration of duloxetine will result in a deterioration in sperm DNA fragmentation in healthy, fertile 
men. To test the hypothesis, a placebo-controlled, randomized control trial will be conducted with 
duloxetine in healthy, fertile men not previously on any antidepressants. Patients will be randomized to 
either the duloxetine or placebo groups for 6 weeks. Changes in sperm DNA fragmentation will be 
assessed at numerous time points before, during, and after drug administration. Other outcomes 
measured will include semen parameters (sperm concentration, motility, morphology), hormone levels 
(testosterone, estrogen, prolactin, LH, FSH), and sexual function (IIEF and MSHQ) surveys. 
 
Study Population  
Study participants will be screened and recruited if they meet the selection criteria. Participants who are 
healthy males aged 18-65 years, with normal or borderline (concentration >10 million/mL, motility >30%, 
morphology >3%) semen parameters on semen analysis, and are willing to engage in sexual activity, 
alone or with a partner, at least weekly for the duration of the study, and are capable of providing semen 
sample will be included in the study. Participants will be excluded if they have clinically detected 
varicocele, diagnosed with oligoasthenospermia or azoospermia on screening semen analysis, ongoing 
attempts to initiate pregnancy, current sexual dysfunction, indicated by moderate or worse dysfunction on 
any International Index of Erectile Function (IIEF) domain, history of seizure disorder, history of previous 
chemotherapy or radiation, current psychiatric disorder or history of bipolar disorder, family history 
(including cousins and grandparents) of bipolar disorder (manic depressive disorder) or suicide, use of 
any psychotropic agents (prescription or herbal) or anticonvulsants, use of sleeping pills more than once 
per week, use of any hormonal medications on a daily or intermittent basis including gluococorticoid pills, 
inhalers, or creams during the preceding 3 months, use of medications which may affect hormonal 
measures or sexual function, use of any prescription or non-prescription medications to enhance sexual 
function, inability to read, follow instructions or complete questionnaires in English, consumption of more 
than 2ounces of alcohol daily, and consumption of tobacco or illicit drugs.   
 
Statistical Analysis Plan 
After consultation with a biostatistician, the required samples size for a proportion difference of 5% of 
patients with abnormal sperm DNA fragmentation in the control group and 30% of patients with abnormal 
sperm DNA fragmentation in the treatment group with 80% power, two-sided alpha 5% is 35 patients per 
group. Descriptive statistics (including mean, standard deviation, median, range, frequency, and percent) 
for demographic and clinical factors of interest will be calculated for the placebo and treatment groups 
separately. The two-sample t-test (or Wilcoxon rank-sum test) and chi-square test (or Fisher's exact test) 
will be used to compare 1) mean (median) TUNEL values and 2) proportions of patients with TUNEL 
values >25%, respectively, between the treatment and placebo groups, at each time point. Analysis of 
covariance (ANCOVA) and multiple logistic regression will also be used to compare mean TUNEL value 
and proportion of patients with TUNEL values > 25%, respectively, between the two groups, after 
adjustment for baseline value (i.e., assuming any remaining imbalance in the baseline assessment 
between the two groups after randomization). The paired t-test and McNemar's chi-square test will be 
used to compare change in mean TUNEL value and change in proportion of abnormal results, 


respectively, between the time points, within each group separately. The secondary outcomes of interest 
will also be compared between the two groups using similar statistical tests as noted above. All p-values 
will be two-sided with statistical significance evaluated at the 0.05 alpha level. Ninety-five percent 
confidence intervals (95% CI) will be calculated to assess the precision of the obtained estimates. All 
analyses will be performed in SAS Version 9.4 (SAS Institute, Inc., Cary, NC) and Stata Version 14.0 
(StataCorp, College Station, TX).