Summary of findings from the FDA regulatory science forum on measuring sexual dysfunction in depression trials.
OBJECTIVE
Sexual dysfunction is a significant treatment-emergent adverse reaction to the serotonergic antidepressants (selective serotonin reuptake inhibitors [SSRIs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]). However, the rate of sexual dysfunction is often underestimated in registration trials, which have relied on unsolicited reports. We conducted a literature search to examine the rates of sexual dysfunction with SSRIs/SNRIs when these rates were ascertained by structured questionnaires or standardized instruments. Additionally, we conducted exploratory analyses of major depressive disorder (MDD) registration trial data.


METHODS
For the literature search, we used the PubMed and EMBASE databases, with a cutoff date of April 1, 2011. We included all the SSRIs and SNRIs that at the time had been approved for the treatment of MDD. For each of these drugs, a search was conducted with the following terms: sexual dysfunction, SD, sexual adverse effects, desire, arousal, excitement, and orgasm. For the exploratory analyses of US Food and Drug Administration in-house trial data, we searched our database for short-term (6-8 weeks), randomized, placebo-controlled MDD monotherapy trials of approved drugs included in New Drug Application submissions that used a standardized instrument to assess sexual function.


METHODS
For the literature search, we initially found a total of 123 nonduplicate articles, some of which included multiple studies. After screening based on our inclusion/exclusion criteria (and to remove duplicate trial-level data), we were left with 7 articles representing 11 unique studies in which sexual dysfunction was assessed with direct questioning or standardized instruments. The Changes in Sexual Functioning Questionnaire-Short-Form (CSFQ-14) and Arizona Sexual Experiences Scale (ASEX) were the only instruments represented. For the exploratory analyses of in-house MDD trial data, we found controlled studies using either the CSFQ-14 (6 trials) or ASEX (5 trials).


METHODS
For the literature search, we were able to pool the results for the studies that included direct questioning. For the studies that used standardized instruments to assess sexual function, we simply describe our findings. For the exploratory analyses of in-house MDD trial data, we constructed a dataset containing all subject-level CSFQ-14 or ASEX item scores for each of the trials as well as demographic and other relevant variables. For each treatment or placebo group, analyses were performed on pooled data, including multiple studies, and on individual studies.


RESULTS
For our literature search, regardless of which method was used to assess sexual function, the data from these articles were informative and showed the expected effects on sexual function with SSRIs/SNRIs. However, for our exploratory analyses, no trend was observed in CSFQ-14 or ASEX results for individual drugs or drug classes.


CONCLUSIONS
These results raise the question as to why the CSFQ-14 and ASEX appeared to perform well in the published studies but not in our exploratory analyses of in-house MDD trial data. We discuss possible reasons and solutions.
Division of Clinical Compliance Evaluation, Office of Scientific Investigations, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Bldg WO51, Rm 5222, Silver Spring, MD 20993-0002 phillip.kronstein@fda.hhs.gov.
Phillip D
PD
Kronstein
Eiji
E
Ishida
Ni A
NA
Khin
Eric
E
Chang
H M James
HM
Hung
Robert J
RJ
Temple
Peiling
P
Yang
D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects*; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000009:adverse effects*; D012735:Sexual Dysfunction, Physiological / Q000139:chemically induced* / Q000175:diagnosis; D014481:United States; D014486:United States Food and Drug Administration / Q000706:statistics & numerical data*
D017367:Selective Serotonin Reuptake Inhibitors; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors