ORIGINAL CONTRIBUTION
Post-SSRI Sexual Dysfunction
Clinical Characterization and Preliminary Assessment of Contributory Factors
and Dose-Response Relationship
Joseph Ben-Sheetrit, MD,* Dov Aizenberg, MD,*† Antonei B. Csoka, PhD,‡
Abraham Weizman, MD,*† and Haggai Hermesh, MD*†
Abstract: Emerging evidence suggests that sexual dysfunction emerging
during treatment with selective serotonin reuptake inhibitors (SSRIs) and/
or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some
patients beyond drug discontinuation (post-SSRI sexual dysfunction
[PSSD]). We sought to identify and characterize a series of such cases
and explore possible explanatory factors and exposure-response relation-
ship. Subjects who responded to an invitation in a forum dedicated to
PSSD filled out a survey via online software. Case probability was defined
according to the following 3 categories of increasing presumed likelihood
of PSSD. Noncases did not meet the criteria for possible cases. Possible
cases were subjects with normal pretreatment sexual function who first ex-
perienced sexual disturbances while using a single SSRI/SNRI, which did
not resolve upon drug discontinuation for 1 month or longer as indicated by
Arizona Sexual Experience Scale scores. High-probability cases were also
younger than 50-year-olds; did not have confounding medical conditions,
medications, or drug use; and had normal scores on the Hospital Anxiety
and Depression Scale. Five hundred thirty-two (532) subjects completed
the survey, among which 183 possible cases were identified, including
23 high-probability cases. Female sex, genital anesthesia, and depression
predicted current sexual dysfunction severity, but dose/defined daily dose
ratio and anxiety did not. Genital anesthesia did not correlate with depres-
sion or anxiety, but pleasureless orgasm was an independent predictor of
both depression and case probability. Limitations of the study include ret-
rospective design and selection and report biases that do not allow general-
ization or estimation of incidence. However, our findings add to previous
reports and support the existence of PSSD, which may not be fully ex-
plained by alternative nonpharmacological factors related to sexual dys-
function, including depression and anxiety.
Key Words: selective serotonin reuptake inhibitors (SSRIs),
serotonin-norepinephrine reuptake inhibitors (SNRIs), persistent sexual
dysfunction, genital anesthesia, pleasureless orgasm, post-SSRI
sexual dysfunction (PSSD)
(J Clin Psychopharmacol 2015;35: 273–278)
S exual dysfunction is a well-documented adverse effect of anti-
depressants, particularly frequent with selective serotonin re-
uptake inhibitors (SSRIs).1 It is now widely acknowledged that
SSRIs can cause disturbances in every aspect of sexual function,
including libido, arousal, erection, lubrication, orgasm,2 and also
genital sensation.3–5 Sexual dysfunction is assumed to resolve
upon drug discontinuation, but emerging evidence indicates that
From the *Geha Mental Health Center, Petah Tikva; †Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel; and ‡Department of Anatomy,
School of Medicine, Howard University, Washington D.C.
Received October 13, 2014; accepted after revision February 11, 2015.
Reprints: Joseph Ben-Sheetrit, MD, Geha Mental Health Center,
1 Helsinki St, PO Box 102, Petah Tikva 4910002, Israel
(e‐mail: joseph.ben.sheetrit@gmail.com).
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0271-0749
DOI: 10.1097/JCP.0000000000000300
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
in some patients, it persists beyond cessation of pharmacological
treatment. In a prospective study of patients with SSRI-induced
sexual dysfunction, Montejo et al6 found that switching treatment
from an SSRI to amineptine, a tricyclic antidepressant that acts
primarily on dopaminergic systems, decreased the frequency of
sexual dysfunction to 55% after 6 months while depression re-
mained in remission. As amineptine was not associated with sex-
ual dysfunction in patients who have not previously taken an
SSRI, Bahrick7 suggested that this observation could be inter-
preted as evidence of enduring post-SSRI sexual dysfunction. In
a prospective randomized placebo-controlled trial of premature
ejaculation successfully treated with citalopram, Safarinejad and
Hosseini8 showed that time to ejaculation remained significantly
delayed in 3- and 6-month follow-up after discontinuation of treat-
ment compared to the placebo arm. From 2006 to 2008, 8 cases
of treatment-emergent sexual dysfunction persisting after SSRI
discontinuation appeared in the literature, in which genital anes-
thesia and pleasureless orgasm emerged as potential markers of
what Csoka et al tentatively termed post-SSRI sexual dysfunc-
tion (PSSD).4,5,9,10 In 2012, the Netherlands Pharmacovigilance
Center (Lareb) published an official report about PSSD, which in-
cluded 19 additional possible cases, calling for further investiga-
tion of the subject.11,12 Stinson13 has conducted an in-depth
qualitative psychological investigation of 9 patients with PSSD,
which showed a pervasive negative impact on the quality of life.
Using data from an Internet portal for reporting adverse events,
Hogan et al14 found 91 reports of persistent sexual dysfunction
linked to treatment with SSRIs or serotonin-norepinephrine reup-
take inhibitors (SNRIs). Waldinger et al15 have recently described
a case study of successful treatment of penile anesthesia by low-
power laser irradiation in a patient with PSSD, hypothesizing that
SSRIs may cause disturbances in transient receptor potential ion
channels of mechano-, thermo-, and chemosensitive nerve end-
ings and receptors, thus leading to the persistent genital anesthesia
reported in PSSD. Csoka and Szyf16 suggested that epigenetic
alterations in the DNA may play a role in the pathogenesis of the
syndrome. To further identify and characterize cases of treatment-
emergent sexual dysfunction persisting after SSRI/SNRI discon-
tinuation, as well as to evaluate possible explanatory factors and
dose-response relationship, we conducted an Internet survey
about sexual adverse effects of antidepressants using a structured
self-report questionnaire and well-defined case-definition criteria.
METHODS
An invitation to participate in the survey was posted in an
Internet forum dedicated to PSSD ("SSRIsex – Persistent SSRI
Sexual Side Effects," URL: http://groups.yahoo.com/neo/groups/
SSRIsex/info). Participants filled out the survey via online survey
software (Qualtrics.com). The study was approved by the Geha
Mental Health Center Review Board. The survey opened with a full
informed consent form that consisted of questions regarding demo-
graphic details (sex, age, relationship status, country of residence),
www.psychopharmacology.com 273
Ben-Sheetrit et al Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
experiences of sexual dysfunction while taking any medication
(yes/no question, additional open-text question for description),
details of all the medications used while experiencing sexual dys-
function (names, doses, durations of use, and time since quitting
each medication; open-text questions), sexual dysfunction before
taking the medications (yes/no question, with space for details),
current sexual function as assessed by the Arizona Sexual Experi-
ence Scale (ASEX),17 questions regarding genital anesthesia and
erectile response to visual stimuli (multiple-choice Likert-scale
items), current medical conditions (open-text question), current
use of medications (names and doses of all medications taken at
the time of the survey; open-text question), consumption of addic-
tive substances (current and past smoking: yes/no question with
space for details; alcohol, marijuana, cocaine: multiple-choice
items regarding use over the last 30 days), and current depression
and anxiety levels as assessed by the Hospital Anxiety and De-
pression Scale (HADS).18,19 The authors received written permis-
sion to use the ASEX and HADS from the copyright owners.
Antidepressant doses were divided by the defined daily dose
(DDD) for each medication, as published by the WHO Collabora-
tive Centre for Drug Statistics Methodology, to create a measure
for dose comparison beyond specific agents (dose/DDD ratio).
Case probability was defined according to the following cate-
gories of increasing presumed likelihood of PSSD: noncase, pos-
sible case, and high-probability case; the criteria for each are listed
in Table 1. Subjects who reported using more than one medica-
tion (whether antidepressant or not) while the sexual dysfunction
emerged were considered as noncases because the complexity of
drug combinations does not allow drawing clear conclusions
as to which drug was the culprit. Absence of any pretreatment
TABLE 1. Criteria for Case Probability Categories
Noncase
One or more of the criteria for a possible case are not met
(see below)
Possible case
All of the following:
(1) Treatment-emergent sexual dysfunction while taking one
antidepressant of the SSRI or SNRI class
(2) As the above treatment-emergent sexual dysfunction appeared,
the patient was not taking any additional medications
(3) The patient reported no pretreatment sexual dysfunction
(4) The antidepressant was discontinued at least 1 month before
the survey
(5) Sexual dysfunction persisted despite drug discontinuation, as
indicated by subject's ASEX scores
High-probability case
All the above criteria for possible case plus all the following:
(6) Subject is younger than 50 years old
(7) Current medical conditions reported by the subject did not
include conditions associated with sexual dysfunction
(8) Current medications reported by the subject did not include
medications associated with sexual dysfunction
(9) The subject did not report use of addictive substances that
may cause sexual dysfunction
(10) Subject's HADS-Depression score is within normal
range (0–7)
(11) Subjects' HADS-Anxiety score is within normal
range (0–7)
ASEX indicates Arizona Sexual Experience Scale; HADS, Hospital
Anxiety and Depression Scale.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
sexual dysfunction was required as an inclusion criterion, since
a comparison of pretreatment versus current sexual dysfunction
is beyond the scope of the survey. Drug discontinuation is a defin-
ing feature of PSSD. A cutoff point of 1 month was chosen for
2 reasons. First, the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5) criterion C for medication-
induced sexual dysfunction seems to indicate that 1 month is a
substantial period of time during which sexual adverse effects of
medications are expected to wear off. Second, virtually all of the
drug is eliminated from the patient's body after 1 month from dis-
continuation, even for the SSRI with the longest half-life (the ac-
tive metabolite of fluoxetine, norfluoxetine, has a t½ of 7.5 days,
which yields approximately 94% washout after 1 month from dis-
continuation20). The ASEX manual indicates specific score-based
criteria highly correlated with physician-diagnosed sexual dys-
function,21 which we used as a definition of current sexual dys-
function in our study. Additional criteria for high-probability
cases aim to exclude cases in which possible alternative causes
of sexual dysfunction are evident. Since the literature points to a
steep increase in sexual dysfunction at approximately age 50,22,23
it was used as a cutoff point for exclusion of age-related sexual
difficulties. Current medical conditions reported by the partici-
pants were searched in Google Scholar along the word "sexual,"
yielding 59 diseases/disorders associated with sexual dysfunction
(not including depressive and anxiety disorders, which are better
addressed by criteria 9 and 10, accordingly). Subjects who re-
ported any of these conditions were not included in the high-
probability cases sample, regardless of treatment. To determine
the frequency of sexual adverse effects of the medications cur-
rently taken by the participants, each was searched individually
in the databases UpToDate (2013) and Micromedex 2.0, and in
few cases where data was insufficient, also in relevant textbooks
and journal articles. Subjects taking medications of which sexual
dysfunction is a nonrare (≥1% frequency) adverse effect were not
included in the high-probability cases sample. Smokers were
allowed as high-probability cases. Subjects who reported consum-
ing alcohol more than the sex-specific low-risk drinking limits as
defined by the National Institute of Alcohol Abuse and Alcohol-
ism (14 drinks per week for men, 7 drinks for women),24 using
marijuana on more than 2 occasions over the past 30 days (which
corresponds to definition of "frequent" user by Schulenberg
et al25), or using cocaine even once over the same period, were
not included as high-probability cases. Owing to the well-
documented association of depression and anxiety with sexual
dysfunction,26 only subjects whose HADS-Depression and HADS-
Anxiety scores were within the normal range (0–7) were included
in the high-probability cases sample. We defined genital anesthe-
sia as any degree of genital numbness as indicated by subject's re-
sponses ("somewhat numb," "very numb," or "completely numb")
to the corresponding question in the survey. Pleasureless orgasm
was defined as a state in which orgasm can be easily achieved
(ASEX-Orgasm ≤ 3) but is experienced as very unsatisfying
(ASEX-Satisfaction = 5).
Statistical Analysis
We used SPSS version 20 (SPSS Inc, Chicago, IL) for statis-
tical analyses. Descriptive statistics are expressed as rate (%) or
mean ± standard deviation (SD). Pearson and partial correlations
were calculated as appropriate. One-way analysis of variance
was used to determine whether different groups of case probability
differed significantly in dose/DDD. We used linear multivariate
regression analysis for the prediction of current sexual dysfunc-
tion severity (total ASEX score). P < 0.05 was considered
statistically significant.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015 Post-SSRI Sexual Dysfunction (PSSD)

RESULTS
Demographic and Clinical Characteristics
Five hundred thirty two (532) subjects consented to partici-
pate and completed the survey, within which 183 possible cases
(34.4%) were identified, including 23 high-probability cases
(12.6% of the possible cases). The possible cases sample included
143 men (78.1%) and 40 women (21.9%), with mean (SD) age
of 36.0 (11.4) years. Most subjects (53.6%) were married or in a
relationship. Most of them reported living in the United States
(43.7%) or the United Kingdom (13.7%), with sizable minorities
from Germany (7.1%), Canada (5.5%), and Australia (3.8%),
the rest being from other countries (30.0%). The medication taken
by the subjects when first experiencing sexual dysfunction was,
in order of frequency: citalopram (23.0%), escitalopram (16.4%),
paroxetine (15.8%), sertraline (14.8%), fluoxetine (13.7%),
venlafaxine (9.8%), duloxetine (2.7%), fluvoxamine (2.7%), and
desvenlafaxine (1.1%). Mean (SD) dose/DDD was 1.54 (0.91).
The mean (SD) duration of treatment was 28.1 (35.2) months
(range, 0.03–180 months), and the mean (SD) time since
quitting the medication was 41.1 (47.3) months (range, 1.0–
228.0 months). The mean (SD) ASEX score was 21.7 (3.8). The
mean (SD) HADS scores were 8.95 (4.99) and 8.96 (4.37) for
the depression and anxiety subscales, accordingly. The high-
probability cases are presented in Table 2. Most of the subjects
in this sample were men (82.6%), single (56.5%), of mean (SD)
age of 32.9 (11.4) years, most frequently from the United States
(21.7%), the Netherlands (17.4%) or Australia (13.0%). None of
them reported using duloxetine or milnacipran. The mean (SD)
dose/DDD was 1.74 (0.93). The medication was used for a
mean (SD) of 18.1 (21.5) months and discontinued 44.9 (50.1)
months before the survey. The mean (SD) ASEX score was 21.6
(3.8), and most subjects (78.3%) had genital anesthesia. The
HADS-Depression scores were 3.96 (2.38), and the HADS-
Anxiety scores were 4.04 (1.87).
Mood, Stress, and Sexual Dysfunction
The following data were calculated using the possible cases
sample (n = 183), except for data concerning case probability,
which was calculated using the entire survey sample (N = 532).
Depression (HADS-D score) was weakly correlated with current
sexual dysfunction severity (ASEX score; r = 0.32; P = 0.001),
but anxiety (HADS-A score) was not (r = 0.02; P = 0.845). De-
pression and anxiety levels were significantly correlated
(r = 0.47; P = 0.001). Subjects who were not in a relationship
had higher depression scores (mean [SD] HADS-D,10.00
[4.97] vs 8.03[4.85]; t = 2.71; P = 0.007) and somewhat more se-
vere sexual dysfunction (mean [SD] ASEX,22.38[3.73] vs 21.16
[3.75]; t = 2.188; P = 0.030). Genital anesthesia score correlated
significantly with sexual dysfunction severity (ASEX score;

TABLE 2. Demographic and Clinical Characteristics of the High-Probability Cases Sample (n = 23) of PSSD in Our Study

Reported Organic
Medical Conditions;
Daily Duration Time Since ASEX Specific HADS Reported Current
Case # Age (y) Sex Medication Dose (mg) of Use Quitting Score Symptoms scores (D;A) Medications
1 28 M Escitalopram 10 1 mo 2y 19 GA 1;4 Tinnitus; none
2 25 M Escitalopram 10 NR 3y 23 GA 5;6 None; none
3 30 M Desvenlafaxine 50 1.5 y 1.2 y 22 GA, PO 3;2 None; none
4 37 F Fluoxetine 20 2.5 y 10 y 26 GA 7;5 None; Zolpidem (for sleep)
5 34 M Venlafaxine 150 1y 5 mo 22 GA 7;3 None; none
6 28 F Citalopram 20 6 mo 3.5 y 21 – 3;4 None; none
7 31 M Sertraline NR 4 days 8 mo 22 GA 4;6 None; none
8 34 F Citalopram 20 2 mo 3y 25 GA 4;4 None*; none
9 45 F Fluoxetine 60 6 mo 12 y 25 GA 0;4 None; none
10 21 M Fluoxetine 40 6y 9 mo 21 GA 7;4 Scoliosis; none
11 32 M Paroxetine 20 2 mo 1.1 y 20 GA 7;5 None; none
12 33 M Citalopram 60 2y 4 mo 16 GA 1;1 None*; none
13 35 M Venlafaxine XR 150 4y 6y 10 PO 2;7 None; none
14 39 M Escitalopram 40 4y 3y 20 – 2;0 High cholesterol; Simvastatin
15 47 M Venlafaxine XR 75 5y 3.5 y 22 GA 3;3 None; none
16 34 M Fluoxetine 40 4 mo 16 y 15 – 5;3 None; none
17 41 M Escitalopram NR 6 mo 5y 20 GA 6;5 Mild headaches; none
18 26 M Sertraline 150 2y 3y 22 GA 3;6 None†; none
19 27 M Citalopram NR 3 mo 9 mo 22 GA, PO 1;1 None; none
20 27 M Citalopram 40 4 mo 4 mo 25 GA 1;3 None; none
21 33 M Fluoxetine 20 2 mo 2y 27 GA 7;5 None†; none
22 37 M Fluoxetine 20 8 mo 1 mo 30 GA 5;7 None; none
23 32 M Escitalopram NR NR 8.5 y 21 – 7;5 None; none
*Past smoker.
†
Current nonheavy smoker (≤20 cigarettes/d).
A indicates HADS-Anxiety score; D, HADS-Depression score; GA, genital anesthesia; mo, months; NR, not reported; PO, pleasureless orgasm; y,years.

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Ben-Sheetrit et al Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
r = 0.56; P = 0.001). Although initially found to correlate with
HADS-D scores (r = 0.286; P = 0.001), genital anesthesia was
not significantly correlated with depression after controlling for
ASEX score (r = 0.134; P = 0.071). There was no significant cor-
relation between anxiety and genital anesthesia (r = 0.08;
P = 0.296). Subjects who had pleasureless orgasm had higher
levels of depression (mean [SD] HADS-D,11.50[5.34] vs 8.56
[4.84]; t = −2.739; P = 0.007) but not anxiety (mean [SD]
HADS-A,10.08[5.12] vs 8.79[4.24]; t = −1.358; P = 0.176),
and this symptom predicted depression beyond ASEX score
(R = 0.435; F = 21.063; BPO = 4.474, BASEX = 0.529;
P = 0.001). Pleasureless orgasm predicted case probability inde-
pendently from sexual dysfunction and depression severity
(R = 0.213, F = 8.378, P = 0.001; BPO = 0.321, P = 0.001;
BASEX = 0.021, P = 0.001; BHADS-D = −0.009, P = 0.089). Time
since quitting the medication did not correlate significantly with
ASEX scores (r = 0.06; P = 0.396) but correlated with decreased
lubrication severity in women (r = 0.45; P = 0.004), even after
controlling for age, depression, and anxiety (r = 0.478;
P = 0.003). The following were entered into linear multivariate
regression analysis (method Enter) as independent variables in
the prediction of current sexual dysfunction severity (total ASEX
score): age, sex (as dummy variable, male = 1), relationship status
(as dummy variable, in a relationship = 1), HADS-Depression
score, HADS-Anxiety score, and genital anesthesia score. A sig-
nificant model was retrieved (R = 0.631, R2 = 0.399,
F = 19.452, P = 0.001; BAge =0.040, P = 0.056; BSex = −1.754,
P = 0.002; BRelationship = −0.488, P = 0.313; BDepression = 0.185,
P = 0.001; BAnxiety = −0.079, P = 0.186; BGenital anesthesia =
1.716, P = 0.000), explaining 39.9% of the total variance of
ASEX score.
Exposure-Response Relationship
Dose/DDD ratios did not differ significantly between case
probability groups in one-way analysis of variance (noncases,
1.50 ± 1.00; possible cases, 1.54 ± 0.91; high-probability cases,
1.74 ± 0.93; df = 2, F = 0.523; P = 0.59). Dose/DDD and treat-
ment duration did not correlate significantly with ASEX score
(r = − 0.90; P = 0.30).
DISCUSSION
The first objective of this work was to identify and character-
ize a series of cases of PSSD, challenging the commonly accepted
assumption that antidepressant-associated sexual dysfunction in-
variably resolves upon drug discontinuation. Using a structured
self-report questionnaire and a validated scale for the assessment
of sexual function (ASEX), we were able to identify 183 subjects
who reported persistent treatment-emergent sexual dysfunction
implicating a single SSRI/SNRI (ie, possible cases). Twenty three
(12.6%) of these subjects remained after taking into account many
alternative factors relevant to sexual dysfunction, including age,
medical conditions, current medical therapy, use of addictive sub-
stances, depression, and anxiety (ie, high-probability cases).
There seems to be an inherent diagnostic challenge in PSSD,
illustrated by the following typical scenario. A patient sees a
doctor for depression or anxiety and is given an antidepressant.
Sexual dysfunction emerges, eventually leading to drug discontin-
uation. When the patient realizes that the sexual dysfunction per-
sists, he or she pays their doctor a visit. At this point, what would
the physician assume as the cause of the sexual disturbance? If the
patient is not currently on antidepressants and is obviously
stressed about his or her situation, then the re-emergence of de-
pression or anxiety is naturally presumed to be the cause.
276 www.psychopharmacology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
However, if the patient resumes antidepressant treatment, then
the current drugs are assumed to be the culprit. Regardless of
how this condition is managed, the persistent nature of an impair-
ment induced by past pharmacological treatment is almost always
confounded. There are 2 notable exceptions, however. First, when
a patient develops treatment-emergent sexual dysfunction as de-
pression and anxiety levels markedly improve in response to anti-
depressants, it could be argued that this should be considered as
evidence that the sexual dysfunction is caused by the treatment
rather than the disorder being treated. The retrospective nature
of our study does not allow capturing this course of events, al-
though it may prove of great diagnostic value to the physician.
Second, some patients experience drug-free remissions of their
depressive or anxiety disorders (either spontaneously or in re-
sponse to psychotherapy), allowing to attribute current sexual dys-
function to previous pharmacological therapy. We aimed to
demonstrate this point by including in the high-probability cases
sample only subjects whose HADS-Depression and HADS-
Anxiety scores were within normal range. A third potential aid
to the diagnosis of PSSD was suggested by Bahrick,7 who pointed
out that certain symptoms such as genital anesthesia and pleasure-
less orgasm seem to be associated with SSRI/SNRI treatment but
are not known to be associated with any of the conditions for
which these drugs are prescribed. Since most of the participants
in our study (both possible cases and noncases) reported taking
an SSRI/SNRI in the past, we cannot substantiate nor disprove this
hypothesis. It is important to note, however, that genital anesthesia
did not correlate with either depression (when controlled for
ASEX score) or anxiety severity in any of the samples in our study
(totaling in 532 subjects), raising doubt about a psychogenic etiol-
ogy. We found genital anesthesia to be a prominent predictor of
sexual dysfunction severity, a finding which could be explained
in 2 ways. First, genital anesthesia probably causes or worsens
sexual dysfunction. Decreased sensation is likely to lead to de-
creased pleasure, which can result in erectile dysfunction or de-
creased lubrication, and the latter may impede libido and arousal
by means of negative feedback. Second, these 2 phenomena
may share a common etiological mechanism in SSRI-treated pa-
tients, namely, enhanced serotonergic load (see below for a brief
discussion on neurotoxicity). Unlike genital anesthesia, pleasure-
less orgasm was an independent predictor of both depression se-
verity and case probability. If further studies confirm that this
symptom is indeed associated with both depression (as found in
the ASEX validity study17) and SSRI treatment, its value in the di-
agnosis of PSSD may be limited. We found a significant associa-
tion between depression and current sexual dysfunction severity,
consistent with the literature.26 Depression may develop as a com-
plication of persistent sexual dysfunction, or it may play a contrib-
uting factor in its etiology, among other factors (including prior
pharmacotherapy). Case probability was not significantly associ-
ated with dose/DDD. This finding could be interpreted in 2 ways.
First, PSSD may represent an idiosyncratic drug reaction and may
not be dose dependent. The rarity, severity, and unpredictability of
this phenomenon support this option. Second, if PSSD is dose de-
pendent, lack of significance may have resulted owing to the small
number of high-probability cases (n = 23), or secondary to an in-
herent artifact created by the case definitions. Possible cases have
by definition more severe sexual dysfunction compared to
noncases, which may indicate low tolerability to SSRIs/SNRIs,
and hence may not have reached higher doses in the first place.
Moreover, high-probability cases have normal scores on both
HADS-Depression and HADS-Anxiety, although they are not
currently on antidepressants. Such patients who have achieved
drug-free remissions may have a less severe disorder (depression
or anxiety), requiring lower doses to begin with.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 35, Number 3, June 2015
The constellation of sexual dysfunction and genital anes-
thesia persisting after SSRI use suggests that serotonergic neuro-
toxicity may play a role in PSSD. It is worth noting that
neurotoxicity induced by 3,4-methylenedioxymethamphetamine,
which stimulates the release and inhibits the reuptake of sero-
tonin, is associated with sexual dysfunction persisting long after
abstinence (data indicate that axonal damage is involved).27
Whereas the potency of the agent is probably the cause in 3,4-
methylenedioxymethamphetamine–associated neurogenic sexual
impairment, we can presume that individual vulnerability may
have a prominent role in PSSD, as most patients treated with
SSRIs never develop the syndrome. Persistent sexual dysfunc-
tion has been described in some patients treated with finasteride
(post-finasteride syndrome), a condition that has a similar symp-
tom profile to PSSD.14,28–30 Although the mechanism of post-
finasteride syndrome is unknown, it could be speculated that
since this 5α-reductase inhibitor decreases the rate of conversion
of testosterone to the more potent dihydrotestosterone (DHT), it
might hamper the direct androgen-receptor-dependent neuro-
protective effects of androgens in the brain31,32 and may thus
eventually lead to persistent sexual dysfunction.
The current study has several limitations. First, the specific
characteristics of the study population, including demographic
characteristics, medical history, and willingness to volunteer to
participate in the study, may represent a selection bias, which does
not allow generalization of the findings. However, such gene-
ralization was not an objective of this preliminary study. The ret-
rospective nature of study may result in recall bias, in which
patients with sexual dysfunction are more prone to remember
previous use of antidepressants. Self-report and anonymity may
result in report biases, including underreporting of sexual dys-
function before therapy. The survey may have selectively attracted
respondents who wished to communicate about their disorder,
leading to a bias favoring a higher prevalence and severity of
sexual dysfunction. Conversely, it is possible that individuals with
severe or significant sexual dysfunction selectively avoided the
survey, leading to an underestimation of prevalence and severity.
It is thus clear that the current study cannot determine the inci-
dence of PSSD. Double participation in the study was prevented
by the survey software, and the study was conducted in a closed
forum, limiting external abuse of the survey. Despite the afore-
mentioned limitations, the current investigation adds to the emerg-
ing evidence that SSRI/SNRI-induced sexual dysfunction persists
in some patients beyond drug discontinuation and suggests that
this phenomenon may not be fully explained by alternative non-
pharmacological factors, including depression and anxiety. Physi-
cians should assess sexual function prior, during, and also after
treatment with antidepressants and be aware of the possibility of
PSSD. As it may have major implications on the informed consent
and choice of therapy in depressive and anxiety disorders, further
research is warranted.
AUTHOR DISCLOSURE INFORMATION
The authors declare no conflicts of interest.
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