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Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry 62(Suppl 3): 10-21

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Abstract and Figures

Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), venlafaxine, and clomipramine, are frequently associated with sexual dysfunction. Other antidepressants (nefazodone, mirtazapine, bupropion, amineptine, and moclobemide) with different mechanisms of action seem to have fewer sexual side effects. The incidence of sexual dysfunction is underestimated, and the use of a specific questionnaire is needed. The authors analyzed the incidence of antidepressant-related sexual dysfunction in a multicenter, prospective, open-label study carried out by the Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. The group collected data from April 1995 to February 2000 on patients with previously normal sexual function who were being treated with antidepressants alone or antidepressants plus benzodiazepines. One thousand twenty-two outpatients (610 women, 412 men; mean age = 39.8 +/- 11.3 years) were interviewed using the Psychotropic-Related Sexual Dysfunction Questionnaire, which includes questions about libido, orgasm, ejaculation, erectile function, and general sexual satisfaction. The overall incidence of sexual dysfunction was 59.1% (604/1022) when all antidepressants were considered as a whole. There were relevant differences when the incidence of any type of sexual dysfunction was compared among different drugs: fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction. The incidence of sexual dysfunction with SSRIs and venlafaxine is high, ranging from 58% to 73%, as compared with serotonin-2 (5-HT2) blockers (nefazodone and mirtazapine), moclobemide, and amineptine.
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SSRI-Induced Sexual Dysfunction:
Fluoxetine, Paroxetine, Sertraline, and
Fluvoxamine
in
a
Prospective, Multicenter,
and
Descriptive Clinical Study
of
344
Patients
ANGEL
L.
MONTEJO-GONaLEZ, G.
LlORCA,J.
A.
IZQUERDO,
A.
LEDESMA, M. BOUSONO,
A.
CALCED0,J.
L.
CARRASC0,J.
CIUDAD,
E.
DANIEL,
J.
DE
LA
GANDARA,
J.
DERECHO,
M.
FRAhKO,
M.
J.
GOMEZ,
J.
A.
MACIAS,
T.
MXRTm,
I?
PEREZ,J.
M.
SANWEZ,
S.
SANCHEZ,
and
E.
WCENS
The
authors analyzed the
incidence
of
sexual dysfunction
(SO)
with
different selective serotonin reuptake inhibitors
(SSRIs;
jluoxetine,
jluvoxamine, paroxetine, and sertraline) and
hence
the qualitative
and quantitative changes
in
SD
throughout time
in
a prospective
and multicenter study. Outpatients
(192
women and
152
men; age
=
39.6511.4 years) under treatment with
SSRIs
were interviewed
with an
SD
questionnaire designed
for
this purpose by the authors
and that included questions about the following: decreased libido,
delayed orgasm
or
anorgasmia, delayed ejaculation, inability to ejac-
ulate, impotence, and general sexual satisfaction. Patients with the
following criteria were included: normal sexual function before
SSRI
intake, exclusive treatment with
SSHs
or
treatment associated with
benzodiazepines, previous heterosexual
or
self-erotic current sexual
practices. Excluded were patients with previous sexual dysfunction,
association
of
SSRIs
with neuroleptics, recent honnone intake, and
signajicant medical illnesses. There was a signajicant increase
in
the
incidence
of
SD
when physicians asked the patients direct questions
(58%)
versus when
SD
was
spontaneously reported (14%). There
were some signijicant differences among d ifferent
SSRls:
paroxetine
provoked more delay
of
orgasm
or
ejaculation and more impotence
than jluvoxamine, jluoxetine and sertraline
(2,
p
C
.05).
Only
This study was presented in part at the 149th Annual Meeting
of
the American Psychiatric Associa-
tion, New York, May 1996 and at the Tenth World Congress
of
Psychiatry, Madrid, Spain, August
1996.
Address correspondence
to
Dr.
Angel
L.
Montejo-Gonzfdez, Servicio de Psiquiatria,
Hospital
Universitario de Salamanca, Paseo de
S.
Vicente
58,
37007
Salamanca, Spain.
Journal
of
Sex
&
Marital
Therapy,
Vol.
23,
No.
3,
Fall
1997
Q
Brunner/Mazel
176
The presence of comorbid disruptive behavior disorders
(oppositional defiant disorder [ODD] or conduct dis-
order [CD]) within children with attention-deficit/
hyperactivity disorder (ADHD) has been well estab-
lished for several decades (e.g., see Bird et al., 1990;
Hinshaw, 1987). Only in the past decade has it become
apparent that internalizing disorders (both anxiety and
depressive disorders) also commonly co-occur with
ADHD. Thus, both clinical and epidemiological studies
have consistently shown that as many as one third of
children with ADHD have co-occurring anxiety dis-
ADHD Comorbidity Findings From the MTA Study:
Comparing Comorbid Subgroups
PETER S. JENSEN, M.D., STEPHEN P. HINSHAW, P
H
.D., HELENA C. KRAEMER, P
H
.D.,
NILANTHA LENORA, B.S., JEFFREY H. NEWCORN, M.D., HOWARD B. ABIKOFF, P
H
.D.,
JOHN S. MARCH, M.D., L. EUGENE ARNOLD, M.D., DENNIS P. CANTWELL, M.D.,
C. KEITH CONNERS, P
H
.D., GLEN R. ELLIOTT, M.D., LAURENCE L. GREENHILL, M.D.,
LILY HECHTMAN, M.D., BETSY HOZA, P
H
.D., WILLIAM E. PELHAM, P
H
.D., JOANNE B. SEVERE, M.S.,
JAMES M. SWANSON, P
H
.D., KAREN C. WELLS, P
H
.D., TIMOTHY WIGAL, P
H
.D.,
AND
BENEDETTO VITIELLO, M.D.
ABSTRACT
Objectives: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comor-
bid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders
(anxiety and/or depression), or with both, should constitute separate clinical entities.Determination of the clinical significance
of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making,
treatment planning, and treatment outcomes. Method: Drawing upon cross-sectional and longitudinal information from 579
children (aged 7–9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of
Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD sub-
jects with and without comorbid internalizing disorders and ODD/CD.Results: Substantial evidence of main effects of internal-
izing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and
ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no
ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments.Children with ADHD-only or
ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral
treatments), while children with multiple comorbid disorders (anxiety
and
ODD/CD) responded optimally to combined (med-
ication and behavioral) treatments. Conclusions: Findings indicate that three clinical profiles, ADHD co-occurring with inter-
nalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX),
ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD +
ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from “pure” ADHD with
neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classifi-
cation options.
J. Am. Acad. Child Adolesc. Psychiatry
, 2001, 40(2):147–158. Key Words: attention-deficit/hyperactivity dis-
order, attention deficit, anxiety, comorbidity, treatment, outcomes, classification, diagnosis.
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 40:2, FEBRUARY 2001 147
Accepted September 26, 2000.
Dr. Jensen is Professor of Psychiatry, Department of Psychiatry, Columbia
University College of Physicians and Surgeons; Dr. Hinshaw is Professor of
Psychology, Department of Psychology, University of California at Berkeley; Dr.
Kraemer is Professor of Biostatistics, Stanford University; Ms. Lenora is a med-
ical student, George Washington University School of Medicine. Other authors
affiliations are listed in the MTA Cooperative Group acknowledgment that
appears at the end of the text.
Reprint requests to Dr. Jensen, Center for the Advancement of Children’s
Mental Health, Columbia University/NYSPI, 1051 Riverside Drive, Unit 78,
New York, NY 10032; e-mail: pj131@columbia.edu.
0890-8567/01/4002-0147q2001 by the American Academy of Child
and Adolescent Psychiatry.
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SSRl-Induced
Sexual
@sfunction
177
24.5%
of
the patients had a good tolerance
of
their sexual dysfunc-
tion. Twelve male patients who suffered @om premature ejaculation
before the treatment preferred to maintain delayed ejaculation, and
their sexual satisfaction, and that
of
their partners, clearly improved.
Sexual dysfunction was positively correlated with dose. Patients expe-
rienced substantial improvement
in
sexual function when the dose
was diminished
or
the drug was withdrawn. Men showed more inci-
dence
of
sexual dysfunction than women, but women
3
sexual dysfunc-
tion was more intense than men's. In only
5.8%
of
patients, the
dysfunction disappeared completely within
6
months, but
81.4%
showed no improvement at all by the end
of
this period. Twelve
of
15
patients experienced total improvement when the treatment was
changed to mclobemide
(450-600
mg/day), and
3
of
5
patients im-
poved when treatment was changed to amineptine
(200
mg/day).
Although a loss of libido is common amon atients suffering from
depression, many researchers since the
1970s'-
have studied the occur-
rence of sexual dysfunction
(SD)
in patients taking antidepressant drugs.
The incidence seems higher with heterotricyclic drugs (especially seroto-
nin reuptake inhibitors such as clomipramineI6 and, to a lesser extent,
drugs with a predominant effect on noradrenaline reuptake, such as
desipramine or n~rtriptyline'~)
,
as well as monoamine oxidase inhibitors
(MAOIs)
,
selective serotonin reuptake inhibitors
(SSRIs)
,
and venlafax-
ine. Others, like bupropion, nefazodone, moclobemide, and amineptine,
seem to have few adverse effects on sexual function. This seems to indi-
cate that the neurochemical mechanism involved in the clinical effect of
each
of
these substances may be directly related to the onset, or other-
wise,
of
secondary sexual dysfunction.
Extremely disparate incidence
of
SD
has been found, varying between
1%
and
96%,
although most of the data published pertain to short series
reports from patients or to anecdote.'a21 Sexual dysfunction can include
a loss
of
libido and problems in initiating and maintaining sexual inter-
course, ejaculation, orgasm, erection, and vaginal lubrication. Other ad-
verse, albeit less frequent, effects (painful ejaculation,22 spontaneous
orgasms associated with yawning,2s25 vaginal anesthesia,26 penile anesthe-
~ia,'~ prolonged e'aculation, increased libido, and priapism, associated
with trazodoneza2'and paroxetine3') have also been observed. It has been
shown that clomipramine (with a potent serotonin reuptake profile) can
cause anorgasmia in a controlled study and that sexual dysfunction sec-
ondary to treatment often goes unnoticed unless interviews are con-
ducted
with
the intention of exploring this side effect."
Since
SSRIs
came onto the market, reports about secondary sexual
dysfunction have increased significantly and have triggered a large num-
ber
of
articles.3245 Placebocontrolled studies have revealed a clear rela-
tionship between the use of antidepressants and the occurrence of sexual
dysfunction,
as
incidence is practically nil on placebo treatment.46 The
effect has even been shown in healthy volunteers."
P
178
Journal
of
Sex
&
Marital
Therapy,
Vol.
23,
No.
3,
Fall
1997
Serotonin appears to play
a
very important role in the development
of
SD
by inhibiting libido, ejaculation, and orgasm.48 This effect can be
explained, especially at the central level, as there is evidence that seroto-
nin causes a decrease in dopamine levels (a neurotransmitter enhancing
sexual function) in the central nervous system of laboratory
animal^.^'
The use of
MDMA
(better known as ecstasy) causes the central release
of
serotonin and dopamine, resulting in increased libido and sexual
satisfaction (through dopamine release) and delayed or inhibited ejacu-
lation and orgasm (through serotonin activation)
.50
The peripheral
blocking
of
alpha-adrenergic and cholinergic receptors in the genitouri-
nary tract also impairs sexual function. Antidepressants that have a po-
tent anticholinergic or alpha-l receptor blocking action are highly
capable of altering the sexual excitation process.51 Cholinergic fibers
help in the filling of the corpora cavernosa (the anticholinergic effect
results in absence
of
erection), whereas adrenergic alpha-1 receptors
help in emptying them (adrenergic alpha-1-blockers such as trazodone
cause priapism)
.52
Although the actual mechanism behind these effects
is somewhat obscure, there is clear evidence that
SSRIs,
owing to the
increase in serotonergic transmission, affect sexual behavior in humans,
especially insofar as libido and attaining orgasm is
In a
placebo-controlled study, a higher abnormal ejaculation incidence was
found with paroxetine than with imi~rarnine.~~
So
far, no significant
differences have been found in the sexual dysfunction caused by the
various
SSRIs,
despite the differences between them in terms of pharma-
cokinetics, selectivity of action, and clinical potency.
For improving sexual dysfunction secondary to the use of antidepres-
sant~~'-~' (loss of libido, delayed orgasm or ejaculation, anorgasmia, and
impotence), several methods have been proposed. These methods in-
clude waiting for spontaneous remission over time,m reducing the dos-
age, adding
an
antidote (cypr~heptadine,"~' y~himbine,~'-~' pent-
~xlfylline,'~ amantadine,75-77 bu~pirone,'~ betanech~l,~~' Ginkgo biloba
extract,@ etc.)
,
switching to another drug with a different pharmacologi-
cal profile (bupropi~n,~~~~ desipramine,86 rno~lobemide,~~ or nefazo-
donea8), or suspending the antidepressant treatment for
48-72
hr prior
to sexual intercourse and continuing with it after~ard.~~ It has been re-
ported that cyproheptadine may reverse the clinical antidepressant effect
of fl~oxetine?~'~
The incidence of
SD
is often undere~timated,~~ as spontaneous notifi-
cations are rare, although it can significantly affect treatment compli-
an~e.'~'~ Technical data sheets for antidepressants report a very low
incidence of sexual dysfunction
(2-16%),
although in clinical practice
it appears to be much higher.
The objectives of this study were (a) to prospectively analyze, using a
questionnaire, the actual incidence of sexual dysfunction in patients
on
SSRI
treatment and (b) to study and compare the occurrence of these
adverse effects with fluoxetine, paroxetine, fluvoxamine, and sertraline.
SSN-Induced
Sexual
Dysfunction
179
METHOD
A questionnaire on sexual dysfunction (see appendix) was prepared
for a prospective, observational, open, and multicenter design. It was
applied to
344
outpatients who met the inclusion criteria
(192
women
and
152
men of mean age
39.65 11.4
years) at a direct clinical interview
held when they visited the clinic. The study
was
carried out from April
1995
to September
1996.
A
group of
20
psychiatrists from several hospi-
tals and mental health services in Spain had previously been trained to
apply the questionnaire correctly. Patients were interviewed every
1
or
2
months if they responded to and tolerated the medication well. Special
attention was made to the patient’s sexual function before starting
SSRI
treatment and to the subsequent onset of
SD.
A
form containing demo-
graphic (name, age, civil status, sex, etc.) and clinical data (diagnostic
DSM-Ncriteria including personality disorders, months from the begin-
ning of treatment, associated medication) was entered into the database
by the coordinator of this study (Angel
L.
Montejo-Gonzglez)
.
The follow-
ing variables were assessed according to severity or frequency: loss of
libido
(0
=
nil,
1
=
mild,
2
=
moderate,
3
=
severe),
delayed orgasm or
ejaculation
(0
=
nil,
1
=
mild,
2
=
moderate,
3
=
severe),
absence
of
orgasm or ejaculation
(0
=
never,
1
=
occasionally,
2
=
often,
3
=
always),
impotence
(0
=
never;
1
=
occasionally,
2
=
often,
3
=
always),
and
patient’s tolerance of the sexual dysfunction
(0
=
good,
1
=
fuir,
2
=
poor).
Data were collected whether the adverse effect was spontaneously
reported or not and with regard to improvement of the
SD
on a reduced
dosage, over time, and with a switch to other antidepressants
of
a differ-
ent neurochemical profile (moclobemide and amineptine).
We included patients (a) with normal sexual function prior to taking
SSRIs,
(b) being treated with an
SSRI
alone or combined with a benzodi-
azepine, (c) who had previously engaged in regular and satisfactory het-
erosexual or self-erotic sexual practices, and (d) who experienced
SD
within
2
months following introduction of an
SSRI.
We excluded patients
(a) with prior sexual dysfunction, (b) being treated with a combination
of
SSRI
and neuroleptics, (c) receiving treatment with hormones or any
other drug capable of interfering with sexual relations, (d) who had
significant intercurrent diseases affecting sexual function, or (e) who
abused alcohol and other illicit drugs.
The patients were suffering from different psychiatric disorders but
predominantly from mood disorders (see Table
1).
The age range was
18-71
years. The age of patients in the paroxetine group
(41.97)
was
appreciably higher than that of patients in the fluoxetine group
(38.13,
p
<
.05).
The mean doses used were similar for the paroxetine and
fluoxetine groups. The time (in months) elapsed since the onset of ther-
apy also was similar (see Table
2).
Statistical analysis was carried out on a Macintosh computer (Program
Stat View
512)
to examine the differences between the diverse variables
involved and
to
compare results between groups.
A
95%
probability was
assumed for rejecting the null hypothesis.
A
parametric statistic (analysis
180
Journal
of
Sex
&Marital
Therapy,
Vol.
23,
No.
3,
Fall
1997
TABLE
1
Diagnostic Distribution
(N
=
344)
Diagnosis
Male Female
(n
=
152)
(n
=
192) Total
Major depression
104 138 242
Dysthymic disorder 8 23 31
Panic disorder
10
18 28
Obsessive-compulsive disorder 16
10
26
Generalized anxiety disorder
5
7 12
Bulimia
0
7
7
Personality disorder
6
4
10
No&.
Some patients had more than one diagnosis.
TABLE
2
Age, Dosage, and Number of Months on Medication
Fluoxetine Paroxetine Fluvoxamine Sertraline
Variable
(n
=
160)
(n
=
85)
(n
=
42)
(n
=
57)
Age"
38.13 41.97
39.95 39.80
Dosage 22.76 23.30
114.30 89.40
Months
on
medication 6.5
6.8 8.1 4.9
a
Significant difference between paroxetine and fluoxetine
(p
<
.05).
of variance, ANOVA) was used for continuous variables (age, time taking
an
SSRI,
and dosage of treatment), and a nonparametric statistic (chi-
squared test) was used for comparing categorical data (sexual func-
tioning).
RESULTS
AND
DISCUSSION
There was a very significant increase in the incidence of
SD
when
patients were directly questioned according to the
SD
questionnaire de-
signed by the work group
(58.14%)
as compared with when patients
reported SD spontaneously as an adverse effect
(14.2%).
Figure
1
shows the incidence of onset of some form
of
SD for each
SSRI
separately. Of the
344
patients,
200
reported some type of sexual
dysfunction. The number of reports of adverse sexual effects was higher
for paroxetine
(64.71
%),
followed by fluvoxamine
(58.94%),
sertraline
(56.4%),
and fluoxetine
(54.38%),
although there were no significant
differences
(x2
test).
Table
3
shows the incidence of each
of
the
SD
effects observed (loss
of libido, delayed orgasm or ejaculation, anorgasmia, or impotence) for
each
SSRI.
Compared with the other
SSRIs,
paroxetine had the highest
incidence of adverse sexual effects, although only impotence (impossibil-
ity of erection in the male or of adequate vaginal lubrication in the
female) was significantly present.
SSH-Induced
Sexual
Dysfunction
181
Spanish
Group
to
study
psychophmawlogy
-
related
sexual
dysfunction
(19%).
AL.
Montejo
h4D
Coordinator.
Figure
1.
Comparative incidence
of
sexual dysfunction
with
selective serotonin
reuptake inhibitors
(SSRIs)
.
TABLE
3
Observed Frequency of Sexual Dysfunction
~~ ~
Fluoxe tine Paroxetine Fluvoxamine Sertraline
Dysfunction
(n
=
160)
(n
=
85)
(n
=
42)
(n
=
57)
Decrease
of
libido”
48.1% 57.6%
40.5% 45.6%
Delay
of
orgasm or ejaculationa
51.1%
58.8%
57.4% 45.6%
Anorgasmia
or
no
ejaculation”
34.4% 48.2%b 30.9% 36.8%
Impotence”
16.2% 34.1%b
09.5% 15.8%
Tolerance
of
sexual dysfunctionc
0.97 1.22
1
.oo
1.14
a
Intensity scale:
0
=
nil,
1
=
mild,
2
=
derute,
3
=
severe.
Significantly different
from
other
SSRIs,
p
<
.05.
Intensity scale:
0
=
good,
1
=
fair,
2
=
poor.
Patient tolerance to the sexual dysfunction was measured on a scale
of
3
(0-1-2),
where
0
=
good: no problems an the patient despite the pesence
of
sexual dysfunction,
1
=
fair: patient discontent although he/she does not
intend to discontinue the treatment for this reason,
and
2
=
poor: patient very
concerned about the sexual dysfunction and seriously considering whether to
continue the treatment as a result
of
it.
Twenty-four and a half percent of
the patients showed good tolerance, whereas
42.5%
and
32.9%
showed
fair or poor tolerance. These results indicate the need for directly ques-
tioning patients concerning the presence of SD secondary to
SSRI
treat-
ment because of the impact it has on their quality
of
life and on potential
noncompliance with treatment. Treatment discontinuation for this rea-
son has been reported in
2
of
7
patients on ~ertraline,’~ although these
182
Journal
of
Sex
&?Marital
Therapy,
Vol.
23,
No.
3,
Fall
1997
figures could be higher as patients do not usually return to treatment
after giving up the medication.
One group of patients showed a high tolerance of the
SD.
Those pa-
tients who suffered from premature ejaculation before the treatment
(12
male patients) preferred to maintain delayed ejaculation. Their sexual
satisfaction, and their partners', clearly improved following
SSRI
treat-
ment
(5
patients were taking fluoxetine,
3
paroxetine,
2
sertraline, and
2
fluvoxamine)
.
These data coincide with reports from other researchers
concerning the benefits of delayed ejaculation in some patients with
premature ejaculation who were using fluoxetine, paroxetine, or sertra-
line96100 or even clomipramine."' Delayed ejaculation has even been
shown in double-blind trials on paroxetine versus placebo for treating
premature ejaculation.'" In addition, loss of libido has proved to be
beneficial in patients suffering from compulsive exhibitionism, who were
treated with fluv~xamine.'~~
SSRIs
possibly have an important role to play
in the treatment of disorders resulting from an increase in libido or
sexual obsession, although controlled studies to prove it are needed. In
our sample,
2
patients with an obsessive disorder involving predomi-
nantly intrusive, unpleasant ideas and thoughts of a sexual nature showed
a clear improvement under fluoxetine treatment
(20
and
40
mg/day)
.
Only
14%
of the patients suffering from sexual dysfunction
(28/200)
spontaneously reported this adverse effect, precisely those whose dysfunc-
tion was more severe and caused greater discomfort. This would explain
the low incidence of sexual dysfunction in the data sheets of the
SSRIs
analyzed (ranging from
1-2%
for fluoxetine, fluvoxamine, and paroxet-
ine and
16%
for sertraline). It is well
known
that most of clinical trials
on pharmaceutical preparations only take into account the sideeffects
reported spontaneously by patients. Many patients are too embarrassed
to report a sexual dysfunction to the physician, which means the figures
on the incidence of this effect remain very low.
Figure
2
shows the severity of the dysfunction caused by each
SSRI
for
each group of symptoms. The severity scale consisted of four grades:
0
=
nil,
1
=
mild,
2
=
moderate,
3
=
severe.
No
differences were found
between the drugs for severity of loss of libido (paroxetine
=
1.80,
sertra-
line
=
1.72,
fluoxetine
=
1.86,
fluvoxamine
=
1.55)
or delayed orgasm
or ejaculation (paroxetine
=
2.32,
sertraline
=
2.13,
fluoxetine
=
2.03,
fluvoxamine
=
2.15).
However, paroxetine caused significantly more an-
orgasmia or absence of ejaculation
(M
=
1.69)
than
sertraline
(M
=
1.44),
fluoxetine
(M
=
1.26),
and fluvoxamine
(M
=
1.00),
~~(€30,
N
=
55)
=
9.295,
p
<
.05.
Where the impotence variable
was
concerned,
paroxetine proved to have a significantly more severe effect
(M
=
0.91)
than the other
SSRIs
(for fluoxetine,
M
=
0.44;
fluvoxamine,
M
=
0.27,
and sertraline,
M
=
0.44), ~'(80,
N
=
55)
=
10.34,
p
C
.05.
This result
can be explained by paroxetine's greater capacity to bind to cholinergic
receptors, as it is
5
to
160
times more powerful in its cholinergic blockin
capacity than sertraline, fluoxetine, and fluv~xamine.'~~ Prior
'
have not shown significant differences between one particular class of
SSRI-related sexual dysfunction, but the small size of those studies did
F
SSN-Induced Sexual Dysfunction
183
Severity:
Om
nll;
I=
&Id;
2=
moderate;
3-
severe.
Spanish Group
to
Study psychopharmacology -related
Sexual
Dysfunction
(1996). Montejo,
AL.
Coordinator.
*
WroXctinc
vs
Fluoxetim
and
nuvoxamim
**
Famxetine vs Fluoxetine. Fluvoxaminc
and
Sertraline.
Figure
2.
Seventy of sexual dysfunction
with
selective serotonin reuptake inhibi-
tors
(SSRIs).
not permit a definite conclusion. In our opinion, some differences be-
tween
SSRIs
may appear when the size
of
the sample is greater.
Hardly any data are available on the comparison of sexual dysfunction
between the sexes. Most studies refer to men or women ~eparate1y.l~~ The
men in
this
sample suffered a higher incidence of SD
(94/152
=
61.84%)
than the women
(106/ 192
=
52.5%),
although the women scored higher
TABLE
4
Sexual Dysfunction: Comparison Between Sexes
Table
4
shows the differences found between men and women
Dysfunction
Female
(n
=
106)
Male
(n
=
94)
p
for
x2
Decrease of libido”
Delay
of
orgasm
or
ejaculation”
Anorgasmia
or
no ejaculation”
Impotence”
Toleranceb
Dosage (mg/day)
Months
elapsed
Age
2.06
2.44
1.81
0.62
1.14
42.1
6.5
36.9
1.44
2.04
0.88
0.46
1.01
50.0
6.3
43.7
.0001
.05
.0001
ns
ns
ns
ns
.0001
“Intensity scale:
0
=
nil,
1
=
mild,
2
=
moderate,
3
=
severe.
bIntensity scale:
0
=
pod,
1
=
fair,
2
=
poor.
184
Journal
of
Sex
0.'
Marital Therapy, Vol.
23,
No.
3,
Fall
1997
TABLE
5
Sexual Dysfunction: Comparison of Marital Status
Single Married
Variable
(n
=
52)
(n
=
148)
p
for
x2
Delayed orgasm
or
ejaculation"
1.80
2.21
.022
Age
30.1
41.6
.0001
Note.
Only variables that
differed
significantly are
shown.
'Intensity scale:
0
=
nil,
1
=
mild,
2
=
moderate,
3
=
seuere.
on severity. There were some differences between men and women con-
cerning the severity of loss of libido, delayed orgasm or ejaculation, and
anorgasmia or failure to ejaculate,
~~(199,
N
=
200)
=
8.35,
p
<
.05.
Sexual dysfunction was more severe in women than in men. There were
no differences regarding the presence of impotence or difficulties in
initiating and maintaining sexual excitation.
No
significant differences
were found in the drug dosage used or the treatment period. Tolerance
of the dysfunction was similar in both sexes. The women's age was sig-
nificantly lower
(36.9)
than the men's
(43.7;
p
=
.OOOl).
Other authors
have observed that women are usually more reluctant about reporting
adverse sexual effects than are men,""j
so
it is especially important to
monitor their sexual function after starting treatment with an antidepres-
sant drug.
When the sample was divided into groups according to marital status,
single
(n
=
52)
versus married
(n
=
148),
significant differences were
noted only with regard to age, the married people of course being sig-
nificantly older, and delayed orgasm, which was more severe in the mar-
ried group (see Table
5).
The inclusion criteria accepted patients' concomitant medication with
benzodiazepines for practical and clinical reasons, as it is difficult to find
patients who do not need anxiolytics during treatment, at least for a
while. The role of benzodiazepines in sexual function
is
not quite clear.
There are conflicting studies in which no dysfunction occurs under diaze-
pam or chlorazepate treatment,'07 whereas others have reported delayed
ejaculation with chlordiazepoxide,Io8 alpraz~lam,'~~-"~ and 10razepam."~
To clarify the incidence of sexual dysfunction among patients taking
anxiolytics, we separated them into
two
groups: those taking benzodiaze-
pines with an
SSRI
(n
=
22'7)
and those taking only an
SSRI
(n
=
117).
The benzodiazepines used were distributed as follows: alprazolam
=
60,
chlorazepate
=
48,
ketazolam
=
38,
diazepam
=
21,
lorazepam
=
19,
bentazepam
=
16,
and others
=
25.
The incidence of SD was higher in
those not taking anxiolytics
(67/117
=
57.3%)
than in those taking
benzodiazepines
(121/227
=
53.3%).
The data suggest that the use of
concomitant medication cannot be held responsible for this side effect.
No
other concomitant medication (other associated antidepressants or
neuroleptics) in patient inclusion criteria was permitted. Other research-
ers have used large series (Jacobsen,
1992)70
with
161
patients and shown
SSRI-Induced
Sexual
Dysfunction
185
that sexual dysfunction secondary to fluoxetine was not due to the combi-
nation of alprazolam or carbamazepine, as the patients had been on this
medication previously without it affecting their sexual function.
To assess whether the patients presented some mechanism of adapta-
tion to the sexual dysfunction over the course of time, improvement was
measured over the months without reducing the initial dose of the drug.
An
average period
of
6
months for fluoxetine, fluvoxamine, and paroxet-
ine and
4
months for sertraline (as the latter was the last one to make
the pass at the market in Spain) was assessed.
A
group of
156
of the total
200
patients complied with this time criterion. In only
5.8%
of the pa-
tients
(9/
156),
the dysfunction disappeared completely within
6
months;
12.82% (20/156)
showed a moderate improvement, and
81.4%
(127,'
156)
showed no improvement at all by the end of the set period.
Al-
though it is possible that a larger number
of
patients may experience
some improvement by the end of
12
months' treatment, many of them
only take the treatment for a shorter period, which makes it difficult to
obtain consistent data on this point.
The occurrence of
SD
correlates with the dose used, as reported by
other re~earchers."~ Some patients appear to be particularly susceptible,
developing
SD
on low doses, whereas others suffer no side effects even
with above average doses. The dose was decreased to
50%
in
30
patients,
23
of whom improved to some extent or quite a lot
(73%).
The
24
patients who were taken
off
the treatment as a result of the total improve-
ment in their clinical condition experienced a complete remission of
their
SD.
There was no statistically significant correlation between in-
creased dosage and severity of sexual dysfunction. This suggests that,
above certain threshold dosages, patients develop sexual dysfunction re-
gardless of any dose increases. This threshold dosage seems to depend
on individual susceptibility or on plasma levels, although it would be
necessary
to
conduct studies correlating these variables before we could
be sure about such affirmations. Other studies have shown that lower
doses of
SSRIs
can eliminate the dysfunction without affecting the drugs'
clinical efficacy.
'"
A
positive correlation between patient's age and a lower tolerance
of
SD
has been shown
(R2
=
.025,
p
C
.05).
This result does not confirm
the initial hypotheses about young patients being the ones who would
least tolerate the dysfunction because of their greater sexual activity.
Quite the contrary, age made the patient more critical about the onset
of sexual problems.
There was also a positive correlation between the severity of impotence
or difficulty in maintaining sexual excitation and the number of months
elapsed since treatment began
(p
<
.01).
This result suggests that the
length of the treatment may be an important variable in the occurrence
of this dysfunction and that the presence of impotence could be second-
ary to libido, orgasm, and ejaculation disorders that have lasted for
months.
In theory, patients with
SD
should not improve when switched to an-
other
SSRI
because the mechanism of action is similar. The literature
186
Journal
of
Sex
&
Marital
Therapy,
Vol.
23,
No.
3,
Fall
I997
offers no data on the usefulness of such a change. However, in our
sample,
13
patients were switched to other
SSRIs
(5
to sertraline,
4
to
paroxetine,
2
to fluoxetine, and
2
to fluvoxamine) for the purpose of
analyzing changes in sexual function. Four of these patients
(30.7%)
showed a partial improvement in their dysfunction, but none im-
proved completely.
Fifteen patients with SD were switched over to moclobemide (a revers-
ible, monoamine oxidase
A
inhibitor;
450-600
mg/day)
,
and the dys-
function disappeared in
12
patients. The great improvement in this
group could be due to moclobemide's different mechanism of action.
These results point to the need for controlled studies to ascertain
whether moclobemide could be an ideal drug for patients who present
severe and poorly tolerated
SD
secondary to
SSRI
therap
.
Moclobemide
data show that the incidence of
SD
is lower than with fluoxetine"' and
that it could even have a better stimulating effect on sexual function than
doxepine.lZ1 The effect of moclobemide on sexual desire and function in
healthy volunteers was recently measured, and there were no differences
between moclobemide and placebo on measures of sexual desire and
function.
'*'
The classic
MAOIs
(phenelzine, tranylcypromine) definitely
cause SD.'2s'26 In placebo-controlled studies, moclobemide had an inci-
dence of loss of libido and delayed ejaculation similar to placebo,
whereas phenelzine had an incidence of
28.6%
and
42.8%,
respec-
tively.'" Selegiline (a
MAO-B
inhibitor used for Parkinson's disease and
a
MAO-A
inhibitor at high doses) seems to have fewer sexual side effects
than other
MAOIS.'~*
Five patients were switched over to amineptine
(200
mg/day), and a
complete improvement was noted in
3
patients, partial improvement in
1
patient, and withdrawal through intolerance in
1
patient. Amineptine's
profile, mainly involving an increase in dopamine turnover and little
effect on serotonin, appears to be responsible for this improvement in
sexual function. To date there are no studies aimed at assessing sexual
side effects with amineptine, but it could be a useful drug for alleviating
sexual dysfunction caused by other antidepressants. Controlled studies
to ascertain the activity of this drug in relation to sexual function
are
needed. Our group is now carrying out a controlled and multicenter
study in a greater sample
(150
patients), using moclobemide versus ser-
traline, as well as another study comparing amineptine versus paroxetine
in patients with SSRI-related sexual dysfunction.
appears not to cause sexual disorders like the
SSRIS."~-'
iy
Some isolated
CONCLUSIONS
The incidence of sexual dysfunction is often underestimated, and a
psychosexual history of the patient must be taken prior to starting antide-
pressant treatment. The high incidence in this study suggests the im-
portance of systematic queries about sexual side effects. Physicians
should openly interview their patients to manage the dysfunction, appro-
priately using suitable assessment strategies'29-'30 and avoiding possible
SSRI-Induced Sexual Dysfunction
187
treatment noncompliance. In addition, there are effective strategies for
approaching sexual dysfunction secondary to psychotropic medication,
which can help the patient to continue
with
the treatment (often long-
term or indefinitely) and achieve a satisfactory quality of
life.
Last,
it is
worth taking into account the use of these drugs in disorders involving
a pathological increase in sexual activity, sexual obsessions,
or
premature
ejaculation in depressed patients.
188
Journal
of
Sex
&
Marital
Therapy,
Vol.
23,
No.
3,
Fall
1997
Questionnaire to Studv Sexual Dvsfunctions.
1996
AL.
Montejo,
G.
LLorca,
J
A.
Ieqderdo. (University
of
SpIpmnaca)
and
Spanish
Group
to
Study
psychopharmacology-related
Sexual
Dysfunction.
Patient's name
(initials)
1
I
I
DOSAGE
1-1
(mdday)
Monthshmtreatment
1-1
OTHER
MEDICATIONS
DIAGNOSTIC
(DSM-IV)
11
El
SEXUAL
DYSFUNCTION? WWNO)
Spontaneous
comnnication?
OF LIBDO
TI
(0
=
nil;l=
mild;
2=
moderate;
3=
severe)
(0
=
nil;l=
mild;
2=
moderate;
3=
severe)
6
(0
=
never;
1=
occasionally;
2=
often;
3=
always)
1-1
(0
=
never;
I=
occasionally;
2=
often;
3=
always)
DELAY ORGASWEJACUL
ANORGASMIA
SEXUAL IMPOTENCE
PREVIOUS SEXUAL FUNCTIONING
1-1
(n0rmal/anonn~)
Improvement
with
time?
-1
Tolerance.
I]
(o=
gomi,
I=
far,
2=
pow)
(&total,
1
=mode&&?==no)
Dosage decrease? New Dosage
rj
Improvement?
Change
of
medication?
I-iNew Treatment
Dosage:
11
Improvement?
1-1
Improvement
start?
(m&W
(O=total,l=vety
rnuc&kmuch,3=wm&ung,4-710)
(days)
Previous withdrawal
to
sexnal interconme?
(YednO)
(intervals
of
12)
Improvement
after
withdrawal?
LI
(O=total,l=very
much,huch,3=some&ing,kno)
Comments
0
I
U
0
(yes/no) (mglday)
(O=total,
l=very
much,2=much,3=somchng,4-71o)
(yedno)
Hours?
SSRI-Induced Sexual Dysfunction
189
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Supplementary resources (15)

... In patients with SCI, different types of SD are reported depending on the location, extent, and severity of the lesion [16,17]; the most common being erectile dysfunction and ejaculation disorders [18]. Although women may have a normal sexual function after SCI [19], it has been estimated that 59% of women reported at least one SD after SCI [20]. ...
... The brain plays a central role in sexual response, which involves an interplay between neurogenic, psychogenic, vascular, and hormonal factors mediated through the hypothalamus, limbic system, and cerebral cortex [17]. Sexual response is divided into four phases: desire, arousal, orgasm, and refractory [48]. ...
... In depressed patients, increased activity of the amygdala and medial OFC, together with reduced ventral striatum and hypothalamus activity, lead to lower sexual desire and arousal [55][56][57]. Moreover, increased serotonin availability (e.g., reuptake inhibition, as with SSRIs) can reduce the effects of dopamine on sexual function [58] and inhibit sexual desire, ejaculation, and orgasm-predominantly via 5-hydroxytryptamines 2 and 3 (5-HT2 and 5-HT3) receptor agonisms-while dopamine release (e.g., atypical antidepressant medications such as bupropion) increases sexual function [17]. ...
Article
Full-text available
Sexual dysfunction (SD) is frequently encountered in patients suffering from depression. There is a bidirectional relationship between various types of SD and depression, so the presence or treatment of one condition may exacerbate or improve the other condition. The most frequent sexual problem in untreated depressed patients is declining sexual desire, while in treated depressed patients it is difficulties with erection/ejaculation and with orgasm. Numerous classes of neuropsychiatric medications, commonly used in depressed patients—such as antidepressant, antipsychotic, alpha sympathetic, and opioid drugs—may cause SD. Photobiomodulation (PBM) therapy, also called low-level light/laser therapy, is a novel neuromodulation technique for neuropsychiatric conditions, such as depression. Transcranial PBM (tPBM) targets the cellular metabolism—through the mitochondrial respiratory enzyme, cytochrome c oxidase—and has numerous cellular and physiological beneficial effects on the central nervous system. This paper represents a comprehensive review of the application of tPBM to SD, coexisting with depression or induced by antidepressant medications.
... 6 Further, this prevalence varies with antidepressants, 30% with imipramine, 25% to 73% with selective serotonin reuptake inhibitors, and 93% of women and men on clomipramine show partial or total anorgasmia. 7,8 However, this incidence of SD is lower with a newer generation of 5-HT2 blockers. 9,10 Different antidepressants are known for one or another alteration in the sexual response cycle. ...
... Participants were asked to rate responses on a 7-point Likert scale ranging from "Not at all" (0) to "definitely" (6), with higher scores indicating more severe depression and vice-versa. Further, the total scale score was also categorized into normal (0-6), mild (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), moderate (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and severe and very severe (>34) for SD. The scale has an excellent reliability index (r = 0.93) and an intraclass coefficient of 0.96, indicating an excellent test-retest reliability. ...
Article
Full-text available
Introduction Depression-associated sexual dysfunction (SD) is a pervasive and ignorant problem among the general population. The antidepressant used to treat depression may further alter the sexual response cycle in one way or another. This study aims to assess the prevalence of SD in females with major depressive disorders and the effects of antidepressant therapy after 4 weeks of follow-ups. Material and Methods In a prospective observational survey, 94 women diagnosed with depression and on antidepressant therapy were purposively enrolled. Female Sexual Functioning Index (FSFI) and Montgomery-Asberg Depression Rating Scale (MADRS) are administered at baseline and 4 weeks of treatment to measure sexual function and depression changes. Relevant descriptive and inferential statistics are applied to compute the results. Results The mean age of the participants was 35.87 (±5.10) years. A total of 95.7% of participants showed SD at baseline assessment. There was a significant difference (31.87 vs 18.51, P < .001) in depression from baselines to 4 weeks after antidepressant therapy. Further, a significant negative correlation was reported between the MADRS scores and the scores of arousals (r = −0.396, P < .001), lubrication (r = −0.453, P < .001), orgasm (r = −0.342, P < .001), satisfaction (r = −0.407, P < .001), pain (r = −0.362, P < .001), and total domains of FSFI (r = −0.412, P < .001) after 4 weeks. Using cut-off scores of different areas, decreased sexual desire was reported in 97.9%, poor vaginal lubrication (100%), a problem with arousal (100%), reduced satisfaction (96.8%), reduced ability to achieve orgasm (100%), and pain during sexual intercourse in 100% of the participants. Conclusions There is a high prevalence of SD in women with depression. There is a marked improvement in depression at the end of 4 weeks. However, sexual function status remains unchanged and indicates the need for time to improve, suggesting different study designs.
... 6 Further, this prevalence varies with antidepressants, 30% with imipramine, 25% to 73% with selective serotonin reuptake inhibitors, and 93% of women and men on clomipramine show partial or total anorgasmia. 7,8 However, this incidence of SD is lower with a newer generation of 5-HT2 blockers. 9,10 Different antidepressants are known for one or another alteration in the sexual response cycle. ...
... Participants were asked to rate responses on a 7-point Likert scale ranging from "Not at all" (0) to "definitely" (6), with higher scores indicating more severe depression and vice-versa. Further, the total scale score was also categorized into normal (0-6), mild (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), moderate (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34), and severe and very severe (>34) for SD. The scale has an excellent reliability index (r = 0.93) and an intraclass coefficient of 0.96, indicating an excellent test-retest reliability. ...
Thesis
Full-text available
Depression-associated sexual dysfunction (SD) is a pervasive and ignorant problem among the general population. The antidepressant used to treat depression may further alter the sexual response cycle in one way or another. This study aims to assess the prevalence of sexual dysfunction in females with major depressive disorders (MDD) and the effects of antidepressant therapy after four weeks of follow-ups.
... Drug-induced SD can lead to any type of SD; some drugs affect desire, leading to a decrease in or entire loss of libido (such as selective serotonin reuptake inhibitors [SSRIs] and digoxin) [3,16,33] or an increase in libido (such as dopamine agonists) [3]. SSRIs and risperidone are examples of drugs that have an impact on the 'arousal' phase, causing vulvovaginal dryness and/or ED. ...
... SSRIs and risperidone are examples of drugs that have an impact on the 'arousal' phase, causing vulvovaginal dryness and/or ED. Delayed orgasm, anorgasmia and spontaneous orgasms are symptoms related to the 'orgasm' phase and are caused by drugs such as escitalopram and alprazolam [3,16,33]. ...