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Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction Following Discontinuation of Citalopram and the Atypical Antidepressant Nefazodone

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Abstract

SSRI therapy is commonly associated with sexual side effects, but it is assumed that these distressing symp-toms resolve with termination of therapy. The atypical antidepressant nefazodone is infrequently associated with sexual dysfunction and may be substituted for SSRI's when sexual symptoms are intolerable. Recently, scattered case reports of persistent sexual dysfunction and genital anesthesia persisting well after termination of SSRI antidepressant therapy have surfaced. In each case, the underlying depressive disorder was in remission. Case: A 32-year old women with major depression was treated with citalopram but switched to nefazodone after 4 weeks of therapy due to genital anesthesia and orgasmic dysfunction. These symptoms continued following institution of nefa-zodone therapy and have persisted for over a year since termination of antidepressant treatment. Her depression remains in full remission. Discussion: It is likely that persistent post-treatment genital anesthesia and other sexual side effects are underreported, and physicians should be aware of this bothersome phenomenon. Formal post-treatment surveillance for this condition is war-ranted. Pharmacogenomic research may ultimately allow physicians to predict who is at risk for antidepressant induced sexual side effects.
The Open Women’ Health Journal, 2007, 1, 1-3 1
1874-2912/07 2007 Bentham Science Publishers Ltd.
Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction
Following Discontinuation of Citalopram and the Atypical Antidepressant
Nefazodone
Robert P. Kauffman* and Amanda Murdock
Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center, School of Medicine, 1400
Coulter Drive, Amarillo, Texas 79106 USA
Abstract: SSRI therapy is commonly associated with sexual side effects, but it is assumed that these distressing symp-
toms resolve with termination of therapy. The atypical antidepressant nefazodone is infrequently associated with sexual
dysfunction and may be substituted for SSRI’s when sexual symptoms are intolerable. Recently, scattered case reports of
persistent sexual dysfunction and genital anesthesia persisting well after termination of SSRI antidepressant therapy have
surfaced. In each case, the underlying depressive disorder was in remission.
Case: A 32-year old women with major depression was treated with citalopram but switched to nefazodone after 4 weeks
of therapy due to genital anesthesia and orgasmic dysfunction. These symptoms continued following institution of nefa-
zodone therapy and have persisted for over a year since termination of antidepressant treatment. Her depression remains in
full remission.
Discussion: It is likely that persistent post-treatment genital anesthesia and other sexual side effects are underreported, and
physicians should be aware of this bothersome phenomenon. Formal post-treatment surveillance for this condition is war-
ranted. Pharmacogenomic research may ultimately allow physicians to predict who is at risk for antidepressant induced
sexual side effects.
Keywords: Citalopram, SSRI, nefazodone, sexual dysfunction, genital anesthesia.
INTRODUCTION
The serotonin reuptake inhibitor (SSRI) antidepressants
are associated with an array of sexual side effects including
diminished libido, delayed orgasm, anorgasmia, erectile dys-
function or vaginal xerosis, and decreased tactile sensitivity
in the genital region [1,2]. Activation of the 5-HT2A subclass
of serotonin receptors appears to account for these untoward
side effects [2,3].
Nefazodone is structurally and pharmacologically distinct
form the SSRI class and infrequently associated with sexual
side effects. Nefazodone is a potent antagonist at the post-
synaptic 5-HT2A receptor site with moderate serotonin and
noradrenergic reuptake inhibition. This unique pharma-
cologic profile likely explains the low order of sexual side
effects associated with usage [2-5]. Nefazodone has been
administered in conjunction with SSRIs in an effort to coun-
teract the undesirable sexual symptoms associated with the
latter [1-3,5,6]. Alternatively, nefazodone may be substituted
for a SSRI in patients with major depression. Although ex-
ceedingly rare, fulminate hepatotoxicity has been reported
following nefazodone administration (one case of death or
liver transplant per 250,000 patients treated per year). In
fairness, physicians and consumers should be aware that
drug induced liver injury (usually reversible) has been rarely
associated with essentially all antidepressant agents [7].
*Address correspondence to this author at the Department of Obstetrics and
Gynecology, Texas Tech University Health Sciences Center, School of
Medicine, 1400 Coulter Drive, Amarillo, Texas 79106 USA; Tel:
806.356.4608; Fax: 806.354.5516; E-mail: robert.kauffman@ttuhsc.edu
It is expected that sexual functioning rapidly returns to
normal once antidepressants are discontinued, but recently,
isolated reports of sustained sexual side effects persisting
months or years after discontinuation of SSRI’s have sur-
faced in the literature [8,9]. In each case, depressive symp-
toms were reported to be in remission and no alternative eti-
ology could be identified.
We present a case of persistent genital anesthesia and
diminished libido which has persisted for over one year fol-
lowing completion of a brief course of citalopram followed
by prolonged nefazodone treatment.
CASE REPORT
A 32 year old woman presented with a six month history
of depressed mood, anhedonia, and difficulty falling asleep.
A prior history of depression and other psychiatric disorders
was absent. The patient denied diminished libido or diffi-
culty achieving orgasm. No significant marital conflicts or
other stressors were identified. Her past medical history and
physical examination were normal. Citalopram 20 mg daily
was prescribed for major depression.
Within days of beginning citalopram therapy, she noted a
substantial decrease in libido, difficulty achieving orgasm,
and diminished orgasmic intensity. Most distressing to the
patient was a sensation of “feeling totally numb” in her geni-
tal region with a greatly diminished capacity to respond to
clitoral and labial tactile stimulation during intercourse.
Her depressive symptoms improved considerably at 4
weeks but the sexual side effects persisted. She requested a
change in drug therapy rather than taking a “wait and see”
2 The Open Women’ Health Journal, 2007, Volume 1 Kauffman and Murdock
approach. Nefazodone was prescribed and citalopram ta-
pered over one week. She achieved an excellent clinical re-
sponse to nefazodone 200 mg twice daily, but unfortunately,
the sexual side effects and genital anesthesia continued un-
abated for the duration of therapy. Bupropion (on a continu-
ous basis) and then sildenafil (prior to intercourse) were
added to her therapeutic regimen, but the patient failed to
experience any improvement.
Nefazodone was discontinued after 14 months, and her
depression remained in full remission. One year following
completion of drug therapy, she continued to complain of
low libido, minimal genital tactile sensation, and orgasmic
dysfunction that was essentially unchanged from the time of
treatment. Lubrication and genital engorgement remained
intact. The patient maintained regular, cyclic menses before,
during, and after treatment.
Neurological examination was normal. Thyrotropin, free
thyroxine, serum testosterone, sex hormone binding globu-
lin, and calculated free androgen index were within normal
limits. Formal psychological consultation and testing were
obtained, but no residual psychopathology was identified.
DISCUSSION
Sexual side-effects associated with neuropsychiatric
drugs, particularly the SSRI class, are relatively common,
and it has been generally assumed that these annoying symp-
toms abate with discontinuation of treatment. In this regard,
the absence of a coordinated post-treatment surveillance
study validating this axiom is surprising.
SSRI related sexual side effects have ranged from 58%
for fluoxetine to 73% for citalopram [10]. In contrast, studies
of nefazodone have consistently reported a low incidence of
sexual side effects [3,10,11]. In a series of 593 patients
treated with nefazodone from four clinical trials, abnormal
orgasm was reported in only 0.2% of the participants [5].
Montejo, et al. pinpointed sexual dysfunction in 4 of 50 de-
pressed patients (8%) treated with nefazodone [10].
Although an element of impaired sexual functioning is
encountered in approximately 40-50% of depressed indi-
viduals [4,12], reduced or absent genital sensation has not
been associated with depression or any other common psy-
chiatric entity [13]. Genital anesthesia appears uniquely as-
sociated with the use of serotonergic antidepressants [1].
Ordinarily, antidepressant induced sexual side effects rapidly
diminish with termination of drug therapy [1,6], but recent
case reports suggest that this is not always the case. Bolton,
et al. described persistence of orgasmic dysfunction, genital
anesthesia, and diminished libido in a 26 year old male six
years following discontinuation of sertraline [8]. Csoka and
Shipko reported three additional cases of sustained genital
anesthesia and poor libido following treatment with either
fluoxetine, sertraline, or citalopram [9]. In each of these
cases, the onset of unwanted sexual side effects first oc-
curred during SSRI therapy, and residual depressive symp-
toms were absent at follow up. Yet another study at least
indirectly implicated paroxetine although patients in that
investigation were continued on amineptine, an atypical tri-
cyclic antidepressant not associated with sexual dysfunction,
following paroxetine discontinuation [14]. Bahrick has pro-
posed that persistent genital anesthesia and orgasmic hypo-
intensity should be considered putative markers of past SSRI
exposure if the condition arose initially during treatment
[13].
In addition to these case reports, the emergence of an
Internet community comprised of individuals claiming per-
sistent sexual dysfunction following discontinuation of vari-
ous SSRI’s, albeit unsubstantiated, suggests that this phe-
nomenon may not be rare [13]. Plainly, such an event pre-
sents a consequential quality of life issue affecting post-
depression sexual functioning with the capacity to compro-
mise intimate relationships in men and women alike.
Early studies of fluoxetine concluded that sexual dys-
function occurred in only 2-16% of those receiving the drug,
but these numbers were based primarily on patient-based
voluntary reporting rather than sophisticated questionnaires
or direct interview [15]. In the same vein, lack of long term
follow up or failure to inquire about sustained sexual side
effects following antidepressant therapy would likely result
in underreporting of these events. Accordingly, persistence
of orgasmic dysfunction and loss of genital tactile sensation
following antidepressant discontinuation may be more com-
mon than suspected.
The mechanism of antidepressant induced sexual dys-
function is not fully understood which renders speculation on
the psychoneuroendocrinological basis of sustained post-
treatment sexual symptoms even more challenging. Perma-
nent changes in serotonin transmission physiology mani-
fested by diminished sexual behavior have been reported in
murine models following neonatal or adolescent SSRI expo-
sure [16,17], and hence, it is biologically plausible that an
analogous alteration of serotonin receptor neurophysiology
might persist in adult humans. Bishop, et al. identified an
association between a specific 5-HT2A single nucleotide
polymorphism (SNP) and sexual side effects in a mixed gen-
der group of individuals receiving SSRIs [18]. This finding
raises the possibility that a specific SNP might predispose
affected individuals to persistent post-treatment sexual dys-
function.
Persistent sexual dysfunction and genital anesthesia fol-
lowing citalopram administration has been described in one
other case report, but there are no published reports of these
symptoms following nefazodone therapy [9]. Parenthetically,
it is entirely possible that this patient’s condition is entirely
attributable to citalopram even though her length of exposure
was only four weeks. Nevertheless, it is logical to hypothe-
size that the unusual nefazodone-treated patient who suffers
sexual side-effects could also develop prolonged post-
treatment sexual side effects similar to individuals treated
with traditional SSRIs.
Long term follow up will be crucial in order to determine
if antidepressant induced sexual dysfunction remains a per-
manent phenomenon. Continued research into antidepressant
pharmacogenomics may ultimately establish precisely who is
predisposed to this perplexing problem and the molecular
basis involved. In addition, a multi-institutional long term
surveillance project designed to detect the true incidence of
persistent post-antidepressant genital anesthesia and sexual
dysfunction should be undertaken. If a positive association is
found, this would have implications for pre-treatment in-
formed consent and could precipitate yet another “black
box” warning by the FDA.
Prolonged Post-Treatment Genital Anesthesia and Sexual Dysfunction The Open Women’ Health Journal, 2007, Volume 1 3
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Received: November 02, 2007 Revised: November 16, 2007 Accepted: November 19, 2007
... In PSSD, the general approach focuses on manipulating the serotonergic and dopaminergic systems, for example by adding 5-HT-2 and 5-HT-3 antagonists such as trazadone and mirtazapine [17,23,24,38,39,41,49] or dopamine agonists [16] such as pramipexole [17,23,24,30,38,39,41] and cabergoline [17,23,24,38,39,41,47] and 5-HT1A agonist as buspirone [17,23,24,38,39,47]. These treatments go along with phospodiesterase type 5 inhibitors (IPDE5) [4,14,17,23,24,38,39,41,47,49,50] as shown in Figure 2. ...
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... In 2007, Kauffman and Murdock reported the case of a 32-year-old female who developed genital anesthesia, diminished orgasmic intensity, diffi culty achieving orgasm, and a substantial decrease in libido within days of starting citalopram [14]. She described her genital region as "feeling totally numb". ...
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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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