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Medscape Psychiatry & Mental Health eJournal [TM]

Treatment of Antidepressant-Induced
Sexual Dysfunction
Michael J. Gitlin, MD 
Disclosures
Medscape Psychiatry & Mental Health eJournal. 1998;3(3) 
 2 comments
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 References
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A variety of antidotes have been reported to treat SSRI-induced sexual
dysfunction effectively; however, virtually all the data on these agents are
derived from open case reports and case series. Insofar as sexual function
improvement may be responsive to placebo effects, it is impossible to
estimate the true efficacy of these antidotes.[27]

Most of these antidotes either have serotonin-blocking properties (especially

5HT-2 antagonistic effects) or augment catecholamine activity, especially that
of dopamine. The antiserotonergic antidotes are cyproheptadine, buspirone,
nefazodone, and mianserin. Medications enhancing dopaminergic tone
include amantadine, bupropion, and stimulants, with yohimbine showing
noradrenergic effects. Among the reported antidotes, the only 2 without
antiserotonergic effects or catecholaminergic activity are gingko biloba and
urecholine.

Cyproheptadine is an antihistamine with antiserotonergic properties that has

been reported for over a decade to reverse antidepressant-induced sexual
dysfunction. Only case reports and case series attest to its efficacy.[13,42-
44]
 Effective doses range from 2mg to 16mg. In the most recent and largest
case series, 12 of 25 patients described improvement in sexual function when
treated with cyproheptadine (mean dose, 8.6mg).[13] Anorgasmia is the sexual
side effect most often reported to be alleviated by cyproheptadine.
Cyproheptadine is effective when taken either on an as-needed basis
(typically, 1 to 2 hours before intercourse) or on a regular basis.

However, cyproheptadine's utility is often limited by its potential side effects.

Excessive sedation and the reversal of the therapeutic effect of the
antidepressant are major problems that limit its usefulness. Effectively treated
depression and bulimic symptoms have been reported to reemerge soon after
cyproheptadine was started.[42,45-48] This reversal of therapeutic effects is itself
reversible upon discontinuation.

Buspirone is a serotonin-IA partial agonist typically prescribed to treat

persistent anxiety. One case series reported that buspirone reversed both
decreased sexual interest and orgasmic dysfunction caused by SSRIs.[49] Most
patients using buspirone to treat sexual dysfunction take it daily. The dosage
is the same as that used for anxiety (15mg to 60mg daily). The mechanism of
action of buspirone in treating sexual dysfunction may be reduction of
serotonergic tone via stimulation of presynaptic autoreceptors or the alpha-2
antagonist effects of one of buspirone's major metabolites, 1-
pyrimidinylpiperazine.

Nefazodone and mianserin are antidepressants with strong postsynaptic

blocking properties. In one case report, nefazodone 150mg taken 1 hour prior
to sexual activity completely reversed sertraline-induced anorgasmia.
[50]
 Mianserin, an antidepressant with 5HT-2 and alpha-2 adrenergic antagonist
properties, is available in many countries but not in the US. It has been
reported to reverse serotonin reuptake inhibitor-induced sexual dysfunction in
9 of 15 patients.[51] Mirtazapine is similar in its biological activity to mianserin
and might also be effective in reversing sexual side effects. No case reports or
case series have yet been published attesting to this, although clinicians have
described such an effect. The putative capacity of mianserin and mirtazapine
to reverse sexual side effects can be attributed either to their serotonergic
activity or presynaptic alpha-2 activity.

Amantadine, a dopamine agonist, is used both as an antiviral agent and as a

treatment for Parkinson's disease. It has been shown in a number of small
case series to reverse anorgasmia.[13,52-54] Reported effective doses have
ranged between 100mg to 400mg taken either on a daily or as-needed basis.
In the most recent case series, 8 (42%) out of 19 patients with SSRI-induced
sexual dysfunction improved with amantadine 200mg daily.[13] Given
dopamine's consistent effect as a neurotransmitter involved in sexual arousal,
a number of other dopamine agonists have been explored as treatments for
sexual side effects.[2,55,56]

Bupropion is another commonly touted antidote for SSRI-induced sexual

dysfunction.[57,58] It is assumed that the mechanism of action by which
bupropion reverses sexual side effects is its weak dopamine agonism. The
evidence for bupropion's efficacy is scant, except for unpublished, anecdotal
reports, one case report,[57] and a case series[58] in which 31 (66%) of 47
patients showed improvement when bupropion was added to the regimen
along with the serotonergic antidepressant. Most patients (18/31) with a
successful outcome responded to as-needed use of bupropion 75mg to
150mg. Libido, arousal, and orgasmic difficulties were all effectively reversed.
Fifteen percent of treated patients stopped taking bupropion because of its
stimulation side effects. It is unclear whether bupropion doses need to be
somewhat lower than usual when added to fluoxetine or paroxetine, to
compensate for pharmacokinetic interactions resulting in increased bupropion
levels.[59]

Stimulants, such as methylphenidate, D-amphetamine, and pemoline, are

reported to reverse a variety of sexual side effects caused by SSRIs or
MAOIs.[60-62] Low doses of 10mg-25mg of methylphenidate or D-amphetamine
have been effective. One should add stimulants to an MAOI with extreme
caution because of the risk of a hypertensive episode. However, use of an
MAOI/stimulant combination has been shown to be safe in a case series.
[63]
 SSRI/stimulant combinations show no similar risks.

Yohimbine is available with or without a prescription (and with unclear purity)

in health food stores. It is an alkaloid from the bark of Corynanthe
yohimbi (family, Rubiaceae) and has been used for decades to reverse
erectile dysfunction.[64-66] Its efficacy in treating sexual dysfunction may be
associated with its ability to block presynaptic alpha-2 adrenergic sites,
leading to enhanced adrenergic tone.[65] A variety of sexual side effects have
been reported to be alleviated by yohimbine in doses ranging from 2.7mg to
16.2mg daily, prescribed either on a regular 5.4mg 3 times daily basis or on
an as-needed basis with single doses up to 16.2mg.[13,67-69] In the largest case
series, 17 (81%) of 21 patients showed improvement of sexual side effects
when treated with yohimbine (mean dose, 16.2mg).[12]

Typical side effects associated with yohimbine include anxiety, nausea,

flushing, urinary urgency, and sweating. Yohimbine has been the subject of
the only double-blind, placebo-controlled study to evaluate treatment of sexual
dysfunction occurring as a drug side effect.[27] Unfortunately, the placebo effect
was marked, showing a minimal drug-placebo difference with yohimbine given
at a dose of 5.4mg 3 times daily. Yohimbine is also available in lower potency
without a prescription. The purity, potency, and safety of these preparations,
however, are unknown.

Bethanechol is a cholinergic agonist that has occasionally been useful in

reversing sexual dysfunction associated with TCAs and MAOIs.[70-73] Typical
doses are 10mg to 20mg as needed or 30mg to 100mg daily in a divided
dose. Potential side effects with bethanechol include diarrhea, cramps, and
diaphoresis. No reports have evaluated or suggested the efficacy of
bethanechol for treating SSRI-induced sexual side effects.

Gingko biloba is an herbal extract reported to reverse a variety of sexual

dysfunctions associated with antidepressants. Information about gingko's
ability in this regard is derived from the experience of 1 clinician presenting a
large case series.[74] The response rate was greater than 80%, with doses
ranging from 60mg twice daily to 120mg twice daily (mean daily dose,
207mg). Reported side effects include gastrointestinal upset,
lightheadedness, and stimulation effects. Because gingko may inhibit platelet-
activating factor, caution should be used in considering its use by any patient
with a bleeding diathesis. The mechanism by which gingko might alleviate
sexual dysfunction is unknown.