Sexual Disfunction and Antidepressants:Article

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Treatment of Antidepressant-Induced Sexual Dysfunction

Author: Michael J. Gitlin, MD

Abstract

Sexual dysfunction is a common side effect of SSRIs, occurring in more
than 30% of patients.

Sexual side effects have emerged as a major clinical concern with many of
the newer antidepressants. Approximately 30% to 40% of patients on
serotonergic antidepressants experience sexual dysfunction. Clinical
trials of techniques to minimize or treat these side effects have been
hampered by a lack of systematic inquiry on sexual dysfunction in
antidepressant-treated patients. General
strategies and specific drug antidotes to treat antidepressant-induced
sexual side effects are discussed. These include such drugs as
cyproheptadine, yohimbine, amantadine, buspirone, stimulants, and gingko
biloba. [Medscape Mental Health 3(3), 1998. © 1998 Medscape, Inc.]

Introduction

Side effects associated with psychotropic medications are associated with
noncompliance that can potentially reduce clinical response to treatment.
Selective serotonin reuptake inhibitors (SSRIs) have emerged as the
dominant treatment for depression and other psychiatric disorders.
However, sexual dysfunction is a major side effect of this group of
psychotropic medications. Unfortunately, despite the astounding popularity
of SSRIs in the US during the
past 10 years, information on the prevalence and treatment of SSRI-induced
sexual dysfunction is scant. This article reviews what is known about
sexual side effects of antidepressants and strategies to treat them,
relying heavily on the anecdotal data and case series that form the bulk
of the published literature.

Differential Diagnosis of Sexual Dysfunction

Depressed patients can manifest sexual dysfunction due to a variety of
causes. Clinicians should consider all possible causes before attributing
sexual dysfunction to a prescribed antidepressant (Table I).[1,2]
Etiologies can be grouped into 3 categories: (1) part of the presenting
psychiatric disorder; (2) comorbid physical or psychiatric disorders; and
(3) drug-induced from medical treatments.

Presenting Disorder
Psychiatric disorders themselves are associated with sexual dysfunction.
Depression is assumed to be linked with alterations in sexual functioning,
although the evidence for this assertion is less consistent than
expected.[3] Only a handful of experimental studies on sexuality in
depressed individuals have been published, and all these have evaluated
only men.[3-9] These studies show that diminished sexual satisfaction, as
opposed to decreased sexual interest or erectile dysfunction, is the most
consistent finding in depressed outpatient men.[3] This complaint of
decreased satisfaction is probably related to the diminished ability of
many patients with depression to enjoy most pleasurable activities.

Comorbid Disorder
Sexual dysfunction can occur as a primary condition from either a medical
disorder or from a poor relationship with the partner. Unfortunately, the
rate of primary sexual dysfunction in a normative population is still in
doubt, although the rate of DSM-IV hypoactive sexual desire is estimated
at 20%.[10,11] Rates of decreased libido in earlier studies of depressed
patients have been estimated as high as 77%.[12]

Given the number of possible causes of sexual dysfunction, clinicians
should ask about sexual function prior to prescribing antidepressants to
any patient. A minimal set of screening questions should include the 3
major areas of sexual function: interest (or libido), arousal (erectile
function in men, lubrication and feelings of arousal in women), and
orgasm.

Drug Effects
A number of medications besides psychotropics can cause sexual
dysfunction, including some antihypertensives and muscle relaxants.
Antidepressants cause sexual side effects in all 3 phases of the normal
sexual response cycle, including decreased libido, erectile dysfunction
(in men), and delayed time to orgasm or anorgasmia in men and women. In
open case series of patients treated with SSRIs, orgasmic dysfunction is
the most common sexual dysfunction, followed by decreased libido; arousal
difficulties represent the least common form.[13]

Painful ejaculation was reported in as many as 20% of men in 2 case series
of men taking tricyclic antidepressants (TCAs).[14,15] As yet, this side
effect has not been reported to occur in association with the newer
antidepressants such as SSRIs, bupropion, nefazodone, and mirtazapine.

Paradoxically, antidepressants (especially those with serotonergic effects
such as SSRIs, monoamine oxidase inhibitors [MAOIs], and trazodone) have
also been reported, albeit infrequently, to cause occasional increased
sexuality. Case reports describe enhanced libido, spontaneous orgasm
without sexual stimulation, and spontaneous orgasm with yawning.[16-20]

Antidepressants and Sexual Dysfunction

All antidepressants are associated with potential sexual side effects.
However, it is difficult to estimate the percentage of patients
experiencing these side effects with any single antidepressant. This is
because of the variability in methodology between studies when
ascertaining sexual side effects and because of a paucity of studies
specifically evaluating the rate of sexual side effects. When patients in
a recent study were asked about sexual dysfunction, the rate of
these complaints from SSRIs was 55%, compared with only 2% to 7% when
sexual side effects were voluntarily reported.[21]

Despite these methodological difficulties, patients taking the highly
serotonergic antidepressants -- SSRIs, clomipramine, and venlafaxine --
seem to show the highest rates of sexual dysfunction, varying from 2% to
92%.[15,22] The best estimate is that 30% to 40% of patients on
serotonergic antidepressants will have some sexual dysfunction. In
descending order, MAOIs seem to be
associated with the next highest rate of sexual dysfunction, followed by
TCAs. Rates of sexual side effects seem to be consistently lowest with
nefazodone, bupropion, and mirtazapine. Rates of sexual dysfunction within
a given drug class are probably equal when equivalent dosages are
compared.[13,23-25]

Strategies

Effective treatment of antidepressant-induced sexual dysfunction has
advanced little since it was first recognized as a significant problem
within the last decade.[26] No double-blind treatment study has yet been
published, although one with predominantly negative results has been
presented.[27] The absence of a systematic study precludes development of
a clinically validated treatment algorithm, since comparison of suggested
treatments has not been researched.
Despite this limitation, treatment of antidepressant-induced sexual
dysfunction can be divided into general strategies and antidotes (Table
II).[2]

General strategies for treating antidepressant-induced sexual side effects
include decreasing the dose, waiting, switching, and transient
discontinuation.

Dosage Reduction
Clinical experience suggests that side effects are generally dose-related,
making dose reduction a reasonable first strategy to consider.[23,24] The
relative paucity of nonsexual side effects seen with SSRIs makes it likely
that at least some patients are on higher doses than necessary for
antidepressant efficacy. SSRIs typically show a flat dose-response curve
in the treatment of depression, meaning that increasing the doses above
the typical doses
administered is not associated with greater efficacy.[28] The hope is that
the dose threshold for efficacy is lower than the dose threshold for
sexual side effects, thereby precipitating fewer side effects while
preserving efficacy.[28]

The length of time needed for side effects to diminish after dose
reduction depends on the half-life of the antidepressant. With
fluoxetine's long half-life, a few weeks at the lower dose may be needed
to evaluate the regression of side effects. One study demonstrated that 14
days after discontinuing fluoxetine, only 13% of patients with sexual side
effects had recovered orgasmic function.[29] For the other serotonergic
agents, a period of a few days (for venlafaxine and paroxetine) to a week
(for sertraline and
fluvoxamine) is probably sufficient to evaluate the success of dose
reduction in diminishing sexual side effects.[30]

Drug Accommodation
This strategy of waiting for the patient to adjust to the medication is
based on the observation that other drug-induced side effects, such as
nausea and excessive stimulation, diminish after several days to weeks of
treatment.[31] A few case reports and case series have noted resolution of
sexual dysfunction secondary to administration of TCAs or
SSRIs.[23,24,32,33] Although accommodation to these side effects may
occur, clinical experience demonstrates that the patient usually
experiences partial rather than absolute improvement,
and it can take many months of treatment, not days to weeks, before
improvements are noted.[20] For example, anorgasmia may diminish to
delayed orgasm but rarely to full baseline orgasmic function.

Drug Switching
Switching to a different antidepressant is a logical and effective
strategy when the first prescribed medication produces a higher rate of
sexual dysfunction than the alternative. This has been clearly
demonstrated in studies in which patients have switched from an SSRI to
bupropion or nefazodone.[23,24,29,34]

In the few studies examining this strategy,[31,35] there is no evidence of
a depressive relapse when patients are switched across antidepressant
classes. However, reemergence of depressive symptoms is always a risk with
this strategy. Switching within a medication class is theoretically less
risky for inducing relapse, but its efficacy as a strategy for reversing
sexual side effects is less clear. Case reports have demonstrated
successful switches from one TCA to another.[35,36] Within the SSRI class,
no systematic data exist, but anecdotes about successful switches have
been reported.[23,24] A study by Ashton and colleagues[13] noted that
sexual dysfunction with one SSRI did not necessarily predict dysfunction
with another; however, no data were provided.

Drug Discontinuation
The most controversial general strategy involves temporary discontinuation
of medication. This technique requires either discontinuing the
antidepressant for 1 or 2 days or dramatically lowering the dose for
several days.[24,37,38] In the largest study examining this strategy, half
the patients taking a short half-life SSRI showed clear improvement in
sexual functioning after a 2-day
discontinuation, whereas patients taking fluoxetine (with its long
half-life) showed no improvement.[37] Other cases have been described in
which even a 1-day discontinuation of fluoxetine resulted in diminished
sexual side effects.[23] One case report described the successful use of a
partial drug holiday with
fluvoxamine to treat anorgasmia: Fluvoxamine was lowered from 300mg daily
to 100mg daily for 2 days, and the patient had complete resolution of
anorgasmia.[38] However, then increasing the daily dose to 200mg rather
than restoring it to 300mg resulted in the re-emergence of depression.

The strategy of transient medication discontinuation to treat side effects
is controversial because of the potential effects on mood, compliance
issues, and withdrawal symptoms. In a study by Rothschild,[37]
discontinuation of medication was associated with a mild increase in the
scores for 2 of 20 patients on the Hamilton Rating Scale for Depression.
Some patients may view this strategy as an indication that compliance with
antidepressants is not to be attended to seriously. Lastly, transient
discontinuation of a short half-life serotonergic medication (especially
paroxetine or venlafaxine) confers the risk of inducing an unpleasant
withdrawal syndrome characterized by dizziness, light-headedness,
insomnia, fatigue, anxiety, nausea, and sensory disturbances.[39-41]

Treatment of Sexual Side Effects: Antidotes

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.

Treating sexual dysfunction associated with antidepressant medication is
an important but relatively unexplored issue in psychopharmacology. A
thoughtful diagnostic evaluation, including examination of the possibility
that some sexual difficulties attributed to the antidepressant may have
another etiology, is mandatory. Should the sexual dysfunction be
reasonably attributed to the
antidepressant, both general and antidote treatments should be considered
using an individualized approach.

--
EJK