ssri - possible treatments

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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.