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A 1986 placebo-controlled study by Riley and Riley found a dose-response
relation between diazepam and orgasm induced by sexual stimulation
with a vibrator in the laboratory (43). It is unclear whether this
effect is common to all the benzodiazepines. Case reports in men
suggest that all the benzodiazepines probably delay orgasm (44).
The effect of antidepressants on sexual function is now well known
by most psychiatrists. Marketing efforts by pharmaceutical companies
promoting some antidepressants having minimal sexual side effects
played a role in the dissemination of this information. Double-blind
controlled studies indicate that phenelzine, imipramine (45), and
clomipramine (46) cause orgasmic delay. Other double-blind studies
indicate that the SSRIs cause orgasmic delay (47). Initially, it
appeared that sexual side effects were more common in men than women.
However, more recent studies have found similar rates of SSRI-induced
sexual dysfunction in both sexes (47,48). Clinical series and studies
in men only suggest that the SSRIs as a class cause orgasmic delay
(49). Among the SSRIs, sexual side effects appear to be less common
with citalopram and fluvoxamine than with paroxetine, sertraline,
and fluoxetine (50,51). By contrast, venlafaxine appears to cause
sexual problems somewhat less frequently than do the SSRIs (52).
The data concerning whether mirtazapine causes sexual dysfunction
are conflicting (53,54). Double-blind studies have clearly indicated
that nefazodone (55) and bupropion (56) have minimal sexual side
effects. In fact, some data suggest that bupropion may have libido-enhancing
effects in women with hypoactive sexual desire disorder (57). A
large number of case reports have addressed the medical management
of SSRI-induced anorgasmia. Interventions include dosage reduction,
waiting for tolerance to develop, drug holidays, switching drugs,
and use of antidotes. The most common approaches are switching antidepressants
(58) or use of antidotes (59). Because of differences in the spectrum
of activity against comorbid conditions such as OCD and panic disorder,
switching drugs is not always an option. Case reports indicate that
various adjunctive medications may reverse SSRI-induced anorgasmia
(60). These include mianserin (61) bupropion and yohimbine (62),
amantadine (63), cyproheptadine (64), dextroamphetamine (65), sildenafil
(66), granisetron (67), and buspirone (68), among others. Of these
drugs, bupropion (69) has probably received the most use. Unfortunately,
few of these antidotes have been tested under double-blind conditions.
One existing double-blind study, however, failed to find efficacy
of gransitron (70). Another double-blind study indicated that bupropion
may have efficacy in reversing SSRI-induced libido problems (71).
Michelson and others reported a double-blind study showing that
100 mg daily amantadine and 30 mg daily buspirone did not differ
from placebo in their efficacy as antidotes (72). However, the dosages
employed in this study were much lower than those usually reported
to be effective in case reports. A recent double-blind study found
that 60 mg daily buspirone differed statistically from placebo in
restoring sexual function in women on SSRIs (73). This effect usually
occurred within 2 weeks. Case reports indicate that sildenafil reverses
SSRI-induced anorgasmia in female patients (74), and double-blind
placebo-controlled studies indicate that sildenafil reverses SSRI-anorgasmia
in male patients (47). To date, there are no published double-blind
studies indicating similar efficacy in female patients.
Case reports and clinical series indicate that most traditional
antipsychotics can cause difficulties with orgasm (75–77).
This effect was not appreciated initially, because most patients
on these agents are reluctant to report sexual problems to their
physicians. Whether the effect is secondary to alpha-adrenergic
blockade or prolactin elevation is unclear (77). However, the newer
antipsychotics, which are prolactin-sparing, appear to be associated
with a much lower incidence of sexual dysfunction than are antipsychotics
that elevate prolactin levels (78). Similarly, rates of sexual dysfunction
appear to correlate with degree of prolactin elevation (79). Clozapine,
olanzapine, and quietiapine appear to be associated with much lower
levels of sexual dysfunction than are conventional antipsychotics,
which cause prolactin elevation. One study reported that clozapine
has rates of sexual dysfunction similar to those of haloperidal
(80), but other investigators have reported dissimilar findings
(81). Risperidone, which is associated with prolactin elevation
(82), has much higher rates of sexual dysfunction than do olanzapine
and quietiapine (83). Case reports indicate several possible approaches
to the medical management of antipsychotic-induced sexual dysfunction.
Switching from a prolactin-elevating antipsychotic to olanzapine
has been reported to restore normal sexual function (84). Other
clinicians have reported that coadministration of dopamine agonists
such as bromocriptine and cabergoline may reverse antipsychotic-induced
sexual dysfunction (85,86).
It is unclear whether mood stabilizers impair female sexual function.
It is difficult to separate illness cycle from drug effect, because
sexual activity frequently increases during manic episodes and decreases
during depressive episodes. Case reports suggest that lithium carbonate
may decrease libido in male subjects with bipolar illness (28).
Long-term therapy with carbamazepine has been shown to increase
serum hormone-binding globulin, decreasing free testosterone. Free
testosterone is assumed to correlate with libido in both sexes,
and there is possibly a mechanism by which carbamazepine could decrease
libido with long-term use (87).
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The successful introduction of sildenafil for the treatment of
male erectile dysfunction has contributed to the search for pharmacologic
treatments for female sexual disorders (88). To date, these approaches
have focused either on the use of peripheral vasodilators or on
agents assumed to increase libido by effects on the central nervous
system. Many investigators assumed that vasoactive drugs would have
benefits for the treatment of female sexual dysfunctions similar
to those they have for erectile dysfunction. In many ways, this
was a logical assumption, because sexual arousal in both sexes involves
vasodilation, and arousal appears to involve an integration of both
central and peripheral stimuli. However, previous epidemiologic
research has indicated that isolated complaints of sexual-arousal
problems in the absence of low-libido complaints were uncommon,
and moreover, extensive research literature predating the introduction
of sildenafil consistently found a large discrepancy between measures
of subjective and objective sexual arousal in women. For example,
female subjects shown erotic videotapes often demonstrate vasocongestive
responses in the absence of subjective arousal (89). Clinical trials
of sildenafil and other vasoactive substances have shown that these
drugs increase genital vasocongestion and lubrication (90,91), but
there is no evidence to date that these agents have therapeutic
benefit for female sexual disorders (92). Caruso and coworkers conducted
a triple-crossover double-blind placebo-controlled study that studied
the efficacy of sildenafil in premenopausal women with normal libido,
but with arousal and orgasm difficulties (93). They found that sildenafil
improved various aspects of sexual function in this population.
It is important to note, however, that the population studied consisted
of premenopausal women in good relationships and with normal libido—a
population that also would have an excellent prognosis with behavioural
therapy.
A clitoral vacuum erection device has been recently approved by
the FDA (94). This small, battery-powered device is designed to
enhance blood flow to the clitoris. There are no large-scale studies
in clinical populations demonstrating a benefit of using this device.
Efforts to increase libido centrally have focused on the use of
dopaminergic agents or androgen supplementation. A recent single-blind
study of women with hypoactive sexual desire found suggestive evidence
that bupropion may have a beneficial effect on libido in premenopausal
women without depression and with hypoactive sexual desire disorder
(95). Approximately 30% of women with severe acquired global hypoactive
sexual desire disorder reported an increase in various measures
of libido while on 300 mg daily in this 8-week trial. Double-blind
trials with this agent are currently in progress.
A fairly extensive research literature suggests that a relation
may exist between libido and androgen levels in women. Studies by
Gelfand and Sherwin studied androgen and estrogen therapy in women
who had total abdominal hysterectomies and bilateral oophorectomies
(96). The women who received androgen-estrogen therapy had higher
levels of sexual desire and arousal than did women who received
placebo plus estrogen. This study has been criticized for using
supraphysiological levels of androgen. A recent multisite double-blind
study of androgen-estrogen therapy delivered transdermally in postmenopausal
women found that high-dosage testosterone increased both subjective
and objective measures of libido (97). The dosage level producing
a better response than placebo produced total testosterone levels
above the normal range and serum free testosterone levels at the
high end of the normal range. It is likely that chronic treatment
at that dosage would have resulted in masculinization and other
side effects. It has not been shown that changes in testosterone
levels that are within normal limits influence libido. A recent
study demonstrated a relation between acute androgen administration
and short-term changes in sexual arousal: Tuiten and coworkers reported
the effect of single sublingual doses of testosterone undeconoate
on subjective and objective responses to sexually explicit films
(98). Plasma testosterone peaked in 90 minutes, whereas genital
responsiveness peaked in 3 to 4 hours. On the day of treatment,
women reported increased sexual sensations and increased libido.
The subjects were normal volunteers, not patients.
It is clear that understanding human sexuality and sexual dysfunction
is important for contemporary psychiatric clinicians. Sexual difficulties
are highly prevalent in the general population, part of the symptomatic
presentation of many psychiatric diseases, a frequent side effect
of psychiatric treatment, and potentially an unspoken cause of treatment
noncompliance. With changes in societal mores concerning human sexuality,
especially female sexuality, patients are becoming less reluctant
to discuss sexual problems with their physicians. We need to be
ready to address these concerns when our patients bring them to
us.
Despite advances in the treatment of human sexual problems, large
gaps remain in our knowledge of human sexuality. Our knowledge of
female sexuality is even less developed than our knowledge of male
sexuality. Numerous pharmacologic interventions for female sexual
concerns are currently being evaluated for efficacy; it is critical
that the field of psychiatry, with its emphasis on the biopsychosocial
approach to diagnosis and treatment, be actively involved in this
research. Human sexuality is an activity with numerous symbolic
meanings to the individual and her partner. These symbolic meanings
also need to considered when intervening on a biological level.
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