Farnia et al Dovepress There are several options for the treatment of MDD. occurs through several brain pathways,it is assumed that These include psychotherapy,physical activity,-13 elec- at least one pathway that involves increases in serotonin troconvulsive therapy,45 and psychopharmacotherapy (5-HT)leads to an inhibition of the ejaculatory reflex by (antidepressants).6In this paper,we focus on the psychop- serotonergic neurotransmission30 and stimulation of post- harmacological treatment of MDD. synaptic 5-HT2 and 5-HT3 receptors;31322)decreases in the The explanation for the occurrence of MDD in terms of release of dopamine and norepinephrine from the substantia monoamine deficiency(depletion of serotonin,norepineph-nigra have been observed;31323)the inhibition of nitric oxide rine,and dopamine in the central nervous system)7argues for synthase has been observed;33 4)increases in corticolimbic treatment with antidepressants(selective serotonin-reuptake 5-HT levels seem to be strongly associated with reductions inhibitors [SSRIs],selective serotonin-norepinephrine in sexual desire,ejaculation,and orgasm.3435 It is therefore reuptake inhibitors,noradrenergic and specific serotonergic perhaps unsurprising that sexual dysfunction is observable in antidepressants,and serotonin antagonist reuptake inhibi- 30%-80%of patients after they begin taking SSRIs.2242735. tors)that should increase monoamine levels.819 However, Again unsurprisingly,sexual dysfunction seems to be one of several studies indicate that the efficacy of antidepressants the main reasons for discontinuing the intake of SSRIs,37-39 is limited:a therapeutic effect is observed at most in 70% a pattern observed in up to 90%of patients treated with of patients suffering from MDD20 with maximum adherence SSRIs.40 Therefore,it is important to identify strategies that of 50%4 weeks after starting treatment.21 This is probably can alleviate SSRI-I SD.25.37.38.40 due to the 2-week or greater time lag for antidepressant to SSRI-I SD is regarded as such a serious disability prob- take effect,20 and is probably also due to various adverse ably because for humans,sexual activity and sexual intimacy side effects such as weight gain,dry mouth,and sexual may serve at least four distinct goals:1)exploring one's dysfunction.22 partner's values;2)reproduction;3)pair-bonding and pair This last side effect,SSRI-induced sexual dysfunction stabilization;4 and 4)joy 42-5 or quality of life.25.45 Among (SSRI-I SD),is considered one of its most disturbing and humans,sexual activity within couples usually signifies disruptive side effects.2-25 Indeed,SSRIs can have a nega- exclusivity,intimacy,and bond-reinforcing behavior.4 The tive impact on any or on all phases of the sexual cycle by sexual activity and sexual intercourse in heterosexual couples causing a decreased libido,an impairment in arousal,and can occur under many different conditions:1)before and erectile dysfunction;SSRIs are most commonly associated after the female's fertile phase(ovulation);2)during preg- with delayed ejaculation and absent or delayed orgasm.26On nancy;and 3)in females,during post-menopausal stage,thus the basis of a meta-analysis of 31 studies,including a total of indicating that,for heterosexual couples,sexual intercourse 10,130 patients,Serretti and Chiesa27 concluded that the total must serve needs beyond mere reproduction.Further,unlike rate ofsexual dysfunction associated with SSRIs ranged from with bonobos and chimpanzees,who belong to the two 25.8%to 80.3%and was significantly higher than the placebo species closest to humans and who are sexually active in rate of 14.2%.More specifically,Clark et al4 reported that the presence and sight of other group members,humans, the SSRIs citalopram,fluoxetine,paroxetine,and sertraline in all cultures and regardless of sexual orientation,engage and the SNRI venlafaxine were associated with significantly in sexual relations in private and beyond the view of others; greater rates(70%80%)ofreported total sexual dysfunction, these practices further reinforce exclusive intimacy between including negative impacts on desire,arousal,and orgasm, partners.Given the exclusivity of sexual activity and its than was the placebo.In this regard,Garlehner et al2s found importance to bonding and bonding quality,it is not surpris- that paroxetine,citalopram,and venlafaxine,when compared ing its impairment is regarded as distressing and disturbing with other antidepressants(fluoxetine,fluvoxamine,nefa-both for the individual and for couple-related quality of life. zodone,sertraline),were associated with a higher rates of This holds particularly true for patients suffering from MDD, reported sexual dysfunction,such as complaints of erectile even during the recovery phase.For example,Clayton et al2s dysfunction in men and decreased vaginal lubrication in reported that among patients suffering from MDD,the use women.In addition,citalopram was associated with reduced of SSRIs was associated with sexual dysfunction and hence sperm quality.29 had further implications for compliance and distress for the How can SSRI-I SD be explained?In the absence of patient and her or his sexual satisfaction. a conclusive neurophysiological rationale,the following Overall,the evidence strongly supports the view that hypotheses are advanced:1)whereas sexual dysfunction among humans,sexual activity has importance beyond mere 626 submit your manuse Neuropsychiatric Disease and Treatment 2015:II DovepressNeuropsychiatric Disease and Treatment 2015:11 submit your manuscript | www.dovepress.com Dovepress Dovepress 626 Farnia et al There are several options for the treatment of MDD. These include psychotherapy,8,9 physical activity,1–13 elec￾troconvulsive therapy,14,15 and psychopharmacotherapy (antidepressants).16 In this paper, we focus on the psychop￾harmacological treatment of MDD. The explanation for the occurrence of MDD in terms of monoamine deficiency (depletion of serotonin, norepineph￾rine, and dopamine in the central nervous system)17 argues for treatment with antidepressants (selective serotonin-reuptake inhibitors [SSRIs], selective serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, and serotonin antagonist reuptake inhibi￾tors) that should increase monoamine levels.18,19 However, several studies indicate that the efficacy of antidepressants is limited; a therapeutic effect is observed at most in 70% of patients suffering from MDD20 with maximum adherence of 50% 4 weeks after starting treatment.21 This is probably due to the 2-week or greater time lag for antidepressant to take effect,20 and is probably also due to various adverse side effects such as weight gain, dry mouth, and sexual dysfunction.22 This last side effect, SSRI-induced sexual dysfunction (SSRI-I SD), is considered one of its most disturbing and disruptive side effects.23–25 Indeed, SSRIs can have a nega￾tive impact on any or on all phases of the sexual cycle by causing a decreased libido, an impairment in arousal, and erectile dysfunction; SSRIs are most commonly associated with delayed ejaculation and absent or delayed orgasm.26 On the basis of a meta-analysis of 31 studies, including a total of 10,130 patients, Serretti and Chiesa27 concluded that the total rate of sexual dysfunction associated with SSRIs ranged from 25.8% to 80.3% and was significantly higher than the placebo rate of 14.2%. More specifically, Clark et al24 reported that the SSRIs citalopram, fluoxetine, paroxetine, and sertraline and the SNRI venlafaxine were associated with significantly greater rates (70%–80%) of reported total sexual dysfunction, including negative impacts on desire, arousal, and orgasm, than was the placebo. In this regard, Garlehner et al28 found that paroxetine, citalopram, and venlafaxine, when compared with other antidepressants (fluoxetine, fluvoxamine, nefa￾zodone, sertraline), were associated with a higher rates of reported sexual dysfunction, such as complaints of erectile dysfunction in men and decreased vaginal lubrication in women. In addition, citalopram was associated with reduced sperm quality.29 How can SSRI-I SD be explained? In the absence of a conclusive neurophysiological rationale, the following hypotheses are advanced: 1) whereas sexual dysfunction occurs through several brain pathways, it is assumed that at least one pathway that involves increases in serotonin (5-HT) leads to an inhibition of the ejaculatory reflex by serotonergic neurotransmission30 and stimulation of post￾synaptic 5-HT2 and 5-HT3 receptors;31,32 2) decreases in the release of dopamine and norepinephrine from the substantia nigra have been observed; 31,32 3) the inhibition of nitric oxide synthase has been observed;33 4) increases in corticolimbic 5-HT levels seem to be strongly associated with reductions in sexual desire, ejaculation, and orgasm.34,35 It is therefore perhaps unsurprising that sexual dysfunction is observable in 30%–80% of patients after they begin taking SSRIs.23,24,27,35,36 Again unsurprisingly, sexual dysfunction seems to be one of the main reasons for discontinuing the intake of SSRIs,37–39 a pattern observed in up to 90% of patients treated with SSRIs.40 Therefore, it is important to identify strategies that can alleviate SSRI-I SD.25,37,38,40 SSRI-I SD is regarded as such a serious disability prob￾ably because for humans, sexual activity and sexual intimacy may serve at least four distinct goals: 1) exploring one’s partner’s values; 2) reproduction; 3) pair-bonding and pair stabilization;41 and 4) joy 42–45 or quality of life.25,45 Among humans, sexual activity within couples usually signifies exclusivity, intimacy, and bond-reinforcing behavior.41 The sexual activity and sexual intercourse in heterosexual couples can occur under many different conditions: 1) before and after the female’s fertile phase (ovulation); 2) during preg￾nancy; and 3) in females, during post-menopausal stage, thus indicating that, for heterosexual couples, sexual intercourse must serve needs beyond mere reproduction. Further, unlike with bonobos and chimpanzees, who belong to the two species closest to humans and who are sexually active in the presence and sight of other group members, humans, in all cultures and regardless of sexual orientation, engage in sexual relations in private and beyond the view of others; these practices further reinforce exclusive intimacy between partners. Given the exclusivity of sexual activity and its importance to bonding and bonding quality, it is not surpris￾ing its impairment is regarded as distressing and disturbing both for the individual and for couple-related quality of life. This holds particularly true for patients suffering from MDD, even during the recovery phase. For example, Clayton et al25 reported that among patients suffering from MDD, the use of SSRIs was associated with sexual dysfunction and hence had further implications for compliance and distress for the patient and her or his sexual satisfaction. Overall, the evidence strongly supports the view that among humans, sexual activity has importance beyond mere