Abstract
Abstract
Sexual dysfunction is one of the more common features of depressive disorders, presenting with dysfunction across sexual response cycle. Variety of factors play a role in causing sexual dysfunction in these patients, such as psychological, biological, social and interpersonal factors. Another cause of sexual dysfunction in these patients can be the side effect of antidepressants making it difficult to conclude if the dysfunction is the result of the depression or the treatment of depression. Clinicians need to be aware about the sexual dysfunction as it can have big impact on the overall quality of life of an individual.
Introduction
Sex is an important biological instinct along with sleep and eating. Sexual behavior is an interesting albeit a complicated interaction between psychology and biology. It forms an integral part in determining the quality of life of an individual, with a study done in 2002 showing that 94% people believed that sex has a positive effect on the overall quality of life. 1
Sexual Dysfunction and General Population
Sexual dysfunction remains an understudied domain, with many factors affecting the prevalence reported in various studies. First is the method of reporting: a study found 14% prevalence of sexual dysfunctions when reported spontaneously by the patients and 58% prevalence of sexual dysfunctions when asked by the doctor directly. 2 Second is the cultural background, which affects the gender roles, gender role expectations, explanation of sexual behavior, and sexual dysfunction. 3 Third is the understanding of what is “normal” regarding sexual behavior from an individual’s point of view. Fourth is the awareness about the availability of treatment for the sexual dysfunctions. 2
A review on the prevalence of sexual dysfunction in general population reported decreased sexual desire in 16% men and 35% women, erectile dysfunction and premature ejaculation in 10%-20% and 35% men, respectively, and problems in female orgasm in 5%-15% women. 4 A study reported sexual dysfunctions to be more prevalent in women (43%) as compared to men (31%). In men, premature ejaculation, erectile dysfunction, and low sexual desire were reported to be 21%, 5%, and 5%, respectively, and in women, low sexual desire, arousal problems, and sexual pain were reported 22%, 14%, and 7%, respectively. 5
Physiology of Sexual Response Cycle
The human sexual response cycle is mediated by various neurotransmitters and hormones acting on the various structures in the brain.
Brain Structures
Ipsilateral temporal activation has been shown in electroencephalographic studies when a right-handed person was given a sexual stimuli. Medial amygdala has been reported to be linked to sexual desire in men and with sexual behavior in women. Hippocampus and septal region electrical stimulation has been reported to result in erection and orgasm, respectively. Nucleus paragigantocellularis has been identified to have a prominent role in orgasm as well as in selective serotonin reuptake inhibitor (SSRI)-induced anorgasmia in both the sexes. 6
Hormones
Testosterone has been shown to be important for sexual desire in both the sexes, it has been shown to influence brain regions that are sensitive to internal and external cues. Prolactin directly inhibits testosterone release. Medications that increase prolactin such as antipsychotics and antidepressants decrease the testosterone levels. Increase in the prolactin levels is also associated with increased endogenous opioids and GABAergic activity which will have negative effect on the sexual response cycle. 7
Increased levels of cortisol—the stress hormone, like in Cushing syndrome—is associated with depression, sleep disturbances, and reduced sexual desire. These problems are more profound if the increased cortisol levels are associated with raised corticotrophin levels as compared to when associated with less corticotrophin levels.
Erection is facilitated when oxytocin is injected in specific areas like periventricular nucleus of hypothalamus, and when injected peripherally is known to shorten ejaculatory latency and postejaculatory interval. Sexual behavior is also increased in females when oxytocin is injected centrally or peripherally. 8
Neurotransmitters
Dopamine plays a crucial role in the human sexual response cycle. Medial preoptic hypothalamic region and nucleus accumbens activation by dopamine is important for sexual desire, and dopamine’s activation of paraventricular nucleus is important for penile erection. All phases of the sexual response cycle are mostly inhibited by serotonin. 5-HT2 and 5-HT3 receptors inhibit the sexual activity, while 5-HT1 receptors stimulate sexual activity.9- 12
Sexual Dysfunctions in Depression
The sexual response cycle is negatively affected in depression. In men suffering from depression, 40% have reduced sexual desire and about 20% have difficulty in reaching ejaculation. In females suffering from depression, functional MRI studies have lesser activation of brain areas, such as middle temporal gyrus, hypothalamus, parahippocampalgyrus, thalamus, and amygdala in response to visual sexual imagery as compared to normal controls. 13
In a study with 132 patients with depressive disorders, 72% with unipolar depression and 77% with bipolar disorders reported loss of sexual desire. 14 Many patients with significant depressive symptoms can have loss of sexual desire as the presenting complaint, while in others, other symptoms of depression may be predated by reduced sexual desire. 15
The incidence of different sexual dysfunctions in depression varies from study to study, though the loss of sexual interest seems more common than erectile, orgasmic, or ejaculatory problems. A study from 1982 reported that sexual desire is more prevalent in patients with depression than problems of arousal and orgasm, which did not differ from that in controls. 16
The Zurich’s study, from 1993, of young adults showed twice the prevalence of sexual problems in depression than in controls, but those findings cannot necessarily be applicable to older people. 17 This study also made a comparison between the intreated patients and those that were treated using either medicine (50% antidepressants, 50% benzodiazepines) or psychotherapy. Those who were on treatment had more prevalence of sexual problems and both had higher sexual problems than the controls. No significant difference was found in the prevalence of specific type of dysfunctions in this comparison. 17
Etiology of Antidepressant-induced Sexual Dysfunction
The cause of antidepressant-induced sexual dysfunction is still an area of ongoing research. Several etiologies have been suggested. It has been suggested and observed that long-term use of 5-HT1A receptors along with increased expression of methyl-binding proteins such as MeCP2 and MDB1 which leads to increased production of HDAC2 mRNA and decreased production of histone H3 deacetylase. 18 Hormonal factors have also been implicated in SSRI-induced sexual dysfunction such as increase in prolactin and decrease in testosterone, oxytocin, and nitric oxide. 19 Through 5-HT2A and 5-HT2C actions, serotonin also regulates the action of proopiomelanocortin and melanocortin, which play a major role in skin coloration as well as in sexual behavior. 20 Serotonergic neurotoxicity in the peripheral nervous system has been postulated as cause as well. 19
Antidepressants and Sexual Dysfunction
Unless the clinician asks about the sexual history before the start of medication, it can be very challenging to assess the impact of medications on the sexual function, as depression itself can affect all the phases of the sexual response cycle. Physical comorbidities and the reluctance of the patient to report sexual problems spontaneously also act as a confounding factor.
Tricyclic Antidepressants (TCAs)
A prospective randomized-controlled trial using amoxapine in the range of 26 mg-70 mg and amitriptyline in the range of 64 mg-107 mg showed prevalence of sexual dysfunction—26% with amoxapine and 31% with amitriptyline. 21 Another randomized-controlled study comparing Monoamine Oxidase inhibitors (MAOIs) with TCAs, using 60 mg-90 mg phenelzine and 200 mg-300 mg of imipramine, found 40% sexual dysfunctions with phenelzine and 30% sexual dysfunctions with imipramine as compared to 6% with placebo. 21
SSRIs
A comparative study of different SSRIs found paroxetine to have the highest sexual dysfunction followed by sertraline and fluoxetine. 22 A non-randomized, open label study found paroxetine to have the highest sexual dysfunction followed by fluvoxamine, sertraline, and fluoxetine. 23 Another study comparing paroxetine and fluvoxamine found significantly higher sexual dysfunction across whole sexual response cycle with paroxetine, though no standardized sexual dysfunction was used. 24
SNRIs
Studies assessing serotonin-norepinephrine reuptake inhibitors (SNRIs) for sexual dysfunction have been inconclusive. Studies comparing duloxetine with SSRIs have shown lower sexual dysfunction with25, 26 duloxetine as compared to paroxetine or escitalopram, but this difference was lost after 12 weeks of treatment, suggesting only a limited time advantage of duloxetine over SSRIs. 27 Studies have shown that desvenlafaxine has more sexual side effects in men as compared to women.28, 29
Mirtazapine
Mirtazapine is hypothesized to have lesser side effects because of its agonistic effects on 5-HT1A and antagonistic effects on 5-HT2 and 5-HT3 receptors. It has been reported that almost half of the patients, with SSRI-induced sexual dysfunction, reported no sexual problems when switched to mirtazapine at the end of the 8-week treatment.30, 31 A large study, from 2002, with 6,000 sample size, reported higher incidence sexual problems with SSRIs, mirtazapine, and venlafaxine and lower incidence sexual problems with nefazodone and bupropion. 2 Studies also report lesser intensity of sexual dysfunction with mirtazapine, whenever induced. 32
Managing Antidepressant-induced Sexual Dysfunction
First of all, a detailed history has to be taken, including determining the sexual functioning of the patient and various contributing factors such as medical, psychological, and interpersonal factors which might be contributing to the sexual dysfunction. Then there are a variety of approaches that can be used to manage antidepressant-induced sexual dysfunction. One of them is switching the offending drug with a drug with lesser propensity for sexual dysfunctions such as mirtazapine, bupropion, or nefazodone. Small open label studies have shown improvement in sexual functioning when switching to mirtazapine or bupropion, but bigger randomized control trials are required. Similarly, some reports suggest adding buspirone to the antidepressant with improvement in sexual functioning, but the results have not been reproduced in larger studies. Another way would be stopping the offending antidepressant for reversing the sexual dysfunction, a “drug holiday,” but this approach is likely to have more negative consequences than benefits. There is only one conclusively effective treatment for antidepressant-induced sexual dysfunction, that is, the addition of a Phosphodiesterase-5 inhibitor, like sildenafil. This approach has been shown to improve problems associated with all the phases of sexual response cycle along with overall satisfaction when taken with antidepressants. It has been reported that there is no loss of beneficial effect of antidepressant when used in combination with sildenafil. 33
Conclusion
By the end of the current decade, depression is slated to become the second most common disease. Sex is one of the basic instincts of human life and sexual fulfillment is one of the key to a good quality of life. Sexual dysfunctions are commonly associated with depression and antidepressants than what a routine clinician might think. It is important for the clinicians to be aware of the enormity of the problem and assess the sexual life and problems of the patients wherever possible. It might not only enhance the quality of life of the patient but may also help in making the treatment successful.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.