The relationship between pharmacological agents (including herbal preparations and medications) and sexual functioning has been explored since the antiquities. For centuries, the main focus was on preparations or foods that could enhance one's sexual functioning or desire—that is, on aphrodisiacs (a word derived from the name of the Greek goddess of love, Aphrodite). Some of the aphrodisiacs may contain chemicals that potentially influence sexual desire or other aspects of sexual functioning. Some of them, such as rhinoceros horn or oysters, were considered to be aphrodisiacs mainly for their symbolic notion.
The human search for aphrodisiacs has continued to the present time. Chocolate has sometimes been promoted as a food that could enhance one's sexual functioning, and many so-called natural preparations have been touted the same way. Phosphodiesterase type 5 (PDE5) inhibitors and testosterone are not considered aphrodisiacs in a strict sense, yet their advertisements frequently border on promoting them as aphrodisiacs. The everlasting interest in pharmacological aids for sexual functioning has been demonstrated numerous times by the huge media attention to even the smallest findings of possible improvement or enhancement of sexual functioning via pharmacological agents.
During the last several decades, the complicated relationship between pharmaceutical agents and sexual functioning has also become a focus. The impairment of sexual functioning has been associated with various pharmacological agents, both psychotropic and nonpsychotropic. Numerous medications have been reported to be associated with impaired sexual functioning, affecting either the entire sexual response cycle or (less frequently) one phase of this cycle (although the phases are interconnected and cannot be clearly and unequivocally separated). Basically, the field of sexual pharmacology has gradually developed over the last few decades (see the books on sexual pharmacology by Crenshaw and Goldberg  and Segraves and Balon ). Impaired sexual functioning due to medications not only can significantly impact the patient's quality of life but also can lead to nonadherence to the medication regimen.
In this chapter, I focus on impaired sexual functioning due to various medications and its possible management, with the main focus on a prototypical group of medications associated with sexual dysfunction—antidepressants. In addition, I briefly mention pharmacological agents used for the treatment of various sexual dysfunctions and disorders, most of which are discussed in more detail in other chapters, and also some substances that may not help as much as previously believed or do not help at all. Importantly, this chapter serves as an overview and offers clinically oriented guidance for the assessment and management of sexual dysfunction associated with medications, not an exhaustive review of sexual pharmacology.
As noted in DSM-IV-TR (American Psychiatric Association 2000), The DSM-IV-TR criteria for sexual dysfunction associated with substances and medications are outlined in Table 4-1.
DSM-IV-TR Diagnostic Criteria for Substance-Induced Sexual Dysfunction
Some of the DSM-IV-TR criteria may not be perfectly clear (e.g., the etiological relationship, like many etiological relationships in psychiatry, is usually presumed) or may be a bit controversial (for recent case reports of persistent sexual dysfunction, see Bolton et al. 2006 and Csoka and Shipko 2006). However, these criteria succinctly summarize the issue in defining medication-induced sexual dysfunction.
Depression is frequently associated with sexual dysfunction (e.g., Baldwin 1996), especially low sexual desire, but also other impairments, such as erectile dysfunction. The impairment of sexual functioning does not, however, mean that depressed and anxious patients consider sexual functioning unimportant, that they do not wish to have a good sexual life, or that they are contented to have their sexual functioning even more impaired due to medications. Therefore, the management of sexual dysfunction associated with antidepressants has emerged as an important clinical area.
Antidepressants have been the most studied group of medications with regard to sexual dysfunction, at least in psychiatry. Case reports and/or case series of sexual dysfunctions associated with antidepressants (tricyclic antidepressants [TCAs], monoamine oxidase inhibitors [MAOIs]) appeared not very long after the introduction of these agents (e.g., Beaumont 1977). However, like many other side effects, sexual dysfunctions associated with antidepressants have not been systematically studied for decades. Paradoxically, the development of newer, better tolerated antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), and their use in treating less severe conditions probably led to an increased awareness and focus on the impairment of sexual functioning associated with antidepressants.
Since the early 1990s, numerous reports, studies, and review articles have addressed sexual dysfunction associated with antidepressants. Nobody questions the existence of sexual dysfunction associated with this group of medications. As Montgomery et al. (2002) pointed out, These authors also felt that findings from the literature were not sufficiently robust to support claims of a difference in the incidence of drug-induced sexual dysfunction between existing antidepressant therapies. Nevertheless, most authors and clinicians would agree (based on some evidence) that various individual antidepressants (not groups), such as bupropion, mirtazapine, moclobemide, and nefazodone, are associated with sexual dysfunctions less frequently than the rest of antidepressants.
The estimates of incidence of sexual dysfunction associated with antidepressants are usually between 30% and 40% (some would claim up to 70%), but the numbers vary widely, from as low as 10% to as high as 90% with some medications (Monteiro et al. 1987). As pointed out by many researchers (e.g., Segraves and Balon 2003), the character and frequency of sexual dysfunction associated with different groups of antidepressants may vary somewhat. For instance, compared with other antidepressants, predominantly serotonergic antidepressants such as SSRIs and clomipramine seem to be more frequently associated with delayed orgasm or anorgasmia, and TCAs seem to be more frequently associated with erectile dysfunction. The reasons for the wide range of estimates include the imprecise definition of sexual dysfunction, the lack of using standard instruments, and the discrepancy between estimates obtained via self-reporting and via active questioning. For instance, in a study by Landen et al. (2005), more patients (41%) reported sexual dysfunction in response to direct questioning than through spontaneous reporting (6%).
The etiology of sexual dysfunction during antidepressant therapy is complicated and not well understood. The impact of antidepressants on various neurotransmitter systems, such as dopamine, norepinephrine, and serotonin systems, certainly plays a major role. Dopamine influences motivated sexual behavior, desire, and the ability to become involved in sexual activity (Clayton and Montejo 2006); norepinephrine stimulates sexual arousal and vasocongestion; and serotonin system activation may suspend vasocongestion, turning off arousal. Serotonin may also diminish nitric oxide function and decrease genital sensation (Clayton and Montejo 2006). As suggested in the study by Safarinejad (2008), some antidepressants (SSRIs) may decrease the levels of hormones involved in the regulation of sexual functioning, such as testosterone, luteinizing hormone, and others.
The complicated interaction of psychotropic medications, neurotransmitters, and the peripheral and central nervous systems was summarized by Segraves (1989). However, as Clayton and Montejo (2006) pointed out, many more potential causes of sexual dysfunction exist during antidepressant therapy, including, besides the mentioned ones, psychiatric illness; medical illness; interpersonal conflicts; substance abuse; developmental issues; sexual trauma; concerns about sexually transmitted diseases; psychological issues (self-esteem); cultural, religious, and environmental issues; pregnancy and childbearing issues; life cycle issues; neurological insult; and partner and/or sexual-specific issues. As pointed out in Chapter 2, "Clinical Evaluation of Sexual Dysfunctions," all these factors should be considered during the baseline evaluation of any sexual dysfunction, including sexual dysfunction associated with medications.
Sexual dysfunction has been linked to typical or traditional antipsychotics since the late 1960s (Kelly and Conley 2004). Kotin and Wilbert (1976) reported that among patients treated with thioridazine, 60% experienced sexual impairment, 44% had troubles with ejaculation, and 35% had difficulty maintaining an erection. The incidence of sexual dysfunction associated with antipsychotics has been estimated to be around 50% among patients with schizophrenia treated with these medications. However, some of the more recent studies reported rates as high as 80%—90% (Kelly and Conley 2004).
Determining the incidence of sexual dysfunction associated with antipsychotics is even more complicated than determining the incidence of sexual dysfunction associated with antidepressants. Although many newer antipsychotics have recently been approved by the U.S. Food and Drug Administration for wider indications, such as treatment of mood and anxiety disorders, most of the incidence reports are from samples of patients with schizophrenia treated with antipsychotics. Patients with schizophrenia are typically less engaged in sexual activities in general and have lower libido. These patients are also fairly unreliable when questioned about their sexual functioning, especially during a psychotic episode. In addition, psychiatrists may not feel comfortable speaking to these patients about their sexual problems or may not feel that this is an important area to address. Another problem is the lack of a reliable and valid instrument for estimating sexual dysfunction in this population. Additionally, most of the data on sexual dysfunction associated with antipsychotics has been obtained from studies and reports involving typical antipsychotics, yet these medications have been prescribed less frequently than the atypical antipsychotics in recent years. The incidence of sexual dysfunction associated with the newer antipsychotics is usually cited as fairly low, 10%—30%, and in some cases even in the single digits.
Sexual problems described as associated with antipsychotics (mostly the typical ones) include decreased libido, impaired erection, priapism, retrograde ejaculation, painful ejaculation, delayed orgasm, amenorrhea, and other disturbances of the menstrual cycle.
The mechanism of sexual dysfunction associated with antipsychotics is complex. Prolactin elevation has frequently been mentioned as the main culprit. Knegtering et al. (2008) reported that around 40% of emerging sexual side effects in patients with schizophrenia in their study were attributable to the prolactin-raising properties of antipsychotics. However, as Kelly and Conley (2004) pointed out, other factors, such as cholinergic antagonism, alpha-adrenergic blockade, serotonin activity, extrapyramidal side effects, tardive dyskinesia, and nonspecific effects such as sedation and weight gain (histamine receptors), may also play a significant role.
Evidence of sexual dysfunction associated with mood stabilizers is scarce. This scarcity of data has several possible explanations. First, with many antipsychotics being approved for various phases of bipolar disorder and claims of their mood-stabilizing properties, it is less clear what a "mood stabilizer" is and what drugs should be classified as mood stabilizers. Second, the incidence of sexual dysfunction with mood stabilizers seems to be low. Third, the available incidence data suffer from the fact that they were obtained mostly from case reports and series or from studies with poor methodology. Fourth, the estimate of sexual dysfunction associated with mood stabilizers is clouded by the changes of libido that typically occur during the course of bipolar disorder. During the manic phase, many patients report hypersexuality, but a few report diminished libido. As already mentioned, depression can be associated with diminished libido, erectile dysfunction, and other problems.
Unless combined with other medications, lithium appears to have limited adverse sexual side effects (Labbate 2008). Most of the data on sexual dysfunction associated with anticonvulsants that are used as mood stabilizers (e.g., carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid) comes from the epilepsy literature; the data on these drugs from bipolar disorder literature are either nonexistent or very limited. Sexual dysfunction associated with lamotrigine and valproic acid is considered to be rare. Carbamazepine induces metabolism of androgen and impacts other hormones, and thus is considered more prone to be associated with sexual dysfunction. Again, however, the evidence of this association is weak.
The mechanism of sexual dysfunction associated with mood stabilizers is probably multifactorial. These medications may combine effects on various neurotransmitters in the peripheral and central nervous systems, on metabolism of various hormones, and on sex hormone-binding globulin.
Medications usually used for treatment of anxiety and anxiety disorders include benzodiazepines, buspirone, various antidepressants, and more recently antipsychotics. All benzodiazepines have occasionally been reported as being associated with sexual dysfunction. However, the evidence is mostly anecdotal, and good studies are nonexistent. Decreased libido and impaired arousal and orgasm have been reported with benzodiazepines (Labbate 2008). Most benzodiazepines seem to have a dose-response relationship between the drug dose and sexual inhibition (Segraves and Balon 2003). Whether an association exists between benzodiazepines and sexual disinhibition is unclear. The estimate of frequency and the evaluation of sexual dysfunction associated with benzodiazepines are confounded by the association of sexual dysfunction with anxiety and anxiety disorders (Zemishlany and Weizman 2008). The mechanism of sexual dysfunction associated with benzodiazepines is not known but may involve gamma-aminobutyric acid receptors in the midbrain central gray or ventral tegmental area.
Buspirone is an anxiolytic that exerts its antianxiety effect through serotonin type 1A (5-HT1A) presynaptic and postsynaptic receptors. It does not seem to have any effect on sexual functioning and has actually been used to reverse sexual dysfunction associated with SSRIs (Norden 1994).
Stimulants and other medications used to treat attention-deficit/hyperactivity disorder
Stimulants, such as various formulas of methylphenidate or amphetamine and its salts, are usually not associated with sexual dysfunction and are occasionally used for alleviation of sexual dysfunction associated with antidepressants. Treatment-emergent decreased libido and erectile dysfunction were described in one study with atomoxetine, a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (Adler et al. 2006); in this study, the incidence of both these sexual side effects was low.
Other medications used to treat mental disorders
Sexual dysfunction has not been reported to be associated with modafinil. The incidence of sexual dysfunction associated with guanfacine is low.
Although the association between sexual functioning and psychotropic medications has received relatively more attention in the scientific and lay literature, nonpsychotropic medications are also frequently associated with impairment of sexual functioning. Frequently, sexual dysfunction is also associated with the physical illness treated by these medications, and the primary or secondary contributing roles of medications to sexual dysfunction are not fully appreciated. The focus in this chapter is on medications used for a longer period of time or chronically, rather than on agents used occasionally or for a brief period of time, such as antibiotics. For a full review of evidence regarding the latter medications, the interested reader is referred to books on sexual pharmacology by Crenshaw and Goldberg (1996) and Segraves and Balon (2003).
The following groups of medications are frequently mentioned as being associated with sexual dysfunction:
Other medications, such as nonsteroidal anti-inflammatory drugs or even topical glaucoma medication (timolol, a beta-blocker), may occasionally be associated with various sexual dysfunctions. Some of the medications used for treatment of substance abuse have been reported to be associated with sexual dysfunction (e.g., methadone has been associated with erectile dysfunction; Hallinan et al. 2008), but others have not (e.g., buprenorphine; naltrexone, which has been actually tested for treating erectile dysfunction).
Although the focus of this chapter is on sexual dysfunction associated with medications, sexual dysfunctions also may be associated with recreational drugs (alcohol, cocaine, heroin, marijuana, nicotine), especially when used chronically (Palha and Esteves 2008). Similarly, numerous workplace toxins (e.g., carbon disulfide, chlordecone, manganese, nitrous oxide, stilbene, trinitrotoluene) may be associated with sexual dysfunctions (Segraves and Balon 2003).
The management of sexual dysfunction associated with medications starts with the initial evaluation of the patient. The clinician has to carefully evaluate the patient's sexual functioning at baseline, prior to starting any medication (for discussion of evaluation, see Chapter 2). Nothing can replace a thorough baseline evaluation. The clinician cannot rely on patient memory in making sure that the sexual dysfunction definitely started after the onset of treatment. Also, because the "cause" of sexual dysfunction can be quite complicated, considerations should include the presenting disorder, the possibility of one or more comorbid disorders (mental and/or physical), more than one medication, interpersonal problems, and even primary sexual dysfunction.
An important part of the baseline evaluation is proactive, pointed questioning. The clinician should ask very specific questions, not general, vague ones. Proactive and specific questioning should continue during follow-up visits and should become part of the clinician's routine, not occurring just in response to a patient's spontaneous reporting of sexual dysfunction (as mentioned earlier, spontaneous reporting and active questioning lead to differences in the numbers of reports of sexual dysfunction associated with medication; see Landen et al. 2005). Some clinicians may decide to use questionnaires completed by patients or by clinicians (see Chapter 2). Patients' self-reports should always be followed by a clinical interview, including going over the questions and possibly asking additional ones (for examples of questions about sexual functioning, see Table 2-2 in Chapter 2). Laboratory testing is almost never necessary in evaluating medication-associated sexual dysfunction (an exception may be measuring prolactin levels in antipsychotic-associated sexual dysfunction).
The clinician should also obtain information about the patient's use of over-the-counter medications, herbal preparations, and contraceptives, and about possible substance abuse (including nicotine and alcohol). The effect of a treated illness (e.g., depression, anxiety, cancer, hypertension, coronary artery disease) on sexual functioning should also be considered. Some preventable and/or treatable risks or factors, such as diabetes mellitus, hypertension, obesity, sleep apnea, or smoking, may be contributing to the sexual dysfunction. Addressing these risks or factors may either decrease the need for the medication that is causing sexual dysfunction or improve the patient's general physical well-being and possibly sexual functioning.
The clinician should also actively discuss the possibility of medication-associated sexual dysfunction with the patient. Patients appreciate being informed by the physician and being part of the clinical decision making, and some patients may have heard that sexual dysfunction may be associated with their medication. Inviting the partner to discuss sexual activity may also be helpful.
For patients with certain diseases, the discussion of sexual activity prior to treatment may include some practical tips (Segraves and Balon 2003). For example, for patients with cardiovascular disease, especially during the post-myocardial infarction period, these tips may include suggestions of avoiding sex after meals (wait 3 hours) or after alcohol consumption; avoiding sex in extreme temperatures; avoiding sex when tired or fatigued; avoiding sex during periods of extreme stress; and reporting to the treating physician any unusual symptoms (e.g., chest pain, long palpitations, marked fatigue, sleeplessness) that occur during or after sexual activity.
Several strategies have been used in the management of sexual dysfunction associated with medications, most of which were used originally for the management of antidepressant-associated sexual dysfunction. Most of these strategies have not been properly evaluated in a gold-standard, double-blind placebo fashion and probably never will be evaluated in this fashion. As Taylor et al. (2005) pointed out in their analysis of management strategies for antidepressant-associated sexual dysfunction, only the addition of sildenafil or tadalafil and possibly bupropion seem to be effective strategies, supported by relatively solid evidence. Thus, the use of management strategies remains a clinical art rather than a science. Again, a complete review of evidence is beyond the scope of this chapter, and the interested reader is referred to the book by Segraves and Balon (2003).
Management strategies for medication-associated sexual dysfunction are discussed below and are summarized in Table 4-2. Importantly, none of the medications mentioned in the management strategies of medication-associated sexual dysfunction has been approved by the U.S. Food and Drug Administration for these indications.
Management Strategies for Medication-Associated Sexual Dysfunction
Final remark regarding the management of medication-associated sexual dysfunction
The management of medication-associated sexual dysfunction should be tailored to the type of dysfunction (e.g., dopaminergic drugs or stimulants for decreased libido, PDE5 inhibitors for erectile dysfunction), the type of medication "causing" the sexual dysfunction, the type of underlying illness (e.g., avoiding use of yohimbine in anxious patients), the patient's comfort, and the physician's expertise and skills.
Many medications have been used for the treatment of primary sexual dysfunctions in recent years, as discussed throughout this book. These medications include hormones (e.g., testosterone) and bupropion for low libido (see Chapter 5, "Disorders of Sexual Desire and Subjective Arousal in Women," and Chapter 6, "Male Hypoactive Sexual Desire Disorder"); PDE5 inhibitors, apomorphine, phentolamine, yohimbine, intraurethral or intracorporeal alprostadil, and other medications for male erectile disorder (see Chapter 8, "Male Erectile Disorder"); using these agents, arginine, and lubricants for female arousal disorder (see Chapter 7, "Female Sexual Arousal Disorders"); and SSRIs, clomipramine, and anesthetizing creams (used locally) for premature ejaculation (see Chapter 10, "Delayed and Premature Ejaculation"). On the other hand, many pharmacological agents, substances of abuse, and herbal remedies (e.g., ginkgo biloba) touted for these indications do not work or lack solid evidence beyond case reports.
A 40-year-old divorced female started taking fluoxetine 20 mg/day for depression, low energy, poor sleep, and low appetite. At the time of her initial evaluation, she confided that she was sexually active with her boyfriend and had no problems achieving orgasm. During her follow-up visit a month later, she felt a bit more depressed because "I had some arguments with my boyfriend regarding his and my kids." When asked about her sexual functioning, she hesitantly responded that her "sex life was OK." However, when asked specifically about her ability to reach orgasm, she reported that it "takes me much longer to come than before, and it happened that I was not able to come at all. You know, we have had some problems with kids, and I don't feel very excited about sex." Because the sexual dysfunction 1) might have been causing some problems in her relationship with her boyfriend and 2) might have been related to fluoxetine, she agreed to the clinician's suggestion that she switch to bupropion. She reported improved mood and a return to premorbid (i.e., prefluoxetine) sexual functioning a month later.
This case illustrates several points made in this chapter: 1) the importance of baseline evaluation, 2) the importance of active questioning at baseline and during follow-up visits, and 3) the fact that patients may interpret their sexual dysfunction as a consequence of interpersonal and other problems when it could be associated with medication.