|
| A) | Atypical agents | ||
| B) | Tricyclic antidepressants (TCAs) | ||
| C) | Monoamine oxidase inhibitors (MAOIs) | ||
| D) | Selective serotonin reuptake inhibitors (SSRIs) and noradrenergic/serotonergic reuptake inhibitors (SNRIs) |
In 2015–2018, 13.2% of adults 18 years of age and older used antidepressant medications in the past 30 days [4]. Antidepressants are among the most widely prescribed drugs in the United States, and SSRIs/SNRIs account for roughly 85% of these prescriptions [5,6]. An estimated 1 in 6 American women have been prescribed antidepressants, the result of women seeking care for depression at higher rates than men and being twice as likely to be prescribed antidepressants for the same complaint [6,7]. Side effects largely contribute to the 31% to 60% non-adherence rate with antidepressants. Sexual side effects are the most frequent antidepressant side effect reported by primary care patients [8]. In a study involving 2,163 adults who had undergone at least eight weeks of treatment with antidepressants, 79% showed some degree of sexual dysfunction [51].
| A) | Insomnia | ||
| B) | Weight gain | ||
| C) | Sexual dysfunction | ||
| D) | Fatigue and drowsiness |
In 2015–2018, 13.2% of adults 18 years of age and older used antidepressant medications in the past 30 days [4]. Antidepressants are among the most widely prescribed drugs in the United States, and SSRIs/SNRIs account for roughly 85% of these prescriptions [5,6]. An estimated 1 in 6 American women have been prescribed antidepressants, the result of women seeking care for depression at higher rates than men and being twice as likely to be prescribed antidepressants for the same complaint [6,7]. Side effects largely contribute to the 31% to 60% non-adherence rate with antidepressants. Sexual side effects are the most frequent antidepressant side effect reported by primary care patients [8]. In a study involving 2,163 adults who had undergone at least eight weeks of treatment with antidepressants, 79% showed some degree of sexual dysfunction [51].
| A) | blocked oxytocin production. | ||
| B) | inhibition of the activity of the enzyme monoamine oxidase. | ||
| C) | increased serotonin (5-HT) neurotransmission via reuptake blockade of serotonin transporters. | ||
| D) | blocked serotonin and norepinephrine transporters, which results in an elevation of the extracellular concentrations of these neurotransmitters. |
In both men and women, antidepressant-induced sexual side effects largely result from increased serotonin (5-HT) neurotransmission via reuptake blockade of serotonin transporters. Antidepressants that primarily increase dopamine and norepinephrine neurotransmission produce markedly fewer sexual side effects. SSRI/SNRI-induced sexual side effects are likely mediated by inhibitory actions on dopamine signaling in sex brain circuits and can be decreased by simultaneously increasing norepinephrine and dopamine neurotransmission but not by increasing norepinephrine alone. This provides the rationale for treatment using bupropion and other agents that simultaneously increase norepinephrine and dopamine signaling. It also suggests the theoretic basis for developing novel antidepressants that increase 5-HT and dopamine signaling. These findings are clinically relevant for patients who develop sexual side effects but also attain substantial clinical improvement or remission of depression with serotonergic agents. All reasonable options to mitigate the antidepressant-induced sexual side effect should be explored before lowering the dose or switching effective antidepressant therapies [9,10]. Serotonergic antidepressants produce the highest rates of sexual side effects, but a multifactorial etiology is more likely than a specific monotransmitter action. Other possible mechanisms for SSRI/SNRI-induced sexual side effects include decreased dopaminergic transmission, cholinergic and alpha-adrenergic blockade, inhibition of nitric oxide synthase 1, and prolactin elevation [11,12].
| A) | Citalopram | ||
| B) | Venlafaxine | ||
| C) | Agomelatine | ||
| D) | Moclobemide |
As discussed, the prevalence of sexual side effects in antidepressant use is highest for SSRIs and venlafaxine. TCAs and MAOIs have moderate rates of sexual side effects, and low rates are noted with bupropion, trazodone, nefazodone, mirtazapine, agomelatine, and vilazodone. Perhaps the lowest rate is associated with moclobemide, a reversible MAOI [1,14]. Women often require considerably more time to climax than men, which can make SSRI-induced delayed orgasm unwanted in women but a desired effect in men. A meta-analysis of sexual side effect rates with SSRIs and venlafaxine reported that orgasm and desire dysfunction are more common in men, while arousal dysfunction is more common in women (Table 1) [15].
| A) | Desire dysfunction | ||
| B) | Arousal dysfunction | ||
| C) | Orgasm dysfunction | ||
| D) | All of the above |
LIKELIHOOD OF SEXUAL SIDE EFFECTS WITH SPECIFIC ANTIDEPRESSANTSa
| Agent | Percent of Male Patients Affected | Percent of Female Patients Affected |
|---|---|---|
| Desire Dysfunction | ||
| Citalopram | 84.11% | 70.78% |
| Fluoxetine | 86.18% | 74.39% |
| Paroxetine | 73.65% | 72.89% |
| Sertraline | 84.15% | 71.92% |
| Venlafaxine | 80.62% | 72.00% |
| Arousal Dysfunction | ||
| Paroxetine | 64.51% | 83.96% |
| Sertraline | 67.05% | 82.00% |
| Venlafaxine | 75.00% | 77.71% |
| Orgasm Dysfunction | ||
| Citalopram | 74.05% | 39.47% |
| Fluoxetine | 77.23% | 40.36% |
| Paroxetine | 80.23% | 44.84% |
| Sertraline | 71.64% | 44.22% |
| Venlafaxine | 82.14% | 44.85% |
| aThese figures are based on data that did not record the duration of, or distress from, sexual side effects. | ||
| A) | Antidepressant dose reduction | ||
| B) | Adding medications with mechanisms that offset the side effect | ||
| C) | Taking a drug holiday, particularly if the agents has a long half-life | ||
| D) | Switching medications to an antidepressant with fewer sexual side effects in patients showing an otherwise positive therapeutic response |
As noted, switching medications to an antidepressant with fewer sexual side effects has been considered highly undesirable and should be avoided, if possible, in patients showing an otherwise positive therapeutic response. However, it may be an option of select patients. A 2019 study analyzed the effects of switching agents on participants with well-treated depressive symptoms but SSRI-associated sexual dysfunction. The patients were directly switched from an SSRI (citalopram, paroxetine, or sertraline) to vortioxetine or escitalopram [50]. Both groups maintained antidepressant efficacy after eight weeks, but patients switched to vortioxetine experienced greater improvements in treatment-emergent sexual dysfunction. The authors concluded that vortioxetine was a safe and effective option for adults with SSRI-induced sexual dysfunction [50].
If low sexual response or libido is a known problem prior to the initiation of antidepressant therapy, selection of an effective agent with the lowest rate of sexual side effects is recommended. Another strategy is antidepressant dose reduction, on the basis of a dose-response relationship in sexual side effects. Although common as a first-line approach and suggested by the American Psychiatric Association, this may precipitate symptomatic relapse and should be avoided in most patients with serious depression [16,17,18]. Taking a drug holiday by stopping the antidepressant for a few days has also been suggested [19]. This may be feasible with fluoxetine, owing to its long half-life, but it is not advised with other antidepressants, as patients can experience discontinuation symptoms, disruption of therapeutic effect, and worsening of depression symptoms [18].
Adding medications with mechanisms that offset the SSRI/SNRI side effects is a valid approach. 5-HT receptor antagonists or agonists or dopamine agonists are most commonly used for this purpose. Several trials have found favorable response with the 5-HT2 and 5-HT3 receptor antagonist mirtazapine, which broadly improves sexual side effects but can cause weight gain; the 5-HT2A antagonist cyproheptadine, which alleviates SSRI-induced orgasm disruption but can cause sedation; the 5-HT1A agonist buspirone; and the norepinephrine and dopamine agonist bupropion, which has the greatest evidence support and most extensive use for this indication [20,21,22,23,24].
| A) | SSRIs/SNRIs. | ||
| B) | monoamine oxidase inhibitors (MAOIs). | ||
| C) | antidepressants with primary adrenergic mechanism. | ||
| D) | antidepressants with primary dopaminergic mechanism. |
The incidence of male sexual dysfunction is much higher with SSRIs/SNRIs and much lower with antidepressants with primary adrenergic or dopaminergic mechanism. Ejaculatory delay is highly prevalent with serotonergic antidepressants. However, as noted, this can be a desired instead of adverse effect in men with premature ejaculation. In fact, the SSRI dapoxetine has become first-line therapy in the treatment of premature ejaculation [25,26]. Certain antidepressants, particularly trazodone, may rarely cause priapism (prolonged and painful erection) [46].
| A) | 2% | ||
| B) | 31% | ||
| C) | 67% | ||
| D) | 96% |
Up to 96% of women taking antidepressants report at least one sexual side effect, with 20% to 50% qualifying as a distinct clinical problem [30,31]. Antidepressants can prominently affect female sexual functioning and cause decreased libido, problems with arousal, and anorgasmia at prevalence rates as high as 80% [32].
| A) | Sertraline | ||
| B) | Sildenafil | ||
| C) | Buspirone | ||
| D) | Bupropion |
Adding bupropion 300 mg/day to a current SSRI regimen seems to improve sexual function in women experiencing sexual side effects [35]. Treatment of SSRI-induced female sexual dysfunction with adjunctive bupropion 300 mg/day for 12 weeks was studied in 218 women (25 to 45 years of age). Compared to placebo, the bupropion group showed greater improvement in mean total Female Sexual Function Index (FSFI) score (17.2 vs. 25.9) and in all FSFI domain scales. The bupropion group showed greatest increase from baseline in FSFI scores for desire (86.4%) and lubrication (69.2%) domains [36].
| A) | Loss of libido | ||
| B) | Delayed orgasm | ||
| C) | Loss of sexual function | ||
| D) | Penile or clitoral anesthesia |
PTESD symptoms can include the entire spectrum of male and female sexual dysfunction, but the triad of penile or clitoral anesthesia, loss of libido, and loss of function is the core characteristic of PTESD, across all identified drug classes and agents [43,44,48]. Pleasureless orgasm has also been reported [45,48].