Primary Care Update
Prescribing to preserve or restore sexual function
Side effects associated with psychotropics, and treatments shown to alleviate them
This article offers evidence-based strategies for preventing and treating psychotropic-induced ED. We also review information psychiatrists need to share with primary care physicians when treating a patient with ED.
Case report: A good relationship
Mr. A, age 52, has experienced diminishing erectile function for 6 months and now cannot achieve an erection. His relationship with his wife is good; he attributes loss of libido to his erection problem.
A pack-a-day smoker since age 18, Mr. A has type 2 diabetes and has been taking metformin, 850 mg bid, for 2 years. For about 2 months he has been taking sertraline, 50 mg, for depression and reports significantly improved mood, sleep, concentration, and appetite. He also has been taking lisinopril, 20 mg/d, for hypertension, and simvastatin, 40 mg nightly, for hyperlipidemia.
Antidepressants associated with sexual dysfunction
Monoamine oxidase inhibitors
ED (rare), retarded ejaculation(rare)
Selective serotonin reuptake inhibitors
Increased serum prolactin (possible)
Increased relative dopamine-to-serotonin reuptake inhibition
ED: Erectile dysfunction
Mr. A’s hemoglobin A1C is 9.8%, indicating poor diabetes control. His blood pressure is 168/94 mm Hg, well above his goal of <135/80. He has no chest pain or history of myocardial infarction; a recent exercise stress test indicated no coronary disease.
Discussion. Several medical causes—diabetes, hypertension, hyperlipidemia, and 34 years of heavy smoking—could explain Mr. A’s ED. Vascular disease is suspected, although the stress test was negative.
Identifying a specific cause is crucial to treating ED but may be difficult. Up to 80% of cases can be traced to one or more organic causes. 1 Mr. A’s depression could be a factor, although psychogenic ED is not common. Adding the selective serotonin reuptake inhibitor (SSRI) sertraline may also have worsened his ED.
Other possible causes of ED include:
- nonpsychotropic drugs (to view a list of agents, see this article at currentpsychiatry.com)
- decreased libido, delayed orgasm, and anorgasmia. Decreased libido and anorgasmia are often misdiagnosed as primary ED because the presenting symptoms are similar.
ED treatment begins with managing underlying medical problems, although optimal control alone may not alleviate ED. Encourage the patient to stop smoking and offer smoking cessation strategies.
Alert the primary care physician and patient when prescribing a psychotropic associated with sexual side effects, and explain the drug’s potential benefits. Assess baseline sexual function before starting the psychotropic so that changes in sexual function can be detected. Report your findings to the referring physician after each visit.
If ED is believed to be psychotropic-induced:
- maintain the psychotropic regimen for 6 to 8 weeksto see if the patient builds a tolerance to its sexual side effects.
- lower the psychotropic dosage. In one study, 2 nearly 75% of patients whose SSRI dosages were reduced by one-half reported improved sexual function with sustained antidepressant effectiveness. This SSRIeffect has been replicated and has also been demonstrated with imipramine. 3-5
- schedule 1- to 2-day drug “holidays” (on weekends, for example) for medications with a short halflife (such as sertraline or paroxetine) if the underlying condition permits. 7
Other psychotropics associated with sexual dysfunction
Increased relative sympathetic nervous syndrome/parasympathetic nervous system activity
Antipsychotics (typical and atypical)
CNS depression, increased serum prolactin
Barbiturates, benzodiazepines, CNS depressants
Decreased androgenic activity
Decreased libido, ED, retarded ejaculation
Increased serum prolactin
ED: Erectile dysfunction
If these measures do not work, individualized treatment of the sexual dysfunction becomes necessary. For some patients, switching psychotropics may be necessary to ensure compliance and preserve response. In cases such as Mr. A’s, however, the physician and patient may not want to stop a psychotropic that is working. For these patients, consider adding a drug to restore sexual function.
If ED persists after treatment, the primary care physician may refer the patient to a urologist.
Mr. A was advised to quit smoking and control his blood pressure and diabetes. His primary care doctor restarted lisinopril, 20 mg/d, increased his metformin to 1,000 mg bid, and added sildenafil, 50 mg before anticipated sexual activity. Mr. A says sildenafil has worked well.
Psychotropics and sexual dysfunction
Several physiologic processes contribute to psychotropics’ sexual side effects.
Libido is primarily a function of hormonal and CNS control. By contrast, erectile functions are mediated through local parasympathetic stimulation and ejaculation, which are controlled by norepinephrine. Orgasm is a cerebral cortical event distinct from ejaculation; either process can be disturbed independently. Elevated central serotonin levels inhibit orgasm and, to a lesser extent, ejaculation. Dopamine elevation over time leads to hyperprolactinemia and resultant hypotestosteronemia, decreasing libido.
SSRIs have been associated with ED and ejaculatory disturbances. A high serotonin-to-dopamine reuptake inhibition ratio associated with these agents may contribute to ED. Paroxetine has a higher serotonin-to-dopamine reuptake inhibition ratio—and is associated with a higher incidence of sexual dysfunction—than other SSRIs. 7
Elevated central serotonin concentrations associated with SSRIs may also inhibit orgasm. SSRIs have been used to prolong orgasm in patients experiencing premature ejaculation. 8
Venlafaxine, a serotonin/norepinephrine reuptake inhibitor, exhibits similar effects on sexual function as SSRIs, probably via the same serotonin/dopamine reuptake mechanisms. The lowest effective dosage can still cause sexual dysfunction but may reduce the likelihood.
TCAs. Tricyclic antidepressants may have fewer effects on sexual function than SSRIs. The mechanisms by which TCAs decrease libido and cause ED seem to be mediated through their CNS sedative and local anticholinergic effects.
MAOIs. Monoamine oxidase inhibitors have fewer effects on sexual function than SSRIs or TCAs, but these agents are rarely used to treat depression because of their adverse effects and drug-drug interactions.
Other antidepressants. Trazodone and nefazodone exhibit similar mechanisms of antidepressant action as SSRIs, but neither agent causes significant ED or ejaculatory disturbances. Priapism has been described with use of these agents, however.
Avoid using nefazodone in patients with hepatic dysfunction and in those who have taken an MAOI within 14 days.
Mirtazapine, a novel antidepressant with antiserotonergic actions, and bupropion, a dopamine and norepinephrine reuptake inhibitor, are not associated with significant sexual dysfunction compared with placebo. These agents are good alternatives to SSRIs 9-11 and may alleviate sexual dysfunction when used to augment SSRIs. 12,13
Lithium has been shown to decrease libido and cause ED. Lithium-mediated CNS sedation contributes to decreased libido; other mechanisms of lithium’s sexual side effects are not known. It is unclear whether lower dosages reduce the likelihood of sexual dysfunction.
Anticonvulsants. In two small studies, phenytoin increased sex hormone-binding globulin, resulting in lower free testosterone levels, which may lead to sexual dysfunction. 18,19 Barbiturates have been shown to decrease libido, probably because of CNS sedation. Carbamazepine and gabapentin exhibit antiandrogenic effects, leading to various types of sexual dysfunction. These effects have not been observed with oxcarbazepine, however.
Lamotrigine may be an effective alternative in patients exhibiting sexual dysfunction with gabapentin. 20
Typical antipsychotics can impair all aspects of sexual function: 14
- CNS sedation and hyperprolactinemia account for decreased libido.
- Local anticholinergic effects may cause ED. Thus, the greater the anticholinergic effects, the presumably higher the incidence of ED.
- Alpha-receptor blockade and inhibition of inner urethral sphincter closure may cause retarded and retrograde ejaculation, respectively.
Of the conventional antipsychotics, thioridazine is associated with the highest incidence of sexual dysfunction. 15
Side effects, drug interactions associated with PDE-5 inhibitors
Dyspepsia, flushing, headache, hypotension, myocardial infarction (rare), nasal congestion, rash, visual disturbances
CYP-2C9 inducers and inhibitors (minor alterations in sildenafil plasma concentration)
Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, pain in limb, visual disturbances
CYP-3A4 inhibitors (increase tadalafil exposure)
Dizziness, dyspepsia, headache, hypotension
CYP-3A4 inducers and inhibitors (altered vardenafil plasma concentration)
* Tadalafil and vardenafil are still undergoing post-marketing surveillance. This explains in part why fewer adverse effects and drug-drug interactions have been reported with these agents than with sildenafil.
Atypical antipsychotics exhibit fewer adverse effects on sexual function than their typical counterparts, but the mechanisms that mediate these effects are the same.
Of these agents, risperidone causes the greatest prolactin elevation. 16 Aripiprazole may also be associated with minimal sexual dysfunction. 17 Other atypicals decrease prolactin levels or raise them transiently, 16,17 so consider switching to one of these agents if a patient experiences ED.
Anxiolytics. Benzodiazepines, with their CNS sedative effects, are associated with decreased libido. Their potential for abuse may augment this effect. Buspirone, a novel anxiolytic that exhibits serotonergic and dopaminergic effects, is not associated with significant sexual dysfunction and may be a viable alternative.
Others. Amphetamines can increase the local sympathetic-to-parasympathetic activity ratio, resulting in ED. This effect is more pronounced with long-term use, though it is also seen with short-term use.
ED also has been reported in patients taking disulfiram, though it is unclear whether the drug or long-term alcohol use caused the dysfunction.
Drug treatment of ED
Because primary ED is a quality-of-life issue and not a health risk, few comparative trials have tested medications that improve erectile function. Thus, ED drug treatment may require trials of two or more agents.
Phosphodiesterase (PDE-5) inhibitors have become widely used as first-line oral medications for ED secondary to numerous causes. Sildenafil has demonstrated effectiveness in treating SSRI-induced ED compared with placebo. Tadalafil and vardenafil have not been studied in patients taking SSRIs.
Side effects, drug interactions associated with other ED agents
Aggression, altered mentation, anxiety, heart failure (rare), insomnia, leukopenia (rare), nausea
Bupropion (increased adverse events)
Cholinergic effects (increased GI motility, lacrimation, miosis, urinary frequency)
Anticholinergics (decreased effects of both agents)
Agitation, amblyopia, arrhythmias (rare), constipation, diaphoresis, dizziness, extrapyramidal symptoms (rare), headache, hypertension
CYP-2D6 inducers and inhibitors (altered bupropion plasma concentration)
Somnolence, constipation, xerostomia, increased appetite, weight gain, dizziness, abnormal dreams, confusion
MAO inhibitors, linezolid, CNS depressants (increased sedative effects)
Abdominal pain, anxiety, arthralgias, confusion, constipation, diaphoresis, dyskinesias, dyspepsia, headache
CYP-1A2 inducers and inhibitors (altered ropinirole plasma concentration)
In one 6-week study, 21 54.4% of patients taking both an SSRI and sildenafil, up to 100 mg, showed significantly improved erectile function, arousal, ejaculation, orgasm, and overall satisfaction. In another study, 22 SSRI-treated patients receiving sildenafil, 5 to 200 mg before sexual activity, reported noticeably improved ability to achieve and maintain erection, ejaculate, and achieve orgasm.
Sildenafil should not be taken concomitantly with agents or products containing nitrates. Use sildenafil with caution in patients with a blood pressure >170/110 mm Hg or <90/50 mm Hg, unstable angina, or retinitis pigmentosa. Also use sildenafil cautiously in patients who have suffered myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months.