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Primary Care Update


Prescribing to preserve or restore sexual function

Side effects associated with psychotropics, and treatments shown to alleviate them

Vol. 3, No. 3 / March 2004
This week's quiz:
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Many psychotropics can cause erectile dysfunction (ED) and other sexual problems (Tables 1 and 2). This side effect can discourage treatment compliance and jeopardize outcomes.

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.

Table 1

Antidepressants associated with sexual dysfunction

Drug class/agent

Proposed mechanism

Dysfunction

Monoamine oxidase inhibitors

Unknown

ED (rare), retarded ejaculation(rare)

Selective serotonin reuptake inhibitors

Increased serum prolactin (possible)
Increased relative dopamine-to-serotonin reuptake inhibition
Increased central serotonin

Decreased libido
ED
Anorgasmia Delayed/retarded ejaculation

Tricyclic antidepressants

CNS depression
Anticholinergic activity

Decreased libido
ED

Venlafaxine

Increased relative dopamine-to-serotonin reuptake inhibition
Increased central serotonin

ED
Anorgasmia Delayed/retarded ejaculation

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

Table 2

Other psychotropics associated with sexual dysfunction

Drug class/agent

Proposed mechanism

Dysfunction

Amphetamines

Increased relative sympathetic nervous syndrome/parasympathetic nervous system activity

ED

Anticholinergics

Anticholinergic activity

ED

Antipsychotics (typical and atypical)

CNS depression, increased serum prolactin
Anticholinergic activity
Alpha1-receptor blockade
Decreased internal urethral sphincter closure

Decreased libido
ED
Retarded ejaculation
Retrograde ejaculation

Barbiturates, benzodiazepines, CNS depressants

CNS depression

Decreased libido

Carbamazepine, gabapentin

Decreased androgenic activity

Decreased libido, ED, retarded ejaculation

Disulfiram

Unknown

ED

Dopamine-receptor agonists

Unknown

ED

Dopamine-receptor antagonists

Increased serum prolactin

Decreased libido

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.

Case report:Continued

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

Table 3

Side effects, drug interactions associated with PDE-5 inhibitors

Drug

Adverse effects

Drug interactions

Sildenafil

Dyspepsia, flushing, headache, hypotension, myocardial infarction (rare), nasal congestion, rash, visual disturbances

CYP-2C9 inducers and inhibitors (minor alterations in sildenafil plasma concentration)
CYP-3A4 inducers and inhibitors (major alterations in sildenafil plasma concentration)
Dihydrocodeine (rare priapism)
Nitrates (severe hypotension)

Tadalafil*

Headache, dyspepsia, back pain, myalgia, nasal congestion, flushing, pain in limb, visual disturbances

CYP-3A4 inhibitors (increase tadalafil exposure)
Alpha blockers other than tamsulosin (hypotension)
Nitrates (severe hypotension)

Vardenafil*

Dizziness, dyspepsia, headache, hypotension

CYP-3A4 inducers and inhibitors (altered vardenafil plasma concentration)
Nitrates (severe hypotension)

* 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.

Adverse effects and drug-drug interactions of selected agents used for ED treatment are listed in Tables 3 and 4.

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.

Table 4

Side effects, drug interactions associated with other ED agents

Drug

Adverse effects

Drug interactions

Amantadine

Aggression, altered mentation, anxiety, heart failure (rare), insomnia, leukopenia (rare), nausea
Livedo reticularis (with extended use), neuroleptic malignant syndrome (upon discontinuation), orthostatic hypotension, psychoses

Bupropion (increased adverse events)
Triamterene (may increase amantadine plasma concentration)

Bethanechol

Cholinergic effects (increased GI motility, lacrimation, miosis, urinary frequency)
Diaphoresis, flushing, headache, hypotension, tachycardia

Anticholinergics (decreased effects of both agents)
Cholinesterase inhibitors (increased cholinergic effects),
Ganglionic blockers (severe hypotension)

Bupropion

Agitation, amblyopia, arrhythmias (rare), constipation, diaphoresis, dizziness, extrapyramidal symptoms (rare), headache, hypertension
Hypoprolactinemia, insomnia, leukopenia (minor), nausea/vomiting
Alcohol psychoses (rare), seizures, serum sickness (rare), taste perversion, tinnitus, tremor, urinary frequency
Urticaria, weight gain (rare), weight loss, xerostomia

CYP-2D6 inducers and inhibitors (altered bupropion plasma concentration)
Dopamine-receptor agonists (increased adverse effects)
MAOIs (increased seizures and psychoses)
QT-prolonging agents (increased QT-prolongation)
Alcohol, systemic steroids, theophylline (increased seizures)

Mirtazapine

Somnolence, constipation, xerostomia, increased appetite, weight gain, dizziness, abnormal dreams, confusion
Hyperlipidemia, flu-like symptoms, back pain

MAO inhibitors, linezolid, CNS depressants (increased sedative effects)
Alcohol (may increase CNS depression)
St John’s wort (may decrease mirtazapine levels)

Ropinirole

Abdominal pain, anxiety, arthralgias, confusion, constipation, diaphoresis, dyskinesias, dyspepsia, headache
Hallucinations, insomnia, nausea/vomiting, orthostatic hypotension, peripheral edema
Somnolence, tremor, upper respiratory infection, urinary tract infection, visual disturbances, xerostomia

CYP-1A2 inducers and inhibitors (altered ropinirole plasma concentration)
Dopamine-receptor antagonists (decreased efficacy of both agents)

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.

Continued...
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