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Painful ear nodules
A. Good-quality patient-oriented evidence
B. Inconsistent or limited-quality patient-oriented evidence
C. Consensus, usual practice, opinion, disease-oriented evidence, case series
A 49-year-old man with a history of hypertension, hypercholesterolemia, polysubstance use, recurrent methicillin-resistant Staphylococcus aureus skin infections, and chronic hepatitis C infection sought care at our emergency department (ED) because parts of his ears had started turning black 3 days earlier. They were also painful to the touch. He denied fever, any similar skin lesions, injury to his ears, or a history of easy bleeding or bruising. A recovering alcoholic, he admitted to regular marijuana use and twice-weekly cocaine use. He had last used cocaine 3 days ago.
The patient was thin and in no acute distress. His vital signs and cardiopulmonary exams were normal. Examination of his ears revealed bilateral violaceous firm, tender purpura on the pinnae (FIGURE).
A complete blood count (CBC) revealed mild leukopenia (white blood cell [WBC] count, 2.0 × 109/L), neutropenia (0.9 × 109/L), and a normal platelet count (264 × 109/L). A chemistry panel, liver function tests, and prothrombin time were normal. Erythrocyte sedimentation rate (ESR) was elevated to 69 mm/h. The patient’s cholesterol level was not elevated. Urine toxicology was positive for cocaine and opioids. A human immunodeficiency virus test was negative.
Figure
Tender purpura on the pinnae
What is your diagnosis?
How would you treat this patient?
Diagnosis: Levamisole toxicity
The patient was diagnosed with levamisole toxicity based on his clinical presentation and the fact that he had used cocaine around the time his ear lesions appeared.
Levamisole—primarily a veterinary antihelmintic medication—is used on rare occasions to treat nephrotic syndrome in children.1 Levamisole is frequently added to cocaine or heroin to increase the street drug’s potency. The Drug Enforcement Administration reports that 69% of seized cocaine lots in the United States contain levamisole.2
The compound is thought to cause a vasculitis and bone marrow suppression resulting in neutropenia. The vasculitis targets small vessels, resulting in thrombosis, which can lead to tissue necrosis.1
Other possibilities in the differential Dx
The differential diagnosis includes a variety of vasculitides and other microvascular pathologies.
Cholesterol emboli arise when cholesterol crystals are released from atherosclerotic plaques, typically after invasive cardiac procedures. In addition, anticoagulants can cause the release of these crystals by inhibiting the formation of protective clots around unstable plaques.3 These emboli can seed the microvasculature anywhere, but the kidneys and skin are most frequently affected. These crystals not only clog the vasculature, causing tissue ischemia, but also activate the complement cascade, triggering a series of inflammatory responses that can lead to luminal fibrosis and narrowing.3
Affected patients have a history of atherosclerotic disease or predisposing factors such as hypertension or diabetes. Ulcerations or frank cyanosis may be found at the tips of the fingers or toes. In severe cases, gangrene will form in these regions. Patients may also have livido reticularis, a lace-like hyperpigmented rash over the lower extremities. Laboratory analysis may indicate acute renal failure or eosinophilia.3
Bacterial endocarditis results from the seeding of bacterial emboli primarily from the mitral or tricuspid valves.4 Streptococci are the primary infectious agent, with staphylococci being more common among intravenous drug users. High-risk populations include patients with artificial valves, the elderly, and the immunocompromised.4
Clinical manifestations include Janeway lesions (asymptomatic hemorrhagic papules on the palms) and Osler’s nodes (tender nodules on the fingertips). Splinter hemorrhages, or linear nonblanching lesions, may be present within the nail beds. Palpable purpura and petechiae may also be found.
Patients may have positive blood cultures, leukocytosis, an elevated ESR, or vegetations on a transesophageal echocardiogram.4 The physical exam may reveal a new cardiac murmur.
High circulating levels of cryoglobulins can arise in the setting of hepatitis C infection, but can also be seen in a number of autoimmune disorders and other infectious diseases.5 Cryoglobulins are immune complexes that are deposited into the lumen of microvasculature. In cold temperatures, these cryoglobulins precipitate, resulting in vasculitis. While most patients are asymptomatic, cutaneous findings in the distal extremities can include palpable purpura, ulcerations, and livido reticularis.5 Patients may complain of arthritis or symptoms consistent with Raynaud’s phenomenon.
Detection of specific serum cryoprecipitates isolated by immunofixation is pathognomonic for this condition, provided the sample is collected in a warm tube. Elevated rheumatoid factor and decreased complement levels may also be seen.5
Henoch-Schönlein purpura (HSP) is a small vessel vasculitis caused by IgA deposition that predominantly affects children. HSP has a host of systemic symptoms, often preceded by a benign upper respiratory infection, consisting of palpable purpura, arthritis, abdominal pain, and glomerulonephritis.6 Palpable purpura will generally be found in dependent portions of the body—especially the buttocks and lower legs.
While the diagnosis is primarily clinical, serum IgA levels and ESR can be elevated, urinalysis may demonstrate hematuria or proteinuria, and a CBC may reveal a leukocytosis with normal platelets.6
Suspect levamisole toxicity in patients using cocaine
Patients with levamisole toxicity present with sudden-onset tender plaques or bullae with necrotic centers within days of cocaine use. Case reports cite lesions primarily on the ears and cheeks. However, they can appear almost anywhere on the body.2,7-9 Physicians should have a high index of suspicion for levamisole toxicity in patients using cocaine who present with unexplained neutropenia or vasculitis.
Laboratory tests. If needed, tissue biopsy and urine detection of levamisole can be used to confirm the diagnosis.1
Management is straight-forward, but not simple
Skin lesions have been reported to improve several weeks after discontinuing use of contaminated cocaine1 (strength of recommendation [SOR]: C). Known users should be referred to drug treatment centers and counseled on the risks of use.
Our patient required hospitalization
When our patient came into the ED, he also complained of left thigh pain and swelling. A computed tomography scan revealed a deep sartorius abscess. The patient was admitted for ultrasound-guided aspiration of the abscess and IV antibiotics. His bilateral painful ear nodules persisted throughout his hospitalization, although his neutropenia resolved after 3 days.
Correspondence: Katherine Winter, MD, 101 Manning Drive, Chapel Hill, NC 27514; [email protected]
1. Lee KC, Culpepper K, Kessler M. Levamisole-induced thrombosis: literature review and pertinent laboratory findings. J Am Acad Dermatol. 2011;65:e128-e129.
2. CDC. Agranulocytosis associated with cocaine use - four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep. 2009;58:1381-1385.
3. Kronzon I, Saric M. Cholesterol embolization syndrome. Circulation. 2010;122:631-641.
4. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330.
5. Tedeschi A, Barate C, Minola E, et al. Cryoglobulinemia. Blood Rev. 2007;21:183-200.
6. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum. 2005;35:143-153.
7. Muirhead TT, Eide MJ. Images in clinical medicine. Toxic effects of levamisole in a cocaine user. N Engl J Med. 2011;364:e52.
8. Bradford M, Rosenberg B, Moreno J, et al. Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole. Ann Intern Med. 2010;152: 758-759.
9. Chung C, Tumeh P, Birnbaum R. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011;65:722-725.
A. Good-quality patient-oriented evidence
B. Inconsistent or limited-quality patient-oriented evidence
C. Consensus, usual practice, opinion, disease-oriented evidence, case series
A 49-year-old man with a history of hypertension, hypercholesterolemia, polysubstance use, recurrent methicillin-resistant Staphylococcus aureus skin infections, and chronic hepatitis C infection sought care at our emergency department (ED) because parts of his ears had started turning black 3 days earlier. They were also painful to the touch. He denied fever, any similar skin lesions, injury to his ears, or a history of easy bleeding or bruising. A recovering alcoholic, he admitted to regular marijuana use and twice-weekly cocaine use. He had last used cocaine 3 days ago.
The patient was thin and in no acute distress. His vital signs and cardiopulmonary exams were normal. Examination of his ears revealed bilateral violaceous firm, tender purpura on the pinnae (FIGURE).
A complete blood count (CBC) revealed mild leukopenia (white blood cell [WBC] count, 2.0 × 109/L), neutropenia (0.9 × 109/L), and a normal platelet count (264 × 109/L). A chemistry panel, liver function tests, and prothrombin time were normal. Erythrocyte sedimentation rate (ESR) was elevated to 69 mm/h. The patient’s cholesterol level was not elevated. Urine toxicology was positive for cocaine and opioids. A human immunodeficiency virus test was negative.
Figure
Tender purpura on the pinnae
What is your diagnosis?
How would you treat this patient?
Diagnosis: Levamisole toxicity
The patient was diagnosed with levamisole toxicity based on his clinical presentation and the fact that he had used cocaine around the time his ear lesions appeared.
Levamisole—primarily a veterinary antihelmintic medication—is used on rare occasions to treat nephrotic syndrome in children.1 Levamisole is frequently added to cocaine or heroin to increase the street drug’s potency. The Drug Enforcement Administration reports that 69% of seized cocaine lots in the United States contain levamisole.2
The compound is thought to cause a vasculitis and bone marrow suppression resulting in neutropenia. The vasculitis targets small vessels, resulting in thrombosis, which can lead to tissue necrosis.1
Other possibilities in the differential Dx
The differential diagnosis includes a variety of vasculitides and other microvascular pathologies.
Cholesterol emboli arise when cholesterol crystals are released from atherosclerotic plaques, typically after invasive cardiac procedures. In addition, anticoagulants can cause the release of these crystals by inhibiting the formation of protective clots around unstable plaques.3 These emboli can seed the microvasculature anywhere, but the kidneys and skin are most frequently affected. These crystals not only clog the vasculature, causing tissue ischemia, but also activate the complement cascade, triggering a series of inflammatory responses that can lead to luminal fibrosis and narrowing.3
Affected patients have a history of atherosclerotic disease or predisposing factors such as hypertension or diabetes. Ulcerations or frank cyanosis may be found at the tips of the fingers or toes. In severe cases, gangrene will form in these regions. Patients may also have livido reticularis, a lace-like hyperpigmented rash over the lower extremities. Laboratory analysis may indicate acute renal failure or eosinophilia.3
Bacterial endocarditis results from the seeding of bacterial emboli primarily from the mitral or tricuspid valves.4 Streptococci are the primary infectious agent, with staphylococci being more common among intravenous drug users. High-risk populations include patients with artificial valves, the elderly, and the immunocompromised.4
Clinical manifestations include Janeway lesions (asymptomatic hemorrhagic papules on the palms) and Osler’s nodes (tender nodules on the fingertips). Splinter hemorrhages, or linear nonblanching lesions, may be present within the nail beds. Palpable purpura and petechiae may also be found.
Patients may have positive blood cultures, leukocytosis, an elevated ESR, or vegetations on a transesophageal echocardiogram.4 The physical exam may reveal a new cardiac murmur.
High circulating levels of cryoglobulins can arise in the setting of hepatitis C infection, but can also be seen in a number of autoimmune disorders and other infectious diseases.5 Cryoglobulins are immune complexes that are deposited into the lumen of microvasculature. In cold temperatures, these cryoglobulins precipitate, resulting in vasculitis. While most patients are asymptomatic, cutaneous findings in the distal extremities can include palpable purpura, ulcerations, and livido reticularis.5 Patients may complain of arthritis or symptoms consistent with Raynaud’s phenomenon.
Detection of specific serum cryoprecipitates isolated by immunofixation is pathognomonic for this condition, provided the sample is collected in a warm tube. Elevated rheumatoid factor and decreased complement levels may also be seen.5
Henoch-Schönlein purpura (HSP) is a small vessel vasculitis caused by IgA deposition that predominantly affects children. HSP has a host of systemic symptoms, often preceded by a benign upper respiratory infection, consisting of palpable purpura, arthritis, abdominal pain, and glomerulonephritis.6 Palpable purpura will generally be found in dependent portions of the body—especially the buttocks and lower legs.
While the diagnosis is primarily clinical, serum IgA levels and ESR can be elevated, urinalysis may demonstrate hematuria or proteinuria, and a CBC may reveal a leukocytosis with normal platelets.6
Suspect levamisole toxicity in patients using cocaine
Patients with levamisole toxicity present with sudden-onset tender plaques or bullae with necrotic centers within days of cocaine use. Case reports cite lesions primarily on the ears and cheeks. However, they can appear almost anywhere on the body.2,7-9 Physicians should have a high index of suspicion for levamisole toxicity in patients using cocaine who present with unexplained neutropenia or vasculitis.
Laboratory tests. If needed, tissue biopsy and urine detection of levamisole can be used to confirm the diagnosis.1
Management is straight-forward, but not simple
Skin lesions have been reported to improve several weeks after discontinuing use of contaminated cocaine1 (strength of recommendation [SOR]: C). Known users should be referred to drug treatment centers and counseled on the risks of use.
Our patient required hospitalization
When our patient came into the ED, he also complained of left thigh pain and swelling. A computed tomography scan revealed a deep sartorius abscess. The patient was admitted for ultrasound-guided aspiration of the abscess and IV antibiotics. His bilateral painful ear nodules persisted throughout his hospitalization, although his neutropenia resolved after 3 days.
Correspondence: Katherine Winter, MD, 101 Manning Drive, Chapel Hill, NC 27514; [email protected]
A. Good-quality patient-oriented evidence
B. Inconsistent or limited-quality patient-oriented evidence
C. Consensus, usual practice, opinion, disease-oriented evidence, case series
A 49-year-old man with a history of hypertension, hypercholesterolemia, polysubstance use, recurrent methicillin-resistant Staphylococcus aureus skin infections, and chronic hepatitis C infection sought care at our emergency department (ED) because parts of his ears had started turning black 3 days earlier. They were also painful to the touch. He denied fever, any similar skin lesions, injury to his ears, or a history of easy bleeding or bruising. A recovering alcoholic, he admitted to regular marijuana use and twice-weekly cocaine use. He had last used cocaine 3 days ago.
The patient was thin and in no acute distress. His vital signs and cardiopulmonary exams were normal. Examination of his ears revealed bilateral violaceous firm, tender purpura on the pinnae (FIGURE).
A complete blood count (CBC) revealed mild leukopenia (white blood cell [WBC] count, 2.0 × 109/L), neutropenia (0.9 × 109/L), and a normal platelet count (264 × 109/L). A chemistry panel, liver function tests, and prothrombin time were normal. Erythrocyte sedimentation rate (ESR) was elevated to 69 mm/h. The patient’s cholesterol level was not elevated. Urine toxicology was positive for cocaine and opioids. A human immunodeficiency virus test was negative.
Figure
Tender purpura on the pinnae
What is your diagnosis?
How would you treat this patient?
Diagnosis: Levamisole toxicity
The patient was diagnosed with levamisole toxicity based on his clinical presentation and the fact that he had used cocaine around the time his ear lesions appeared.
Levamisole—primarily a veterinary antihelmintic medication—is used on rare occasions to treat nephrotic syndrome in children.1 Levamisole is frequently added to cocaine or heroin to increase the street drug’s potency. The Drug Enforcement Administration reports that 69% of seized cocaine lots in the United States contain levamisole.2
The compound is thought to cause a vasculitis and bone marrow suppression resulting in neutropenia. The vasculitis targets small vessels, resulting in thrombosis, which can lead to tissue necrosis.1
Other possibilities in the differential Dx
The differential diagnosis includes a variety of vasculitides and other microvascular pathologies.
Cholesterol emboli arise when cholesterol crystals are released from atherosclerotic plaques, typically after invasive cardiac procedures. In addition, anticoagulants can cause the release of these crystals by inhibiting the formation of protective clots around unstable plaques.3 These emboli can seed the microvasculature anywhere, but the kidneys and skin are most frequently affected. These crystals not only clog the vasculature, causing tissue ischemia, but also activate the complement cascade, triggering a series of inflammatory responses that can lead to luminal fibrosis and narrowing.3
Affected patients have a history of atherosclerotic disease or predisposing factors such as hypertension or diabetes. Ulcerations or frank cyanosis may be found at the tips of the fingers or toes. In severe cases, gangrene will form in these regions. Patients may also have livido reticularis, a lace-like hyperpigmented rash over the lower extremities. Laboratory analysis may indicate acute renal failure or eosinophilia.3
Bacterial endocarditis results from the seeding of bacterial emboli primarily from the mitral or tricuspid valves.4 Streptococci are the primary infectious agent, with staphylococci being more common among intravenous drug users. High-risk populations include patients with artificial valves, the elderly, and the immunocompromised.4
Clinical manifestations include Janeway lesions (asymptomatic hemorrhagic papules on the palms) and Osler’s nodes (tender nodules on the fingertips). Splinter hemorrhages, or linear nonblanching lesions, may be present within the nail beds. Palpable purpura and petechiae may also be found.
Patients may have positive blood cultures, leukocytosis, an elevated ESR, or vegetations on a transesophageal echocardiogram.4 The physical exam may reveal a new cardiac murmur.
High circulating levels of cryoglobulins can arise in the setting of hepatitis C infection, but can also be seen in a number of autoimmune disorders and other infectious diseases.5 Cryoglobulins are immune complexes that are deposited into the lumen of microvasculature. In cold temperatures, these cryoglobulins precipitate, resulting in vasculitis. While most patients are asymptomatic, cutaneous findings in the distal extremities can include palpable purpura, ulcerations, and livido reticularis.5 Patients may complain of arthritis or symptoms consistent with Raynaud’s phenomenon.
Detection of specific serum cryoprecipitates isolated by immunofixation is pathognomonic for this condition, provided the sample is collected in a warm tube. Elevated rheumatoid factor and decreased complement levels may also be seen.5
Henoch-Schönlein purpura (HSP) is a small vessel vasculitis caused by IgA deposition that predominantly affects children. HSP has a host of systemic symptoms, often preceded by a benign upper respiratory infection, consisting of palpable purpura, arthritis, abdominal pain, and glomerulonephritis.6 Palpable purpura will generally be found in dependent portions of the body—especially the buttocks and lower legs.
While the diagnosis is primarily clinical, serum IgA levels and ESR can be elevated, urinalysis may demonstrate hematuria or proteinuria, and a CBC may reveal a leukocytosis with normal platelets.6
Suspect levamisole toxicity in patients using cocaine
Patients with levamisole toxicity present with sudden-onset tender plaques or bullae with necrotic centers within days of cocaine use. Case reports cite lesions primarily on the ears and cheeks. However, they can appear almost anywhere on the body.2,7-9 Physicians should have a high index of suspicion for levamisole toxicity in patients using cocaine who present with unexplained neutropenia or vasculitis.
Laboratory tests. If needed, tissue biopsy and urine detection of levamisole can be used to confirm the diagnosis.1
Management is straight-forward, but not simple
Skin lesions have been reported to improve several weeks after discontinuing use of contaminated cocaine1 (strength of recommendation [SOR]: C). Known users should be referred to drug treatment centers and counseled on the risks of use.
Our patient required hospitalization
When our patient came into the ED, he also complained of left thigh pain and swelling. A computed tomography scan revealed a deep sartorius abscess. The patient was admitted for ultrasound-guided aspiration of the abscess and IV antibiotics. His bilateral painful ear nodules persisted throughout his hospitalization, although his neutropenia resolved after 3 days.
Correspondence: Katherine Winter, MD, 101 Manning Drive, Chapel Hill, NC 27514; [email protected]
1. Lee KC, Culpepper K, Kessler M. Levamisole-induced thrombosis: literature review and pertinent laboratory findings. J Am Acad Dermatol. 2011;65:e128-e129.
2. CDC. Agranulocytosis associated with cocaine use - four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep. 2009;58:1381-1385.
3. Kronzon I, Saric M. Cholesterol embolization syndrome. Circulation. 2010;122:631-641.
4. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330.
5. Tedeschi A, Barate C, Minola E, et al. Cryoglobulinemia. Blood Rev. 2007;21:183-200.
6. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum. 2005;35:143-153.
7. Muirhead TT, Eide MJ. Images in clinical medicine. Toxic effects of levamisole in a cocaine user. N Engl J Med. 2011;364:e52.
8. Bradford M, Rosenberg B, Moreno J, et al. Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole. Ann Intern Med. 2010;152: 758-759.
9. Chung C, Tumeh P, Birnbaum R. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011;65:722-725.
1. Lee KC, Culpepper K, Kessler M. Levamisole-induced thrombosis: literature review and pertinent laboratory findings. J Am Acad Dermatol. 2011;65:e128-e129.
2. CDC. Agranulocytosis associated with cocaine use - four States, March 2008-November 2009. MMWR Morb Mortal Wkly Rep. 2009;58:1381-1385.
3. Kronzon I, Saric M. Cholesterol embolization syndrome. Circulation. 2010;122:631-641.
4. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330.
5. Tedeschi A, Barate C, Minola E, et al. Cryoglobulinemia. Blood Rev. 2007;21:183-200.
6. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum. 2005;35:143-153.
7. Muirhead TT, Eide MJ. Images in clinical medicine. Toxic effects of levamisole in a cocaine user. N Engl J Med. 2011;364:e52.
8. Bradford M, Rosenberg B, Moreno J, et al. Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole. Ann Intern Med. 2010;152: 758-759.
9. Chung C, Tumeh P, Birnbaum R. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011;65:722-725.
Prescribing to preserve or restore sexual function
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 SSRIs9-11 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.
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.
Bupropion. In double-blind trials,11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.
Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.
Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.23
Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.
Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.12,13
Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.
Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.24 Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.
Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.
Related resources
- Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
- Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
- British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction
Drug brand names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Bethanechol • Urecholine
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Carbamazepine • Tegretol
- Dihydrocodeine • Synalgos
- Disulfiram • Antabuse
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Linezolid • Zyvox
- Lisinopril • Prinivil, others
- Lithium • Eskalith, others
- Metformin • Glucophage
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Phenytoin • Dilantin
- Risperidone • Risperdal
- Ropinirole • Requip
- Sertraline • Zoloft
- Sildenafil • Viagra
- Simvastatin • Zocor
- Tadalafil • Cialis
- Triamterene • Dyazide, others
- Trazodone • Desyrel, others
- Vardenafil • Levitra
- Warfarin • Coumadin
Disclosure
Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.
1. National Institutes of Health consensus conference on impotence. JAMA 1993;270:83-90.
2. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23:176-94.
3. Harrison WM, Rabkin JG, Ehrhardt AA, et al. Effects of antidepressant medication on sexual function: a controlled study. J Clin Psychopharmacol 1986;6:144-9.
4. Benazzi F, Mazzoli M. Fluoxetine-induced sexual dysfunction: a dose-dependent effect? Pharmacopsychiatry 1994;27:246.-
5. Clinical management of depression: bupropion—an update. Monograph series, vol.1, no. 1. Proceedings of a closed symposium: Antidepressant drug therapy: bupropion—an update meeting, Boca Raton, FL, October 30-31, 1992.
6. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995;152:1514-16.
7. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999;19:67-85.
8. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol 1998;18:274-81.
9. Koutouvidis N, Pratikakis M, Fotiadou A. The use of mirtazapine in a group of 11 patients following poor compliance to selective serotonin reuptake inhibitor treatment due to sexual dysfunction. Int Clin Psychopharmacol 1999;14:253-5.
10. Gelenberg AJ, McGahuey C, Laukes C, et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000;61:356-60.
11. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol 2000;20:122-8.
12. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001;158:805-7.
13. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry 1999;60:260-1.
14. Smith SM, O’Keane V, Murray R. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002;181:49-55.
15. Kotin J, Wilbert DE, Verburg D, Soldinger SM. Thioridazine and sexual dysfunction. Am J Psychiatry 1976;133:82-5.
16. Guthrie SK. Clinical issues associated with maintenance treatment of patients with schizophrenia. Am J Health-Syst Pharm 2002;59(suppl 5):519-24.
17. Goodnick PJ, Rodriguez L, Santana O. Antipsychotics: impact on prolactin levels. Expert Opin Pharmacother 2002;3:1381-91.
18. Brunet M, Rodamilans M, Martinez-Osaba MJ, et al. Effects of long-term antiepileptic therapy on the catabolism of testosterone. Pharmacol Toxicol 1995;76:371-5.
19. Heroz AG, Levesque LA, Drislane FW, et al. Phenytoin-induced elevation of serum estradiol and reproductive dysfunction in men with epilepsy. Epilepsia 1991;32:550-3.
20. Husain AM, Carwile ST, Miller PP, Radtke RA. Improved sexual function in three men taking lamotrigine for epilepsy. South Med J 2000;93:335-6.
21. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil. A randomized controlled trial. JAMA 2003;289:56-64.
22. Nurnberg HG, Gelenberg A, Hargreave TB, et al. Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. Am J Psychiatry 2001;158:1926-8.
23. Shrivastava RK, Shrivastava S, Overweg N, Schmitt M. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1995;15:83-4.
24. Worthington JJ, 3rd, Simon NM, Korbly NB, et al. Ropinirole for antidepressant-induced sexual dysfunction. Int Clin Psychopharmacol 2002;17:307-10.
25. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry 1982;139:1193-4.
26. Yager J. Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report. J Clin Psychiatry 1986;47:210-11.
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 SSRIs9-11 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.
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.
Bupropion. In double-blind trials,11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.
Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.
Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.23
Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.
Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.12,13
Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.
Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.24 Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.
Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.
Related resources
- Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
- Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
- British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction
Drug brand names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Bethanechol • Urecholine
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Carbamazepine • Tegretol
- Dihydrocodeine • Synalgos
- Disulfiram • Antabuse
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Linezolid • Zyvox
- Lisinopril • Prinivil, others
- Lithium • Eskalith, others
- Metformin • Glucophage
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Phenytoin • Dilantin
- Risperidone • Risperdal
- Ropinirole • Requip
- Sertraline • Zoloft
- Sildenafil • Viagra
- Simvastatin • Zocor
- Tadalafil • Cialis
- Triamterene • Dyazide, others
- Trazodone • Desyrel, others
- Vardenafil • Levitra
- Warfarin • Coumadin
Disclosure
Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.
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 SSRIs9-11 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.
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.
Bupropion. In double-blind trials,11,12 the agent’s sustained-release form has shown effectiveness as an alternative or adjunct to SSRIs in treating SSRI-induced ED. Prescribe at 150 mg nightly when used as an adjunct.
Bupropion is contraindicated in patients with bulimia, anorexia nervosa, and seizure disorders, and in patients taking MAOIs. Use bupropion cautiously in patients with cranial trauma, renal or hepatic insufficiency, uncontrolled hypertension, myocardial infarction, unstable cardiovascular disease, psychosis, and bipolar disorder, and in patients abusing alcohol or taking warfarin.
Amantadine, an oral dopamine-receptor agonist with innate cholinergic effects, has shown effectiveness against SSRI-induced ED when given at 200 mg bid in a small trial.23
Avoid using amantadine in patients with closed-angle glaucoma, and use with caution in patients with heart failure and in persons age 65 and older.
Mirtazapine, 15 mg/d, has shown effectiveness as an SSRI alternative and as SSRI augmentation therapy to alleviate sexual dysfunction.12,13
Mirtazapine is contraindicated in patients with hypersensitivity or in patients who have used an MAOI within 14 days. Be careful when combining mirtazapine with an SSRI as the combination may increase the risk of serotonin syndrome.
Ropinirole, an oral dopamine 2-receptor agonist used to treat Parkinson’s disease, has shown effectiveness against antidepressant-induced ED when given at 0.25 mg/d and titrated across 4 weeks to 2 to 4 mg/d.24 Use ropinirole carefully in patients with bradycardia, dyskinesias, hallucinations, renal or hepatic insufficiency, and hypotension.
Bethanechol, an oral cholinergic agent used to treat urinary retention, has been described in case reports to alleviate TCA-induced ED when given at 20 mg 1 to 2 hours before sexual activity.25,26 Bethanechol is contraindicated in patients with hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, Parkinson’s disease, urinary bladder neck obstruction, spastic GI disturbances, acute inflammatory GI lesions, peritonitis, and vagotonia.
Related resources
- Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-110.
- Viera AJ, Clenney TL, Shenenberger DW, Green GF. Newer pharmacologic alternatives for erectile dysfunction. Am Fam Physician 1999;60:1159-72.
- British Medical Journal Web site search: erectile dysfunction. http://bmj.bmjjournals.com/cgi/collection/erectile_dysfunction
Drug brand names
- Amantadine • Symmetrel
- Aripiprazole • Abilify
- Bethanechol • Urecholine
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Carbamazepine • Tegretol
- Dihydrocodeine • Synalgos
- Disulfiram • Antabuse
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Linezolid • Zyvox
- Lisinopril • Prinivil, others
- Lithium • Eskalith, others
- Metformin • Glucophage
- Mirtazapine • Remeron
- Nefazodone • Serzone
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Phenytoin • Dilantin
- Risperidone • Risperdal
- Ropinirole • Requip
- Sertraline • Zoloft
- Sildenafil • Viagra
- Simvastatin • Zocor
- Tadalafil • Cialis
- Triamterene • Dyazide, others
- Trazodone • Desyrel, others
- Vardenafil • Levitra
- Warfarin • Coumadin
Disclosure
Dr. Viera and Mr. Conrad report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
Dr. Choksi is a regional scientific manager for cardiovascular medicine with Novartis Pharmaceuticals Corp. When he co-wrote this article he was clinical coordinator, pharmacy department, Naval Hospital, Jacksonville, FL.
1. National Institutes of Health consensus conference on impotence. JAMA 1993;270:83-90.
2. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23:176-94.
3. Harrison WM, Rabkin JG, Ehrhardt AA, et al. Effects of antidepressant medication on sexual function: a controlled study. J Clin Psychopharmacol 1986;6:144-9.
4. Benazzi F, Mazzoli M. Fluoxetine-induced sexual dysfunction: a dose-dependent effect? Pharmacopsychiatry 1994;27:246.-
5. Clinical management of depression: bupropion—an update. Monograph series, vol.1, no. 1. Proceedings of a closed symposium: Antidepressant drug therapy: bupropion—an update meeting, Boca Raton, FL, October 30-31, 1992.
6. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995;152:1514-16.
7. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999;19:67-85.
8. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol 1998;18:274-81.
9. Koutouvidis N, Pratikakis M, Fotiadou A. The use of mirtazapine in a group of 11 patients following poor compliance to selective serotonin reuptake inhibitor treatment due to sexual dysfunction. Int Clin Psychopharmacol 1999;14:253-5.
10. Gelenberg AJ, McGahuey C, Laukes C, et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000;61:356-60.
11. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol 2000;20:122-8.
12. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001;158:805-7.
13. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry 1999;60:260-1.
14. Smith SM, O’Keane V, Murray R. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002;181:49-55.
15. Kotin J, Wilbert DE, Verburg D, Soldinger SM. Thioridazine and sexual dysfunction. Am J Psychiatry 1976;133:82-5.
16. Guthrie SK. Clinical issues associated with maintenance treatment of patients with schizophrenia. Am J Health-Syst Pharm 2002;59(suppl 5):519-24.
17. Goodnick PJ, Rodriguez L, Santana O. Antipsychotics: impact on prolactin levels. Expert Opin Pharmacother 2002;3:1381-91.
18. Brunet M, Rodamilans M, Martinez-Osaba MJ, et al. Effects of long-term antiepileptic therapy on the catabolism of testosterone. Pharmacol Toxicol 1995;76:371-5.
19. Heroz AG, Levesque LA, Drislane FW, et al. Phenytoin-induced elevation of serum estradiol and reproductive dysfunction in men with epilepsy. Epilepsia 1991;32:550-3.
20. Husain AM, Carwile ST, Miller PP, Radtke RA. Improved sexual function in three men taking lamotrigine for epilepsy. South Med J 2000;93:335-6.
21. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil. A randomized controlled trial. JAMA 2003;289:56-64.
22. Nurnberg HG, Gelenberg A, Hargreave TB, et al. Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. Am J Psychiatry 2001;158:1926-8.
23. Shrivastava RK, Shrivastava S, Overweg N, Schmitt M. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1995;15:83-4.
24. Worthington JJ, 3rd, Simon NM, Korbly NB, et al. Ropinirole for antidepressant-induced sexual dysfunction. Int Clin Psychopharmacol 2002;17:307-10.
25. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry 1982;139:1193-4.
26. Yager J. Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report. J Clin Psychiatry 1986;47:210-11.
1. National Institutes of Health consensus conference on impotence. JAMA 1993;270:83-90.
2. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther 1997;23:176-94.
3. Harrison WM, Rabkin JG, Ehrhardt AA, et al. Effects of antidepressant medication on sexual function: a controlled study. J Clin Psychopharmacol 1986;6:144-9.
4. Benazzi F, Mazzoli M. Fluoxetine-induced sexual dysfunction: a dose-dependent effect? Pharmacopsychiatry 1994;27:246.-
5. Clinical management of depression: bupropion—an update. Monograph series, vol.1, no. 1. Proceedings of a closed symposium: Antidepressant drug therapy: bupropion—an update meeting, Boca Raton, FL, October 30-31, 1992.
6. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995;152:1514-16.
7. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 1999;19:67-85.
8. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B. Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol 1998;18:274-81.
9. Koutouvidis N, Pratikakis M, Fotiadou A. The use of mirtazapine in a group of 11 patients following poor compliance to selective serotonin reuptake inhibitor treatment due to sexual dysfunction. Int Clin Psychopharmacol 1999;14:253-5.
10. Gelenberg AJ, McGahuey C, Laukes C, et al. Mirtazapine substitution in SSRI-induced sexual dysfunction. J Clin Psychiatry 2000;61:356-60.
11. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol 2000;20:122-8.
12. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry 2001;158:805-7.
13. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry 1999;60:260-1.
14. Smith SM, O’Keane V, Murray R. Sexual dysfunction in patients taking conventional antipsychotic medication. Br J Psychiatry 2002;181:49-55.
15. Kotin J, Wilbert DE, Verburg D, Soldinger SM. Thioridazine and sexual dysfunction. Am J Psychiatry 1976;133:82-5.
16. Guthrie SK. Clinical issues associated with maintenance treatment of patients with schizophrenia. Am J Health-Syst Pharm 2002;59(suppl 5):519-24.
17. Goodnick PJ, Rodriguez L, Santana O. Antipsychotics: impact on prolactin levels. Expert Opin Pharmacother 2002;3:1381-91.
18. Brunet M, Rodamilans M, Martinez-Osaba MJ, et al. Effects of long-term antiepileptic therapy on the catabolism of testosterone. Pharmacol Toxicol 1995;76:371-5.
19. Heroz AG, Levesque LA, Drislane FW, et al. Phenytoin-induced elevation of serum estradiol and reproductive dysfunction in men with epilepsy. Epilepsia 1991;32:550-3.
20. Husain AM, Carwile ST, Miller PP, Radtke RA. Improved sexual function in three men taking lamotrigine for epilepsy. South Med J 2000;93:335-6.
21. Nurnberg HG, Hensley PL, Gelenberg AJ, et al. Treatment of antidepressant-associated sexual dysfunction with sildenafil. A randomized controlled trial. JAMA 2003;289:56-64.
22. Nurnberg HG, Gelenberg A, Hargreave TB, et al. Efficacy of sildenafil citrate for the treatment of erectile dysfunction in men taking serotonin reuptake inhibitors. Am J Psychiatry 2001;158:1926-8.
23. Shrivastava RK, Shrivastava S, Overweg N, Schmitt M. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 1995;15:83-4.
24. Worthington JJ, 3rd, Simon NM, Korbly NB, et al. Ropinirole for antidepressant-induced sexual dysfunction. Int Clin Psychopharmacol 2002;17:307-10.
25. Gross MD. Reversal by bethanechol of sexual dysfunction caused by anticholinergic antidepressants. Am J Psychiatry 1982;139:1193-4.
26. Yager J. Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report. J Clin Psychiatry 1986;47:210-11.
Heparin prevents recurrent VTE in cancer patients
In patients with cancer and venous thromboembolism, low-molecular-weight heparin effectively reduces symptomatic recurrent venous thromboembolism (VTE) more effectively than warfarin. Although cost and logistical considerations should be considered, this study demonstrates that the use of low-molecular-weight heparin is an effective approach for the prevention of recurrent VTE in cancer patients.
In patients with cancer and venous thromboembolism, low-molecular-weight heparin effectively reduces symptomatic recurrent venous thromboembolism (VTE) more effectively than warfarin. Although cost and logistical considerations should be considered, this study demonstrates that the use of low-molecular-weight heparin is an effective approach for the prevention of recurrent VTE in cancer patients.
In patients with cancer and venous thromboembolism, low-molecular-weight heparin effectively reduces symptomatic recurrent venous thromboembolism (VTE) more effectively than warfarin. Although cost and logistical considerations should be considered, this study demonstrates that the use of low-molecular-weight heparin is an effective approach for the prevention of recurrent VTE in cancer patients.