Applied Evidence

Gastroesophageal reflux disease (GERD) is a common, multifactorial condition that often results in decreased quality of life with interruptions of sleep, work, and social activities. Patients have reported that GERD affects emotional well-being to a greater degree than diabetes or hypertension.^1,2 GERD is also associated with well-established complications, including Barrett’s esophagus. The role of reflux in carcinogenesis is controversial; the possibility of an association, however, implies that GERD should be treated aggressively and early.³

Symptoms of gerd

The typical symptoms of GERD are heartburn and regurgitation. Heartburn is best defined as a burning retrosternal discomfort starting in the epigastrium or lower chest and moving upwards towards the neck. Regurgitation is the effortless movement of gastric contents up into the esophagus or pharynx.

Most patients with GERD do not have endoscopically visible lesions; a careful analysis of symptoms generally forms the basis of a preliminary diagnosis.

The occurrence of heartburn on 2 or more days a week has been suggested as a basis for further investigation for GERD.⁴ However, symptoms vary greatly. Patients may be asymptomatic or experience symptoms that more closely resemble gastric disorders, infectious and motor disorders of the esophagus, biliary tract disease, or even coronary artery disease.

Extraesophageal manifestations

Adding to the complexity of diagnosis, GERD has been shown to have extraesophageal manifestations, including chronic cough, asthma, recurrent aspiration, chronic sore throat, reflux laryngitis, and paroxysmal laryngospasm or voice changes.

Although the relationship between asthma and GERD remains unclear, it has been estimated that 24% to 98% of patients with asthma also have GERD.⁵ Some patients with asthma have been shown to have excess acid reflux into the esophagus. Reflux-like symptoms may precede episodes of asthma that occur after meals or when lying down.^{6 8}

Additionally, GERD has been noted in 10% to 50% of patients with non-cardiac chest pain.^9,10

Diagnostic strategies

Trial of treatment

Diagnosis is usually based on typical symptoms—heartburn or regurgitation—in the clinical history. (The Figure shows a treatment algorithm for both severe and mild symptoms.)

A 2-week trial of treatment with a proton pump inhibitor (PPI) provides the quickest and most cost-effective confirmation of diagnosis and is recommended for the patient whose history suggests uncomplicated GERD. A positive response to PPI treatment in a patient with symptoms suggestive of GERD is at least as sensitive and specific as 24-hour intraesophageal pH monitoring, which is still often considered the “gold standard” for the diagnosis of GERD. Furthermore, complete lack of improvement in response to PPI treatment is highly predictive that the patient does not have GERD and indicates the need for further evaluation and a possible revision of diagnosis.^11,12

H₂ receptor antagonists (H₂RAs) have also been investigated in empirical trials for usefulness in diagnosing GERD. H₂RAs are less effective than PPIs.^13,14

FIGURE Medical management of suspected GERD

Endoscopy

No data support routine endoscopy for patients with the recent onset of uncomplicated heartburn who respond to medical therapy. Endoscopy is recommended, however, for patients with severe or atypical GERD symptoms, when other diseases may be present, or when a treatment trial with a PPI is ineffective.¹⁵ Endoscopy is useful for diagnosing complications of GERD, such as Barrett’s esophagus, esophagitis, and strictures. Fewer than 50% of patients with GERD symptoms have evidence of esophagitis on endoscopy.¹⁶

The American Society for Gastrointestinal Endoscopy recommends endoscopy when there are clinical suggestions of severe reflux or other disease.¹⁷ The American College of Gastroenterology recommends further testing

• when empiric therapy has failed
• when symptoms of complicated disease exist
• when there is dysphagia, bleeding, weight loss, choking, chest pain, or long-standing symptoms
• when continuous therapy is required
• to screen for Barrett’s esophagus.¹⁸

The Canadian Consensus Conference recommends endoscopy in the presence of

• dysphagia
• odynophagia
• bleeding
• weight loss
• noncardiac chest pain
• failure to respond to 4 to 8 weeks of pharmacologic therapy.¹⁹

It also recommends a single test if maintenance therapy is required.

Other diagnostic tests

Other diagnostic tools may be of use in some settings.

A barium esophagram can document reflux, and Bernstein testing (esophageal acid infusion test) can identify esophageal hypersensitivity to acid, although neither establishes a diagnosis of GERD. Ambulatory 24-hour intraesophageal pH monitoring can help to establish the presence of GERD by documenting the proportion of time during which the intraesophageal pH is acidic (<4) and can also establish the degree of association between patients’ symptoms and episodes of esophageal acidification.

Esophageal manometry is not recommended as a routine diagnostic test for GERD. It is important in selected patients to exclude an esophageal motility disorder and may be necessary as part of the pre-operative evaluation for patients in whom a surgical operation for GERD is being considered.

Management of gerd

GERD commonly requires long-term management that includes dietary, lifestyle, and pharmacological interventions. Surgery may be considered for the long-term management of the condition in carefully selected patients.

Diet and lifestyle

Dietary modifications. Patients should not consume large meals and should avoid lying down for 3 to 4 hours after eating. Caffeinated products, peppermint, fatty foods, chocolate, spicy foods, citrus fruits and juices, tomato-based products, and alcohol may contribute to episodes of GERD.^18,21 Lozenges of any kind are able to stimulate salivary secretion, help clear refluxed acid, and hence, help relieve symptoms.

Lifestyle modifications. Changes in lifestyle may include such seemingly sensible interventions as sleeping with the head elevated, stopping smoking, and losing weight. There is little or no established evidence for the efficacy of these and other lifestyle modifications in the management of GERD. However, in1 trial of 63 patients, elevating the head of the bed with 6-inch blocks resulted in 1 less episode of heartburn or acid regurgitation per night when compared with lying flat.²² In another trial of 71 patients with esophagitis, elevating the bed was nearly as effective as ranitidine for reducing symptoms and producing endoscopically verifiable healing.²³

Drug interventions

Pharmacological interventions include over-the-counter remedies such as antacids and H₂RAs (Table 1), as well as prescription-only doses of H₂RAs and PPIs. At the time of writing, no PPI was available in an over-the-counter preparation in the United States, although over-the-counter omeprazole may soon be approved. Many authorities believe an incremental approach to the management of GERD is appropriate, beginning with lifestyle modifications and over-the-counter preparations, continuing with H₂ blockers, and reserving PPIs for nonresponders. While this approach may have appeal from a cost perspective, we believe another approach (as illustrated in the Figure) is clinically superior.

Antacids. Over-the-counter antacids rapidly increase the pH of the intraesophageal contents and also neutralize acidic gastric contents that might be refluxed. They are frequently used to treat heartburn. However, few clinical trials have evaluated the efficacy of antacids. Published trials^24-26 are limited by small sample sizes and a lack of intention-to-treat analysis. Only 1 showed positive evidence for antacid efficacy.²⁵

The utility of antacids is limited by the need for frequent dosing and possible interactions with such drugs as fluoroquinolones, tetracycline, and ferrous sulfate.²⁷ Alginate/antacids have shown statistically significant benefit compared with placebo for relief of mild-to-moderate GERD symptoms and healing of esophagitis.^24,28-34

H ₂ receptor antagonists. H₂RAs have shown positive effects on symptoms in some studies, although symptomatic response rates observed were only around 60% to 70%. Additionally, most of the trials to date have been for 2 to 6 weeks in duration.^{35 43} An issue worthy of consideration with the H₂RAs is the development of tolerance with continuous use.⁴⁴

An H₂RA-antacid combination was recently evaluated in a trial that compared it with monotherapy using either agent. Of the patients receiving combination therapy, 81% reported an excellent or good symptom response. Those receiving famotidine or atacid alone reported a 72% excellent or good symptom response.³

Proton pump inhibitors. PPIs potently reduce gastric acid secretion by inhibiting the H⁺-K⁺adenosine triphosphatase pump of the parietal cell. As a result, they suppress gastric acid secretion for a longer period than H₂RAs.⁴⁵ Evidence from randomized, controlled trials has demonstrated the superiority of PPIs over any other class of drugs for the relief of GERD symptoms, for healing esophagitis, and for maintaining patients in remission. Standard doses of omeprazole, lansoprazole, panto-prazole, esomeprazole, and rabeprazole have, for the most part, shown comparable rates of healing and remission in erosive esophagitis.^46-52

PPIs are best absorbed in the absence of food. Ingestion of food after a PPI stimulates parietal cell activity when blood levels of the PPI are increasing; this promotes uptake of the PPI by the parietal cells. Therefore, patients should be advised to take their PPI between 30 and 60 minutes before eating. For patients on a once-daily PPI, the best time to take it is about 30 to 60 minutes before breakfast. Despite these recommendations, a recent survey of over 1000 US primary care physicians found that 36% instructed their patients to take their PPI with or after a meal or did not specify the timing of dosing.⁵³

PPI therapy can be tailored to control GERD symptoms. Treatment can start with the most effective dosage and then be stepped down, or start with a minimum dosage and then be stepped up (Table 2). Patients with predominantly daytime symptoms should take PPIs before breakfast. Concerns that were once expressed about the long-term use of PPIs, such as predisposing patients to stomach cancer, have been refuted by extensive clinical experience and intensive monitoring (Table 3).³

TABLE 1

Over-the-counter therapy for GERD

TABLE 2

Step-down and step-up treatments: advantages and disadvantages

TABLE 3

Potential concerns associated with the use of proton pump inhibitors

Surgery

Surgical antireflux therapy is an option in carefully selected patients. Those who respond best to surgical therapy will have had clearly documented acid reflux, typical symptoms, and symptomatic improvement while on PPI treatment.⁵⁴

Unfortunately, a recent survey suggests that physicians tend to recommend surgery for patients in whom medical therapy has failed.⁵³ However, patients who failed to respond to PPI therapy are unlikely to have GERD and, therefore, are highly unlikely to have a good outcome from antireflux surgery. Recent studies suggest that up to 62% of patients who have had open surgery for GERD continue to require medical treatment afterward. Although some studies demonstrate that surgery has greater efficacy over medical therapy initially, long-term follow-up has shown that surgically treated patients often need further medical therapy for persistent GERD symptoms.⁵⁵ Community-based studies of antireflux surgery indicate that many patients develop new symptoms that they did not have before surgery and that these substantially diminish quality of life.

New endoscopic therapies, including radiofrequency energy delivery to the region of the lower esophageal sphincter and endoscopic suturing, have recently been approved for use by the FDA. This approval was based largely on safety rather than efficacy data. Clinical evidence is limited to uncontrolled studies in patients with no or mild esophagitis.³ These techniques should not be used in preference to established medical treatment unless and until data from randomized, controlled trials become available that demonstrate safety and efficacy.⁵⁶

Gastroesophageal reflux disease (GERD) is a common, multifactorial condition that often results in decreased quality of life with interruptions of sleep, work, and social activities. Patients have reported that GERD affects emotional well-being to a greater degree than diabetes or hypertension.^1,2 GERD is also associated with well-established complications, including Barrett’s esophagus. The role of reflux in carcinogenesis is controversial; the possibility of an association, however, implies that GERD should be treated aggressively and early.³

Symptoms of gerd

The typical symptoms of GERD are heartburn and regurgitation. Heartburn is best defined as a burning retrosternal discomfort starting in the epigastrium or lower chest and moving upwards towards the neck. Regurgitation is the effortless movement of gastric contents up into the esophagus or pharynx.

Most patients with GERD do not have endoscopically visible lesions; a careful analysis of symptoms generally forms the basis of a preliminary diagnosis.

The occurrence of heartburn on 2 or more days a week has been suggested as a basis for further investigation for GERD.⁴ However, symptoms vary greatly. Patients may be asymptomatic or experience symptoms that more closely resemble gastric disorders, infectious and motor disorders of the esophagus, biliary tract disease, or even coronary artery disease.

Extraesophageal manifestations

Adding to the complexity of diagnosis, GERD has been shown to have extraesophageal manifestations, including chronic cough, asthma, recurrent aspiration, chronic sore throat, reflux laryngitis, and paroxysmal laryngospasm or voice changes.

Although the relationship between asthma and GERD remains unclear, it has been estimated that 24% to 98% of patients with asthma also have GERD.⁵ Some patients with asthma have been shown to have excess acid reflux into the esophagus. Reflux-like symptoms may precede episodes of asthma that occur after meals or when lying down.^{6 8}

Additionally, GERD has been noted in 10% to 50% of patients with non-cardiac chest pain.^9,10

Diagnostic strategies

Trial of treatment

Diagnosis is usually based on typical symptoms—heartburn or regurgitation—in the clinical history. (The Figure shows a treatment algorithm for both severe and mild symptoms.)

A 2-week trial of treatment with a proton pump inhibitor (PPI) provides the quickest and most cost-effective confirmation of diagnosis and is recommended for the patient whose history suggests uncomplicated GERD. A positive response to PPI treatment in a patient with symptoms suggestive of GERD is at least as sensitive and specific as 24-hour intraesophageal pH monitoring, which is still often considered the “gold standard” for the diagnosis of GERD. Furthermore, complete lack of improvement in response to PPI treatment is highly predictive that the patient does not have GERD and indicates the need for further evaluation and a possible revision of diagnosis.^11,12

H₂ receptor antagonists (H₂RAs) have also been investigated in empirical trials for usefulness in diagnosing GERD. H₂RAs are less effective than PPIs.^13,14

FIGURE Medical management of suspected GERD

Endoscopy

No data support routine endoscopy for patients with the recent onset of uncomplicated heartburn who respond to medical therapy. Endoscopy is recommended, however, for patients with severe or atypical GERD symptoms, when other diseases may be present, or when a treatment trial with a PPI is ineffective.¹⁵ Endoscopy is useful for diagnosing complications of GERD, such as Barrett’s esophagus, esophagitis, and strictures. Fewer than 50% of patients with GERD symptoms have evidence of esophagitis on endoscopy.¹⁶

The American Society for Gastrointestinal Endoscopy recommends endoscopy when there are clinical suggestions of severe reflux or other disease.¹⁷ The American College of Gastroenterology recommends further testing

• when empiric therapy has failed
• when symptoms of complicated disease exist
• when there is dysphagia, bleeding, weight loss, choking, chest pain, or long-standing symptoms
• when continuous therapy is required
• to screen for Barrett’s esophagus.¹⁸

The Canadian Consensus Conference recommends endoscopy in the presence of

• dysphagia
• odynophagia
• bleeding
• weight loss
• noncardiac chest pain
• failure to respond to 4 to 8 weeks of pharmacologic therapy.¹⁹

It also recommends a single test if maintenance therapy is required.

Other diagnostic tests

Other diagnostic tools may be of use in some settings.

A barium esophagram can document reflux, and Bernstein testing (esophageal acid infusion test) can identify esophageal hypersensitivity to acid, although neither establishes a diagnosis of GERD. Ambulatory 24-hour intraesophageal pH monitoring can help to establish the presence of GERD by documenting the proportion of time during which the intraesophageal pH is acidic (<4) and can also establish the degree of association between patients’ symptoms and episodes of esophageal acidification.

Esophageal manometry is not recommended as a routine diagnostic test for GERD. It is important in selected patients to exclude an esophageal motility disorder and may be necessary as part of the pre-operative evaluation for patients in whom a surgical operation for GERD is being considered.

Management of gerd

GERD commonly requires long-term management that includes dietary, lifestyle, and pharmacological interventions. Surgery may be considered for the long-term management of the condition in carefully selected patients.

Diet and lifestyle

Dietary modifications. Patients should not consume large meals and should avoid lying down for 3 to 4 hours after eating. Caffeinated products, peppermint, fatty foods, chocolate, spicy foods, citrus fruits and juices, tomato-based products, and alcohol may contribute to episodes of GERD.^18,21 Lozenges of any kind are able to stimulate salivary secretion, help clear refluxed acid, and hence, help relieve symptoms.

Lifestyle modifications. Changes in lifestyle may include such seemingly sensible interventions as sleeping with the head elevated, stopping smoking, and losing weight. There is little or no established evidence for the efficacy of these and other lifestyle modifications in the management of GERD. However, in1 trial of 63 patients, elevating the head of the bed with 6-inch blocks resulted in 1 less episode of heartburn or acid regurgitation per night when compared with lying flat.²² In another trial of 71 patients with esophagitis, elevating the bed was nearly as effective as ranitidine for reducing symptoms and producing endoscopically verifiable healing.²³

Drug interventions

Pharmacological interventions include over-the-counter remedies such as antacids and H₂RAs (Table 1), as well as prescription-only doses of H₂RAs and PPIs. At the time of writing, no PPI was available in an over-the-counter preparation in the United States, although over-the-counter omeprazole may soon be approved. Many authorities believe an incremental approach to the management of GERD is appropriate, beginning with lifestyle modifications and over-the-counter preparations, continuing with H₂ blockers, and reserving PPIs for nonresponders. While this approach may have appeal from a cost perspective, we believe another approach (as illustrated in the Figure) is clinically superior.

Antacids. Over-the-counter antacids rapidly increase the pH of the intraesophageal contents and also neutralize acidic gastric contents that might be refluxed. They are frequently used to treat heartburn. However, few clinical trials have evaluated the efficacy of antacids. Published trials^24-26 are limited by small sample sizes and a lack of intention-to-treat analysis. Only 1 showed positive evidence for antacid efficacy.²⁵

The utility of antacids is limited by the need for frequent dosing and possible interactions with such drugs as fluoroquinolones, tetracycline, and ferrous sulfate.²⁷ Alginate/antacids have shown statistically significant benefit compared with placebo for relief of mild-to-moderate GERD symptoms and healing of esophagitis.^24,28-34

H ₂ receptor antagonists. H₂RAs have shown positive effects on symptoms in some studies, although symptomatic response rates observed were only around 60% to 70%. Additionally, most of the trials to date have been for 2 to 6 weeks in duration.^{35 43} An issue worthy of consideration with the H₂RAs is the development of tolerance with continuous use.⁴⁴

An H₂RA-antacid combination was recently evaluated in a trial that compared it with monotherapy using either agent. Of the patients receiving combination therapy, 81% reported an excellent or good symptom response. Those receiving famotidine or atacid alone reported a 72% excellent or good symptom response.³

Proton pump inhibitors. PPIs potently reduce gastric acid secretion by inhibiting the H⁺-K⁺adenosine triphosphatase pump of the parietal cell. As a result, they suppress gastric acid secretion for a longer period than H₂RAs.⁴⁵ Evidence from randomized, controlled trials has demonstrated the superiority of PPIs over any other class of drugs for the relief of GERD symptoms, for healing esophagitis, and for maintaining patients in remission. Standard doses of omeprazole, lansoprazole, panto-prazole, esomeprazole, and rabeprazole have, for the most part, shown comparable rates of healing and remission in erosive esophagitis.^46-52

PPIs are best absorbed in the absence of food. Ingestion of food after a PPI stimulates parietal cell activity when blood levels of the PPI are increasing; this promotes uptake of the PPI by the parietal cells. Therefore, patients should be advised to take their PPI between 30 and 60 minutes before eating. For patients on a once-daily PPI, the best time to take it is about 30 to 60 minutes before breakfast. Despite these recommendations, a recent survey of over 1000 US primary care physicians found that 36% instructed their patients to take their PPI with or after a meal or did not specify the timing of dosing.⁵³

PPI therapy can be tailored to control GERD symptoms. Treatment can start with the most effective dosage and then be stepped down, or start with a minimum dosage and then be stepped up (Table 2). Patients with predominantly daytime symptoms should take PPIs before breakfast. Concerns that were once expressed about the long-term use of PPIs, such as predisposing patients to stomach cancer, have been refuted by extensive clinical experience and intensive monitoring (Table 3).³

TABLE 1

Over-the-counter therapy for GERD

TABLE 2

Step-down and step-up treatments: advantages and disadvantages

TABLE 3

Potential concerns associated with the use of proton pump inhibitors

Surgery

Surgical antireflux therapy is an option in carefully selected patients. Those who respond best to surgical therapy will have had clearly documented acid reflux, typical symptoms, and symptomatic improvement while on PPI treatment.⁵⁴

Unfortunately, a recent survey suggests that physicians tend to recommend surgery for patients in whom medical therapy has failed.⁵³ However, patients who failed to respond to PPI therapy are unlikely to have GERD and, therefore, are highly unlikely to have a good outcome from antireflux surgery. Recent studies suggest that up to 62% of patients who have had open surgery for GERD continue to require medical treatment afterward. Although some studies demonstrate that surgery has greater efficacy over medical therapy initially, long-term follow-up has shown that surgically treated patients often need further medical therapy for persistent GERD symptoms.⁵⁵ Community-based studies of antireflux surgery indicate that many patients develop new symptoms that they did not have before surgery and that these substantially diminish quality of life.

New endoscopic therapies, including radiofrequency energy delivery to the region of the lower esophageal sphincter and endoscopic suturing, have recently been approved for use by the FDA. This approval was based largely on safety rather than efficacy data. Clinical evidence is limited to uncontrolled studies in patients with no or mild esophagitis.³ These techniques should not be used in preference to established medical treatment unless and until data from randomized, controlled trials become available that demonstrate safety and efficacy.⁵⁶

Gastroesophageal reflux disease (GERD) is a common, multifactorial condition that often results in decreased quality of life with interruptions of sleep, work, and social activities. Patients have reported that GERD affects emotional well-being to a greater degree than diabetes or hypertension.^1,2 GERD is also associated with well-established complications, including Barrett’s esophagus. The role of reflux in carcinogenesis is controversial; the possibility of an association, however, implies that GERD should be treated aggressively and early.³

Symptoms of gerd

The typical symptoms of GERD are heartburn and regurgitation. Heartburn is best defined as a burning retrosternal discomfort starting in the epigastrium or lower chest and moving upwards towards the neck. Regurgitation is the effortless movement of gastric contents up into the esophagus or pharynx.

Most patients with GERD do not have endoscopically visible lesions; a careful analysis of symptoms generally forms the basis of a preliminary diagnosis.

The occurrence of heartburn on 2 or more days a week has been suggested as a basis for further investigation for GERD.⁴ However, symptoms vary greatly. Patients may be asymptomatic or experience symptoms that more closely resemble gastric disorders, infectious and motor disorders of the esophagus, biliary tract disease, or even coronary artery disease.

Extraesophageal manifestations

Adding to the complexity of diagnosis, GERD has been shown to have extraesophageal manifestations, including chronic cough, asthma, recurrent aspiration, chronic sore throat, reflux laryngitis, and paroxysmal laryngospasm or voice changes.

Although the relationship between asthma and GERD remains unclear, it has been estimated that 24% to 98% of patients with asthma also have GERD.⁵ Some patients with asthma have been shown to have excess acid reflux into the esophagus. Reflux-like symptoms may precede episodes of asthma that occur after meals or when lying down.^{6 8}

Additionally, GERD has been noted in 10% to 50% of patients with non-cardiac chest pain.^9,10

Diagnostic strategies

Trial of treatment

Diagnosis is usually based on typical symptoms—heartburn or regurgitation—in the clinical history. (The Figure shows a treatment algorithm for both severe and mild symptoms.)

A 2-week trial of treatment with a proton pump inhibitor (PPI) provides the quickest and most cost-effective confirmation of diagnosis and is recommended for the patient whose history suggests uncomplicated GERD. A positive response to PPI treatment in a patient with symptoms suggestive of GERD is at least as sensitive and specific as 24-hour intraesophageal pH monitoring, which is still often considered the “gold standard” for the diagnosis of GERD. Furthermore, complete lack of improvement in response to PPI treatment is highly predictive that the patient does not have GERD and indicates the need for further evaluation and a possible revision of diagnosis.^11,12

H₂ receptor antagonists (H₂RAs) have also been investigated in empirical trials for usefulness in diagnosing GERD. H₂RAs are less effective than PPIs.^13,14

FIGURE Medical management of suspected GERD

Endoscopy

No data support routine endoscopy for patients with the recent onset of uncomplicated heartburn who respond to medical therapy. Endoscopy is recommended, however, for patients with severe or atypical GERD symptoms, when other diseases may be present, or when a treatment trial with a PPI is ineffective.¹⁵ Endoscopy is useful for diagnosing complications of GERD, such as Barrett’s esophagus, esophagitis, and strictures. Fewer than 50% of patients with GERD symptoms have evidence of esophagitis on endoscopy.¹⁶

The American Society for Gastrointestinal Endoscopy recommends endoscopy when there are clinical suggestions of severe reflux or other disease.¹⁷ The American College of Gastroenterology recommends further testing

• when empiric therapy has failed
• when symptoms of complicated disease exist
• when there is dysphagia, bleeding, weight loss, choking, chest pain, or long-standing symptoms
• when continuous therapy is required
• to screen for Barrett’s esophagus.¹⁸

The Canadian Consensus Conference recommends endoscopy in the presence of

• dysphagia
• odynophagia
• bleeding
• weight loss
• noncardiac chest pain
• failure to respond to 4 to 8 weeks of pharmacologic therapy.¹⁹

It also recommends a single test if maintenance therapy is required.

Other diagnostic tests

Other diagnostic tools may be of use in some settings.

A barium esophagram can document reflux, and Bernstein testing (esophageal acid infusion test) can identify esophageal hypersensitivity to acid, although neither establishes a diagnosis of GERD. Ambulatory 24-hour intraesophageal pH monitoring can help to establish the presence of GERD by documenting the proportion of time during which the intraesophageal pH is acidic (<4) and can also establish the degree of association between patients’ symptoms and episodes of esophageal acidification.

Esophageal manometry is not recommended as a routine diagnostic test for GERD. It is important in selected patients to exclude an esophageal motility disorder and may be necessary as part of the pre-operative evaluation for patients in whom a surgical operation for GERD is being considered.

Management of gerd

GERD commonly requires long-term management that includes dietary, lifestyle, and pharmacological interventions. Surgery may be considered for the long-term management of the condition in carefully selected patients.

Diet and lifestyle

Dietary modifications. Patients should not consume large meals and should avoid lying down for 3 to 4 hours after eating. Caffeinated products, peppermint, fatty foods, chocolate, spicy foods, citrus fruits and juices, tomato-based products, and alcohol may contribute to episodes of GERD.^18,21 Lozenges of any kind are able to stimulate salivary secretion, help clear refluxed acid, and hence, help relieve symptoms.

Lifestyle modifications. Changes in lifestyle may include such seemingly sensible interventions as sleeping with the head elevated, stopping smoking, and losing weight. There is little or no established evidence for the efficacy of these and other lifestyle modifications in the management of GERD. However, in1 trial of 63 patients, elevating the head of the bed with 6-inch blocks resulted in 1 less episode of heartburn or acid regurgitation per night when compared with lying flat.²² In another trial of 71 patients with esophagitis, elevating the bed was nearly as effective as ranitidine for reducing symptoms and producing endoscopically verifiable healing.²³

Drug interventions

Pharmacological interventions include over-the-counter remedies such as antacids and H₂RAs (Table 1), as well as prescription-only doses of H₂RAs and PPIs. At the time of writing, no PPI was available in an over-the-counter preparation in the United States, although over-the-counter omeprazole may soon be approved. Many authorities believe an incremental approach to the management of GERD is appropriate, beginning with lifestyle modifications and over-the-counter preparations, continuing with H₂ blockers, and reserving PPIs for nonresponders. While this approach may have appeal from a cost perspective, we believe another approach (as illustrated in the Figure) is clinically superior.

Antacids. Over-the-counter antacids rapidly increase the pH of the intraesophageal contents and also neutralize acidic gastric contents that might be refluxed. They are frequently used to treat heartburn. However, few clinical trials have evaluated the efficacy of antacids. Published trials^24-26 are limited by small sample sizes and a lack of intention-to-treat analysis. Only 1 showed positive evidence for antacid efficacy.²⁵

The utility of antacids is limited by the need for frequent dosing and possible interactions with such drugs as fluoroquinolones, tetracycline, and ferrous sulfate.²⁷ Alginate/antacids have shown statistically significant benefit compared with placebo for relief of mild-to-moderate GERD symptoms and healing of esophagitis.^24,28-34

H ₂ receptor antagonists. H₂RAs have shown positive effects on symptoms in some studies, although symptomatic response rates observed were only around 60% to 70%. Additionally, most of the trials to date have been for 2 to 6 weeks in duration.^{35 43} An issue worthy of consideration with the H₂RAs is the development of tolerance with continuous use.⁴⁴

An H₂RA-antacid combination was recently evaluated in a trial that compared it with monotherapy using either agent. Of the patients receiving combination therapy, 81% reported an excellent or good symptom response. Those receiving famotidine or atacid alone reported a 72% excellent or good symptom response.³

Proton pump inhibitors. PPIs potently reduce gastric acid secretion by inhibiting the H⁺-K⁺adenosine triphosphatase pump of the parietal cell. As a result, they suppress gastric acid secretion for a longer period than H₂RAs.⁴⁵ Evidence from randomized, controlled trials has demonstrated the superiority of PPIs over any other class of drugs for the relief of GERD symptoms, for healing esophagitis, and for maintaining patients in remission. Standard doses of omeprazole, lansoprazole, panto-prazole, esomeprazole, and rabeprazole have, for the most part, shown comparable rates of healing and remission in erosive esophagitis.^46-52

PPIs are best absorbed in the absence of food. Ingestion of food after a PPI stimulates parietal cell activity when blood levels of the PPI are increasing; this promotes uptake of the PPI by the parietal cells. Therefore, patients should be advised to take their PPI between 30 and 60 minutes before eating. For patients on a once-daily PPI, the best time to take it is about 30 to 60 minutes before breakfast. Despite these recommendations, a recent survey of over 1000 US primary care physicians found that 36% instructed their patients to take their PPI with or after a meal or did not specify the timing of dosing.⁵³

PPI therapy can be tailored to control GERD symptoms. Treatment can start with the most effective dosage and then be stepped down, or start with a minimum dosage and then be stepped up (Table 2). Patients with predominantly daytime symptoms should take PPIs before breakfast. Concerns that were once expressed about the long-term use of PPIs, such as predisposing patients to stomach cancer, have been refuted by extensive clinical experience and intensive monitoring (Table 3).³

TABLE 1

Over-the-counter therapy for GERD

TABLE 2

Step-down and step-up treatments: advantages and disadvantages

TABLE 3

Potential concerns associated with the use of proton pump inhibitors

Surgery

Surgical antireflux therapy is an option in carefully selected patients. Those who respond best to surgical therapy will have had clearly documented acid reflux, typical symptoms, and symptomatic improvement while on PPI treatment.⁵⁴

Unfortunately, a recent survey suggests that physicians tend to recommend surgery for patients in whom medical therapy has failed.⁵³ However, patients who failed to respond to PPI therapy are unlikely to have GERD and, therefore, are highly unlikely to have a good outcome from antireflux surgery. Recent studies suggest that up to 62% of patients who have had open surgery for GERD continue to require medical treatment afterward. Although some studies demonstrate that surgery has greater efficacy over medical therapy initially, long-term follow-up has shown that surgically treated patients often need further medical therapy for persistent GERD symptoms.⁵⁵ Community-based studies of antireflux surgery indicate that many patients develop new symptoms that they did not have before surgery and that these substantially diminish quality of life.

New endoscopic therapies, including radiofrequency energy delivery to the region of the lower esophageal sphincter and endoscopic suturing, have recently been approved for use by the FDA. This approval was based largely on safety rather than efficacy data. Clinical evidence is limited to uncontrolled studies in patients with no or mild esophagitis.³ These techniques should not be used in preference to established medical treatment unless and until data from randomized, controlled trials become available that demonstrate safety and efficacy.⁵⁶

The American Cancer Society’s ABCDE criteria and the revised 7-point checklist are the most reliable means of detecting or ruling out malignant melanoma. Each has its strengths and weaknesses, a knowledge of which will increase the accuracy of assessment and minimize chances of misdiagnosis.

In addition to these 2 clinical prediction rules, we examine the evidence on physician’s global assessment of nonmelanoma skin cancers and review the risk factors for the major types of skin cancer. As a result of a comprehensive evidence-based review on the incidence, risk factors, and diagnosis of skin malignancies, we present an algorithm for evaluating skin lesions.

Impact of skin cancer

The incidence of malignant melanoma has increased from 1 in 1500 in 1930 to 1 in 75 for the year 2000.¹ Although it is the rarest skin cancer (1% of skin malignancies), it is also the deadliest, accounting for 60% of skin cancer deaths.²

Nonmelanoma skin cancers, which include squamous cell cancers and basal cell cancers, account for one third of all cancers in the United States. Approximately 1 million cases were diagnosed in 1999.³ Deaths from nonmelanoma skin cancers are in steady decline, and the overall 5-year survival rate is high (over 95%).⁴ Recurrent nonmelanoma skin cancer, however, carries a very poor prognosis, with only a 50% cure rate.⁵

Treatment of nonmelanoma skin cancer costs over $500 million yearly in the US.⁴

Primary care physicians help improve prognosis

More persons visit primary care physicians (38.2%) than dermatologists (29.9%) for evaluation of suspicious skin lesions.⁶ Such lesions are usually benign, but a malignancy must be excluded. A primary care physician can expect to diagnose 6 to 7 cases of basal cell cancer, 1 to 2 cases of squamous cell cancer, and approximately 1 case of melanoma every year, according to population-based studies.⁴

Primary care practitioners contribute to a more favorable prognosis. For each additional family physician per 10,000 population, the chances of diagnosing malignant melanoma earlier increase significantly (odds ratio= 1.21, 95% confidence interval, 1.09–1.33, P<.001).⁷

Primary care physicians who diagnose non-melanoma skin cancers can select therapies that offer maximum efficacy and cost-effectiveness.

Differential diagnosis

According to a study of 1215 biopsies conducted in a primary care population, over 80% of biopsied lesions were benign and included nevi, seborrheic keratoses, cysts, dermatofibromas, fibrous histiocytomas, and polyps or skin tags. Pre-malignant lesions (including actinic keratoses and lentigo maligna) represented 7% of the total. Thirteen percent were malignancies: basal cell carcinomas (73%), followed by squamous cell carcinomas (14%), and malignant melanomas (12%). One metastatic adenomacarcinoma was included in the series (1%) (level of evidence [LOE]: 4).⁸

The differential diagnosis for basal cell carcinoma includes superficial basal cell carcinoma, pigmented basal cell carcinoma, infiltrating basal cell carcinoma, tricoepithelioma, keloid, molluscum contagiosum, and dermatofibromas.

For squamous cell cancer, the differential includes squamous cell carcinoma, keratoacanthoma, eczema and atopic dermatitis, contact dermatitis, psoriasis, and seborrheic dermatitis.

The differential diagnosis for malignant melanoma includes seborrheic keratosis, traumatized or irritated nevus, pigmented basal cell carcinoma, lentigo, blue nevus, angiokeratoma, traumatic hematoma, venous lake, hemangioma, dermatofibroma, and pigmented actinic keratosis.

Using the history and physical examination

Nearly 70% of melanomas are discovered by patients or their family (LOE: 4).⁹ Patients may express concern about changed size or appearance of a lesion; associated pain, pruritis, ulceration, or bleeding; location in a cosmetically sensitive area; or worry voiced by a family member. Additionally, a patient may have a family or personal history of skin malignancy, history of skin biopsy, or predisposition to sunburns.

Nurses and physicians identify lesions before a patient does approximately one quarter of the time while examining a patient for an unrelated condition or as part of a comprehensive work-up (LOE: 4).⁹

Types of skin malignancies

See Photo Rounds, page 219, for images of many types of skin cancer.

Basal cell carcinoma

The patterns of basal cell carcinoma are nodular, superficial, micronodular, infiltrative, morpheaform, and mixed.¹⁰ They may be pigmented and are sometimes misdiagnosed as melanoma.¹¹ However, most basal cell carcinomas are typical in appearance and easily diagnosed by visual and tactile inspection.

The most common nodular type is a smooth, skin-colored, indurated, dome-shaped papule with a rolled edge. Other attributes include a pearly appearance, overlying telangiectatic vessels, and a history of bleeding with minor trauma.^7,11

Superficial basal cell carcinoma is similar to dermatitis but more often has distinct borders and a bright pink appearance.¹¹ If in doubt about the diagnosis, obtain a tissue sample for pathology.

Squamous cell carcinoma

Squamous cell carcinoma most often is a small, firm, hyperkaratotic nodule sitting atop an inflamed base. It may also be skin-colored and smooth. The history can include itching, pain, and nonhealing after minor trauma.^7,11,12 As with basal cell carcinoma, diagnosis is made by tissue pathology.

Malignant melanoma

Malignant melanoma usually appears as a changing or unusual mole with haphazard color variegation, including combinations of brown, black, blue, gray, white, and (rarely) pink. Most melanomas are larger than 5 mm in diameter at time of diagnosis.¹³

There are 4 main types of malignant melanoma:

• Superficial spreading melanoma accounts for 50% of cases and occurs more frequently in younger adults.
• Nodular melanoma also occurs in younger adults, representing 20% to 25% of cases.
• Lentigo maligna melanoma occurs in older adults and accounts for only 15% of cases.
• Acral or acral-lentiginous melanomas are the least common form (10% of cases). They appear on the palms, soles, and around the first toenail.¹⁴

Risk factors for skin malignancies

Factors conferring the highest relative risk for malignant melanoma include:¹³

• atypical nevus syndrome with a personal and family history of melanoma
• history of a changing mole
• atypical nevus syndrome with just a family history of melanoma
• age greater than or equal to 15 years
• history of dysplastic moles.

Table 1 provides a list of risk factors that should prompt an annual skin survey (LOE: 5).

For nonmelanoma skin cancers, the strongest risk factors ( Table 2) include Caucasian race; age 55 to 75 years; and male sex.² There is good evidence that a history of nonmelanoma skin cancer confers a 10-fold risk for recurrence (LOE: 2a).¹⁵ A distinct risk factor for squamous cell carcinoma is immunosuppression.² Table 2 also provides a complete list of risk factors for nonmelanoma skin cancer.

Precursor lesions for nonmelanoma skin cancers include Bowen’s disease and erythroplasia of Queyrat (forms of squamous cell carcinoma in situ that will progress if left untreated). Actinic keratoses are common precursor lesions, but their overall annual rate of malignant transformation is only 1 in 400. In the case of SCC, up to 60% of cancers develop from an existing actinic keratosis.²

TABLE 1
Risk factors for malignant melanoma ¹³

TABLE 2
Risk factors for nonmelanoma skin cancer

Clinical prediction rules for skin malignancies

Malignant melanoma

ABCDE criteria. A useful clinical prediction rule for malignant melanoma is the American Cancer Society’s “ABCDE criteria” (Table 3). This rule was validated in 4 dermatology clinics, studying a total of 1118 lesions, although the studies were not homogenous (strength of recommendation [SOR]: A).^16-19 Results of the study are summarized in Table 4. The test is normally considered positive if one or more of the criteria are met; however, as more criteria are met, specificity increases while sensitivity decreases.^17-19

For lesions lacking any of the ABCDE criteria, 99.8% are something other than melanoma (using a prevalence of 1% found in the US population) (SOR: A). Use caution, however, as this rule will miss amelanotic melanomas, as well as smaller melanomas that are changing in size or have other features suggestive of malignant melanoma.

Conversely, if one of the criteria is met, there is nearly a 1.5% (positive predictive value) probability it is melanoma. Excisional biopsy of the lesion is indicated if good clinical judgment is used and it cannot be identified with certainty as a typical benign lesion (SOR: A). This test thus guides clinicians when making a decision to biopsy, as well as in choosing a biopsy technique.

The ABCDE criteria establish a risk of malignancy if the lesion is 6 mm in diameter or greater. Some evidence, however, suggests that this value should not be used as an absolute cutoff for diagnosing malignant melanoma. A large retrospective study performed in Australia found that 31% of biopsy-confirmed melanomas were less than 6 mm in diameter (LOE: 2b).²⁰

Revised 7-point checklist. Another potentially useful diagnostic test is the revised 7-point checklist developed in the United Kingdom ( Table 5). This test was found to have a high sensitivity, but low specificity ( Table 4) . Therefore, it has a low false-negative rate, and is useful for ruling out the diagnosis of melanoma when negative. However, the test yields a significant number of false positive results, leading to possibly unnecessary biopsies and increased patient anxiety (SOR: B).^16,21,22

Note: the described sensitivities and specificities for both tests apply only to malignant melanomas, and their accuracy decreases when including basal cell and squamous cell carcinomas. Also, the 2 tests were scored differently in some of the validation studies, making attempts to generalize problematic.

Studies of physicians’ global assessments to detect melanomas ( Table 4) vary widely for sensitivity (50% to 97%) but are consistent for specificity (96% to 99%) (SOR: B).^23-28 Additionally, some studies have shown higher percentages of correct diagnosis of malignant melanoma among dermatologists compared with nondermatologists, but all these studies (except for a small subset of patients in one) used lesion images rather than patient examinations (SOR: B).^23,29-33

More importantly, when the choice of correct treatment was evaluated, no statistically significant difference was found between the two groups. Further prospective cohort trials using patient examinations are needed to evaluate dermatologist performance versus nondermatologist performance.

TABLE 3
American Cancer Society's ABCDE criteria

The test is considered positive if a lesion exhibits 1 or more of the 5 criteria
Assymetry—one half of the lesion not identical to the other
Border irregularity—lesion has an uneven or ragged border
Color variegation—lesion has more than one color (ie, black, blue, pink, red, or white)
Diameter—lesion has a diameter greater than 6 mm
Elevation or Enlargement—elevation of lesion above skin surface or enlargement by patient report

TABLE 4
Clinical prediction tests for skin malignancies

TABLE 5
Revised 7-point checklist for assessing risk of melanoma

No validated tool for diagnosis of nonmelanoma skin cancers

A useful diagnostic tool has not yet been validated for nonmelanoma skin cancers. Over 60% of non-melanoma skin cancers occur on the face and neck, and these areas bear careful inspection. Lesions behind the ear, at the medial canthus, and within the nasolabial folds are most easily missed.

How to proceed in assessing lesions

When evaluating skin lesions, remember the gold standard for diagnosis of skin malignancies is a tissue biopsy. If you or your patient has any doubt about the diagnosis, a biopsy should be performed.

To review: Good evidence supports the use the ABCDE criteria or the revised 7-point checklist in determining whether lesions are likely to be malignant melanomas. No similar diagnostic rules exist for basal cell and squamous cell carcinomas. The decision to biopsy these lesions must be based on global assessment and typical characteristics.

Based on this information, we developed an algorithm for evaluating patients at risk for skin malignancies ( Figure) . The first step is to apply the ABCDE criteria and the revised 7-point checklist to identify or rule out possible malignant melanomas. An excisional biopsy should be performed if either test is positive (and the lesion is not clinically benign), or if you or your patient has any doubt.

If neither of these diagnostic tests yields a positive result, the lesion should be classified as typically benign or as having characteristics suggestive of a squamous cell or basal cell carcinoma.

Lesions that have characteristics of squamous cell or basal cell cancer should be biopsied, and benign lesions can be observed and the patient reassured.

FIGURE
Approach to the patient with a skin lesion

Acknowledgments

The authors wish to thank Barbara Zuckerman and Michael Campese, PhD for their assistance in preparation of this manuscript. We also gratefully acknowledge Dr. Richard P. Usatine for preparing the accompanying Photo Rounds.

The American Cancer Society’s ABCDE criteria and the revised 7-point checklist are the most reliable means of detecting or ruling out malignant melanoma. Each has its strengths and weaknesses, a knowledge of which will increase the accuracy of assessment and minimize chances of misdiagnosis.

In addition to these 2 clinical prediction rules, we examine the evidence on physician’s global assessment of nonmelanoma skin cancers and review the risk factors for the major types of skin cancer. As a result of a comprehensive evidence-based review on the incidence, risk factors, and diagnosis of skin malignancies, we present an algorithm for evaluating skin lesions.

Impact of skin cancer

The incidence of malignant melanoma has increased from 1 in 1500 in 1930 to 1 in 75 for the year 2000.¹ Although it is the rarest skin cancer (1% of skin malignancies), it is also the deadliest, accounting for 60% of skin cancer deaths.²

Nonmelanoma skin cancers, which include squamous cell cancers and basal cell cancers, account for one third of all cancers in the United States. Approximately 1 million cases were diagnosed in 1999.³ Deaths from nonmelanoma skin cancers are in steady decline, and the overall 5-year survival rate is high (over 95%).⁴ Recurrent nonmelanoma skin cancer, however, carries a very poor prognosis, with only a 50% cure rate.⁵

Treatment of nonmelanoma skin cancer costs over $500 million yearly in the US.⁴

Primary care physicians help improve prognosis

More persons visit primary care physicians (38.2%) than dermatologists (29.9%) for evaluation of suspicious skin lesions.⁶ Such lesions are usually benign, but a malignancy must be excluded. A primary care physician can expect to diagnose 6 to 7 cases of basal cell cancer, 1 to 2 cases of squamous cell cancer, and approximately 1 case of melanoma every year, according to population-based studies.⁴

Primary care practitioners contribute to a more favorable prognosis. For each additional family physician per 10,000 population, the chances of diagnosing malignant melanoma earlier increase significantly (odds ratio= 1.21, 95% confidence interval, 1.09–1.33, P<.001).⁷

Primary care physicians who diagnose non-melanoma skin cancers can select therapies that offer maximum efficacy and cost-effectiveness.

Differential diagnosis

According to a study of 1215 biopsies conducted in a primary care population, over 80% of biopsied lesions were benign and included nevi, seborrheic keratoses, cysts, dermatofibromas, fibrous histiocytomas, and polyps or skin tags. Pre-malignant lesions (including actinic keratoses and lentigo maligna) represented 7% of the total. Thirteen percent were malignancies: basal cell carcinomas (73%), followed by squamous cell carcinomas (14%), and malignant melanomas (12%). One metastatic adenomacarcinoma was included in the series (1%) (level of evidence [LOE]: 4).⁸

The differential diagnosis for basal cell carcinoma includes superficial basal cell carcinoma, pigmented basal cell carcinoma, infiltrating basal cell carcinoma, tricoepithelioma, keloid, molluscum contagiosum, and dermatofibromas.

For squamous cell cancer, the differential includes squamous cell carcinoma, keratoacanthoma, eczema and atopic dermatitis, contact dermatitis, psoriasis, and seborrheic dermatitis.

The differential diagnosis for malignant melanoma includes seborrheic keratosis, traumatized or irritated nevus, pigmented basal cell carcinoma, lentigo, blue nevus, angiokeratoma, traumatic hematoma, venous lake, hemangioma, dermatofibroma, and pigmented actinic keratosis.

Using the history and physical examination

Nearly 70% of melanomas are discovered by patients or their family (LOE: 4).⁹ Patients may express concern about changed size or appearance of a lesion; associated pain, pruritis, ulceration, or bleeding; location in a cosmetically sensitive area; or worry voiced by a family member. Additionally, a patient may have a family or personal history of skin malignancy, history of skin biopsy, or predisposition to sunburns.

Nurses and physicians identify lesions before a patient does approximately one quarter of the time while examining a patient for an unrelated condition or as part of a comprehensive work-up (LOE: 4).⁹

Types of skin malignancies

See Photo Rounds, page 219, for images of many types of skin cancer.

Basal cell carcinoma

The patterns of basal cell carcinoma are nodular, superficial, micronodular, infiltrative, morpheaform, and mixed.¹⁰ They may be pigmented and are sometimes misdiagnosed as melanoma.¹¹ However, most basal cell carcinomas are typical in appearance and easily diagnosed by visual and tactile inspection.

The most common nodular type is a smooth, skin-colored, indurated, dome-shaped papule with a rolled edge. Other attributes include a pearly appearance, overlying telangiectatic vessels, and a history of bleeding with minor trauma.^7,11

Superficial basal cell carcinoma is similar to dermatitis but more often has distinct borders and a bright pink appearance.¹¹ If in doubt about the diagnosis, obtain a tissue sample for pathology.

Squamous cell carcinoma

Squamous cell carcinoma most often is a small, firm, hyperkaratotic nodule sitting atop an inflamed base. It may also be skin-colored and smooth. The history can include itching, pain, and nonhealing after minor trauma.^7,11,12 As with basal cell carcinoma, diagnosis is made by tissue pathology.

Malignant melanoma

Malignant melanoma usually appears as a changing or unusual mole with haphazard color variegation, including combinations of brown, black, blue, gray, white, and (rarely) pink. Most melanomas are larger than 5 mm in diameter at time of diagnosis.¹³

There are 4 main types of malignant melanoma:

• Superficial spreading melanoma accounts for 50% of cases and occurs more frequently in younger adults.
• Nodular melanoma also occurs in younger adults, representing 20% to 25% of cases.
• Lentigo maligna melanoma occurs in older adults and accounts for only 15% of cases.
• Acral or acral-lentiginous melanomas are the least common form (10% of cases). They appear on the palms, soles, and around the first toenail.¹⁴

Risk factors for skin malignancies

Factors conferring the highest relative risk for malignant melanoma include:¹³

• atypical nevus syndrome with a personal and family history of melanoma
• history of a changing mole
• atypical nevus syndrome with just a family history of melanoma
• age greater than or equal to 15 years
• history of dysplastic moles.

Table 1 provides a list of risk factors that should prompt an annual skin survey (LOE: 5).

For nonmelanoma skin cancers, the strongest risk factors ( Table 2) include Caucasian race; age 55 to 75 years; and male sex.² There is good evidence that a history of nonmelanoma skin cancer confers a 10-fold risk for recurrence (LOE: 2a).¹⁵ A distinct risk factor for squamous cell carcinoma is immunosuppression.² Table 2 also provides a complete list of risk factors for nonmelanoma skin cancer.

Precursor lesions for nonmelanoma skin cancers include Bowen’s disease and erythroplasia of Queyrat (forms of squamous cell carcinoma in situ that will progress if left untreated). Actinic keratoses are common precursor lesions, but their overall annual rate of malignant transformation is only 1 in 400. In the case of SCC, up to 60% of cancers develop from an existing actinic keratosis.²

TABLE 1
Risk factors for malignant melanoma ¹³

TABLE 2
Risk factors for nonmelanoma skin cancer

Clinical prediction rules for skin malignancies

Malignant melanoma

ABCDE criteria. A useful clinical prediction rule for malignant melanoma is the American Cancer Society’s “ABCDE criteria” (Table 3). This rule was validated in 4 dermatology clinics, studying a total of 1118 lesions, although the studies were not homogenous (strength of recommendation [SOR]: A).^16-19 Results of the study are summarized in Table 4. The test is normally considered positive if one or more of the criteria are met; however, as more criteria are met, specificity increases while sensitivity decreases.^17-19

For lesions lacking any of the ABCDE criteria, 99.8% are something other than melanoma (using a prevalence of 1% found in the US population) (SOR: A). Use caution, however, as this rule will miss amelanotic melanomas, as well as smaller melanomas that are changing in size or have other features suggestive of malignant melanoma.

Conversely, if one of the criteria is met, there is nearly a 1.5% (positive predictive value) probability it is melanoma. Excisional biopsy of the lesion is indicated if good clinical judgment is used and it cannot be identified with certainty as a typical benign lesion (SOR: A). This test thus guides clinicians when making a decision to biopsy, as well as in choosing a biopsy technique.

The ABCDE criteria establish a risk of malignancy if the lesion is 6 mm in diameter or greater. Some evidence, however, suggests that this value should not be used as an absolute cutoff for diagnosing malignant melanoma. A large retrospective study performed in Australia found that 31% of biopsy-confirmed melanomas were less than 6 mm in diameter (LOE: 2b).²⁰

Revised 7-point checklist. Another potentially useful diagnostic test is the revised 7-point checklist developed in the United Kingdom ( Table 5). This test was found to have a high sensitivity, but low specificity ( Table 4) . Therefore, it has a low false-negative rate, and is useful for ruling out the diagnosis of melanoma when negative. However, the test yields a significant number of false positive results, leading to possibly unnecessary biopsies and increased patient anxiety (SOR: B).^16,21,22

Note: the described sensitivities and specificities for both tests apply only to malignant melanomas, and their accuracy decreases when including basal cell and squamous cell carcinomas. Also, the 2 tests were scored differently in some of the validation studies, making attempts to generalize problematic.

Studies of physicians’ global assessments to detect melanomas ( Table 4) vary widely for sensitivity (50% to 97%) but are consistent for specificity (96% to 99%) (SOR: B).^23-28 Additionally, some studies have shown higher percentages of correct diagnosis of malignant melanoma among dermatologists compared with nondermatologists, but all these studies (except for a small subset of patients in one) used lesion images rather than patient examinations (SOR: B).^23,29-33

More importantly, when the choice of correct treatment was evaluated, no statistically significant difference was found between the two groups. Further prospective cohort trials using patient examinations are needed to evaluate dermatologist performance versus nondermatologist performance.

TABLE 3
American Cancer Society's ABCDE criteria

The test is considered positive if a lesion exhibits 1 or more of the 5 criteria
Assymetry—one half of the lesion not identical to the other
Border irregularity—lesion has an uneven or ragged border
Color variegation—lesion has more than one color (ie, black, blue, pink, red, or white)
Diameter—lesion has a diameter greater than 6 mm
Elevation or Enlargement—elevation of lesion above skin surface or enlargement by patient report

TABLE 4
Clinical prediction tests for skin malignancies

TABLE 5
Revised 7-point checklist for assessing risk of melanoma

No validated tool for diagnosis of nonmelanoma skin cancers

A useful diagnostic tool has not yet been validated for nonmelanoma skin cancers. Over 60% of non-melanoma skin cancers occur on the face and neck, and these areas bear careful inspection. Lesions behind the ear, at the medial canthus, and within the nasolabial folds are most easily missed.

How to proceed in assessing lesions

When evaluating skin lesions, remember the gold standard for diagnosis of skin malignancies is a tissue biopsy. If you or your patient has any doubt about the diagnosis, a biopsy should be performed.

To review: Good evidence supports the use the ABCDE criteria or the revised 7-point checklist in determining whether lesions are likely to be malignant melanomas. No similar diagnostic rules exist for basal cell and squamous cell carcinomas. The decision to biopsy these lesions must be based on global assessment and typical characteristics.

Based on this information, we developed an algorithm for evaluating patients at risk for skin malignancies ( Figure) . The first step is to apply the ABCDE criteria and the revised 7-point checklist to identify or rule out possible malignant melanomas. An excisional biopsy should be performed if either test is positive (and the lesion is not clinically benign), or if you or your patient has any doubt.

If neither of these diagnostic tests yields a positive result, the lesion should be classified as typically benign or as having characteristics suggestive of a squamous cell or basal cell carcinoma.

Lesions that have characteristics of squamous cell or basal cell cancer should be biopsied, and benign lesions can be observed and the patient reassured.

FIGURE
Approach to the patient with a skin lesion

Acknowledgments

The authors wish to thank Barbara Zuckerman and Michael Campese, PhD for their assistance in preparation of this manuscript. We also gratefully acknowledge Dr. Richard P. Usatine for preparing the accompanying Photo Rounds.

The American Cancer Society’s ABCDE criteria and the revised 7-point checklist are the most reliable means of detecting or ruling out malignant melanoma. Each has its strengths and weaknesses, a knowledge of which will increase the accuracy of assessment and minimize chances of misdiagnosis.

In addition to these 2 clinical prediction rules, we examine the evidence on physician’s global assessment of nonmelanoma skin cancers and review the risk factors for the major types of skin cancer. As a result of a comprehensive evidence-based review on the incidence, risk factors, and diagnosis of skin malignancies, we present an algorithm for evaluating skin lesions.

Impact of skin cancer

The incidence of malignant melanoma has increased from 1 in 1500 in 1930 to 1 in 75 for the year 2000.¹ Although it is the rarest skin cancer (1% of skin malignancies), it is also the deadliest, accounting for 60% of skin cancer deaths.²

Nonmelanoma skin cancers, which include squamous cell cancers and basal cell cancers, account for one third of all cancers in the United States. Approximately 1 million cases were diagnosed in 1999.³ Deaths from nonmelanoma skin cancers are in steady decline, and the overall 5-year survival rate is high (over 95%).⁴ Recurrent nonmelanoma skin cancer, however, carries a very poor prognosis, with only a 50% cure rate.⁵

Treatment of nonmelanoma skin cancer costs over $500 million yearly in the US.⁴

Primary care physicians help improve prognosis

More persons visit primary care physicians (38.2%) than dermatologists (29.9%) for evaluation of suspicious skin lesions.⁶ Such lesions are usually benign, but a malignancy must be excluded. A primary care physician can expect to diagnose 6 to 7 cases of basal cell cancer, 1 to 2 cases of squamous cell cancer, and approximately 1 case of melanoma every year, according to population-based studies.⁴

Primary care practitioners contribute to a more favorable prognosis. For each additional family physician per 10,000 population, the chances of diagnosing malignant melanoma earlier increase significantly (odds ratio= 1.21, 95% confidence interval, 1.09–1.33, P<.001).⁷

Primary care physicians who diagnose non-melanoma skin cancers can select therapies that offer maximum efficacy and cost-effectiveness.

Differential diagnosis

According to a study of 1215 biopsies conducted in a primary care population, over 80% of biopsied lesions were benign and included nevi, seborrheic keratoses, cysts, dermatofibromas, fibrous histiocytomas, and polyps or skin tags. Pre-malignant lesions (including actinic keratoses and lentigo maligna) represented 7% of the total. Thirteen percent were malignancies: basal cell carcinomas (73%), followed by squamous cell carcinomas (14%), and malignant melanomas (12%). One metastatic adenomacarcinoma was included in the series (1%) (level of evidence [LOE]: 4).⁸

The differential diagnosis for basal cell carcinoma includes superficial basal cell carcinoma, pigmented basal cell carcinoma, infiltrating basal cell carcinoma, tricoepithelioma, keloid, molluscum contagiosum, and dermatofibromas.

For squamous cell cancer, the differential includes squamous cell carcinoma, keratoacanthoma, eczema and atopic dermatitis, contact dermatitis, psoriasis, and seborrheic dermatitis.

The differential diagnosis for malignant melanoma includes seborrheic keratosis, traumatized or irritated nevus, pigmented basal cell carcinoma, lentigo, blue nevus, angiokeratoma, traumatic hematoma, venous lake, hemangioma, dermatofibroma, and pigmented actinic keratosis.

Using the history and physical examination

Nearly 70% of melanomas are discovered by patients or their family (LOE: 4).⁹ Patients may express concern about changed size or appearance of a lesion; associated pain, pruritis, ulceration, or bleeding; location in a cosmetically sensitive area; or worry voiced by a family member. Additionally, a patient may have a family or personal history of skin malignancy, history of skin biopsy, or predisposition to sunburns.

Nurses and physicians identify lesions before a patient does approximately one quarter of the time while examining a patient for an unrelated condition or as part of a comprehensive work-up (LOE: 4).⁹

Types of skin malignancies

See Photo Rounds, page 219, for images of many types of skin cancer.

Basal cell carcinoma

The patterns of basal cell carcinoma are nodular, superficial, micronodular, infiltrative, morpheaform, and mixed.¹⁰ They may be pigmented and are sometimes misdiagnosed as melanoma.¹¹ However, most basal cell carcinomas are typical in appearance and easily diagnosed by visual and tactile inspection.

The most common nodular type is a smooth, skin-colored, indurated, dome-shaped papule with a rolled edge. Other attributes include a pearly appearance, overlying telangiectatic vessels, and a history of bleeding with minor trauma.^7,11

Superficial basal cell carcinoma is similar to dermatitis but more often has distinct borders and a bright pink appearance.¹¹ If in doubt about the diagnosis, obtain a tissue sample for pathology.

Squamous cell carcinoma

Squamous cell carcinoma most often is a small, firm, hyperkaratotic nodule sitting atop an inflamed base. It may also be skin-colored and smooth. The history can include itching, pain, and nonhealing after minor trauma.^7,11,12 As with basal cell carcinoma, diagnosis is made by tissue pathology.

Malignant melanoma

Malignant melanoma usually appears as a changing or unusual mole with haphazard color variegation, including combinations of brown, black, blue, gray, white, and (rarely) pink. Most melanomas are larger than 5 mm in diameter at time of diagnosis.¹³

There are 4 main types of malignant melanoma:

• Superficial spreading melanoma accounts for 50% of cases and occurs more frequently in younger adults.
• Nodular melanoma also occurs in younger adults, representing 20% to 25% of cases.
• Lentigo maligna melanoma occurs in older adults and accounts for only 15% of cases.
• Acral or acral-lentiginous melanomas are the least common form (10% of cases). They appear on the palms, soles, and around the first toenail.¹⁴

Risk factors for skin malignancies

Factors conferring the highest relative risk for malignant melanoma include:¹³

• atypical nevus syndrome with a personal and family history of melanoma
• history of a changing mole
• atypical nevus syndrome with just a family history of melanoma
• age greater than or equal to 15 years
• history of dysplastic moles.

Table 1 provides a list of risk factors that should prompt an annual skin survey (LOE: 5).

For nonmelanoma skin cancers, the strongest risk factors ( Table 2) include Caucasian race; age 55 to 75 years; and male sex.² There is good evidence that a history of nonmelanoma skin cancer confers a 10-fold risk for recurrence (LOE: 2a).¹⁵ A distinct risk factor for squamous cell carcinoma is immunosuppression.² Table 2 also provides a complete list of risk factors for nonmelanoma skin cancer.

Precursor lesions for nonmelanoma skin cancers include Bowen’s disease and erythroplasia of Queyrat (forms of squamous cell carcinoma in situ that will progress if left untreated). Actinic keratoses are common precursor lesions, but their overall annual rate of malignant transformation is only 1 in 400. In the case of SCC, up to 60% of cancers develop from an existing actinic keratosis.²

TABLE 1
Risk factors for malignant melanoma ¹³

TABLE 2
Risk factors for nonmelanoma skin cancer

Clinical prediction rules for skin malignancies

Malignant melanoma

ABCDE criteria. A useful clinical prediction rule for malignant melanoma is the American Cancer Society’s “ABCDE criteria” (Table 3). This rule was validated in 4 dermatology clinics, studying a total of 1118 lesions, although the studies were not homogenous (strength of recommendation [SOR]: A).^16-19 Results of the study are summarized in Table 4. The test is normally considered positive if one or more of the criteria are met; however, as more criteria are met, specificity increases while sensitivity decreases.^17-19

For lesions lacking any of the ABCDE criteria, 99.8% are something other than melanoma (using a prevalence of 1% found in the US population) (SOR: A). Use caution, however, as this rule will miss amelanotic melanomas, as well as smaller melanomas that are changing in size or have other features suggestive of malignant melanoma.

Conversely, if one of the criteria is met, there is nearly a 1.5% (positive predictive value) probability it is melanoma. Excisional biopsy of the lesion is indicated if good clinical judgment is used and it cannot be identified with certainty as a typical benign lesion (SOR: A). This test thus guides clinicians when making a decision to biopsy, as well as in choosing a biopsy technique.

The ABCDE criteria establish a risk of malignancy if the lesion is 6 mm in diameter or greater. Some evidence, however, suggests that this value should not be used as an absolute cutoff for diagnosing malignant melanoma. A large retrospective study performed in Australia found that 31% of biopsy-confirmed melanomas were less than 6 mm in diameter (LOE: 2b).²⁰

Revised 7-point checklist. Another potentially useful diagnostic test is the revised 7-point checklist developed in the United Kingdom ( Table 5). This test was found to have a high sensitivity, but low specificity ( Table 4) . Therefore, it has a low false-negative rate, and is useful for ruling out the diagnosis of melanoma when negative. However, the test yields a significant number of false positive results, leading to possibly unnecessary biopsies and increased patient anxiety (SOR: B).^16,21,22

Note: the described sensitivities and specificities for both tests apply only to malignant melanomas, and their accuracy decreases when including basal cell and squamous cell carcinomas. Also, the 2 tests were scored differently in some of the validation studies, making attempts to generalize problematic.

Studies of physicians’ global assessments to detect melanomas ( Table 4) vary widely for sensitivity (50% to 97%) but are consistent for specificity (96% to 99%) (SOR: B).^23-28 Additionally, some studies have shown higher percentages of correct diagnosis of malignant melanoma among dermatologists compared with nondermatologists, but all these studies (except for a small subset of patients in one) used lesion images rather than patient examinations (SOR: B).^23,29-33

More importantly, when the choice of correct treatment was evaluated, no statistically significant difference was found between the two groups. Further prospective cohort trials using patient examinations are needed to evaluate dermatologist performance versus nondermatologist performance.

TABLE 3
American Cancer Society's ABCDE criteria

The test is considered positive if a lesion exhibits 1 or more of the 5 criteria
Assymetry—one half of the lesion not identical to the other
Border irregularity—lesion has an uneven or ragged border
Color variegation—lesion has more than one color (ie, black, blue, pink, red, or white)
Diameter—lesion has a diameter greater than 6 mm
Elevation or Enlargement—elevation of lesion above skin surface or enlargement by patient report

TABLE 4
Clinical prediction tests for skin malignancies

TABLE 5
Revised 7-point checklist for assessing risk of melanoma

No validated tool for diagnosis of nonmelanoma skin cancers

A useful diagnostic tool has not yet been validated for nonmelanoma skin cancers. Over 60% of non-melanoma skin cancers occur on the face and neck, and these areas bear careful inspection. Lesions behind the ear, at the medial canthus, and within the nasolabial folds are most easily missed.

How to proceed in assessing lesions

When evaluating skin lesions, remember the gold standard for diagnosis of skin malignancies is a tissue biopsy. If you or your patient has any doubt about the diagnosis, a biopsy should be performed.

To review: Good evidence supports the use the ABCDE criteria or the revised 7-point checklist in determining whether lesions are likely to be malignant melanomas. No similar diagnostic rules exist for basal cell and squamous cell carcinomas. The decision to biopsy these lesions must be based on global assessment and typical characteristics.

Based on this information, we developed an algorithm for evaluating patients at risk for skin malignancies ( Figure) . The first step is to apply the ABCDE criteria and the revised 7-point checklist to identify or rule out possible malignant melanomas. An excisional biopsy should be performed if either test is positive (and the lesion is not clinically benign), or if you or your patient has any doubt.

If neither of these diagnostic tests yields a positive result, the lesion should be classified as typically benign or as having characteristics suggestive of a squamous cell or basal cell carcinoma.

Lesions that have characteristics of squamous cell or basal cell cancer should be biopsied, and benign lesions can be observed and the patient reassured.

FIGURE
Approach to the patient with a skin lesion

Acknowledgments

The authors wish to thank Barbara Zuckerman and Michael Campese, PhD for their assistance in preparation of this manuscript. We also gratefully acknowledge Dr. Richard P. Usatine for preparing the accompanying Photo Rounds.

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.

Is the preparticipation physical examination the best way to determine whether a student athlete can participate fully in his or her chosen sport? This examination has become the standard of care for the over 6 million high school and college students. While most athletes pass the exam without significant medical or orthopedic abnormalities being noted, it often detects conditions that may predispose an athlete to injury or limit full participation in certain activities. We describe an efficient approach to the preparticipation examination.

Although many organizations have adopted the preparticipation exam there has been considerable debate on its content and usefulness.^1-4 Nevertheless, sponsoring institutions continue to require the medical evaluation prior to competition in organized athletics, so family physicians should be knowledgeable about the objectives and limitations of the exam.

The American Academy of Family Physicians, the American Academy of Pediatrics, the American Medical Society for Sports Medicine, the American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine established the Preparticipation Physical Examination Task Force. The recommendations of this task force serve as a guide for the physician conducting these examinations for high school and collegiate athletes.^5,6

Assessing risks of mortality and morbidity

The mortality associated with athletic participation is most often the result of sudden cardiac death, which occurs in about 0.5 per 100,000 high school athletes per academic year and is most commonly due to hypertrophic cardiomyopathy.^7,8 Screening for predisposing conditions is limited by the low prevalence of relevant cardiovascular lesions in the general youth population, the low risk of sudden death even among persons with an unsuspected abnormality, and the large number of school athletes.^7-9

An estimated 200,000 children and adolescents would have to be screened to detect the 500 athletes who are at risk for sudden cardiac death and the 1 person who would actually experience it.¹⁰ Even when cardiac abnormalities are detected, the findings leading to disqualification are most often rhythm and conduction abnormalities, valvular abnormalities, and systemic hypertension, which are not the cardiac abnormalities usually associated with sudden cardiac death in athletes.^11,12

The majority of sudden deaths are associated with 4 sports: football, basketball, track, and soccer. Approximately 90% of athletic-field deaths have occurred in males, mostly high school athletes.^7,13

More frequently than mortality, athletic participation places the individual at risk for acute injury or worsening of an underlying medical condition. These conditions are most commonly musculoskeletal, cardiovascular, or ophthalmologic (Table 1).^5,9,21

Nine studies of the preparticipation exam done between 1980 and 1999 show general agreement on the rates at which it qualifies (84.8% to 96.6%), qualifies with conditions (3.1% to 13.9%), and disqualifies students for sports participation (0.2% to 2.6%).^14-22

TABLE 1
Medical and orthopedic conditions resulting in additional evaluations

What should the medical history include?

The examining physician should obtain a medical history from each participant (strength of recommendation [SOR]: D). A complete medical history will identify approximately 75% of problems that will affect initial athletic participation and serves as the cornerstone of the exam.^14,19 Most conditions requiring further evaluation or restriction will be identified from the medical history. Rifat and colleagues²¹ noted that a complete medical history accounted for 88% of the abnormal findings and 57% of the reasons cited for activity restriction. The Preparticipation Physical Evaluation Task Force has developed a history form that emphasizes the areas of greatest concern.⁵

In particular, examining physicians should ask regarding risk factors and symptoms of cardiovascular disease ( Table 2 ). You should confirm a positive response to any of these questions, and conduct further evaluation if necessary. Unfortunately, most athletes with hypertrophic cardiomyopathy do not report a history of syncope with exercise or a family history of premature sudden cardiac death due to the disease.

Musculoskeletal injury is a common cause for disqualification of an athlete.^14,19,21 The most common injury to restrict participation is a knee injury, with an ankle injury the next most common.²³ The strongest independent predictor of sports injuries is a previous injury (odds ratio [OR]=9.4) and exposure time (OR=6.9).²⁴ DuRant and colleagues²³ found that a previous knee injury or knee surgery was significantly associated with further knee injuries during the subsequent sports season when compared with individuals who did not report previous knee injury or surgery (30.6% vs. 7.2%, P=.0001).

Additional historical information has been recommended for inclusion (SOR: D). For example, the examining physician should question the athlete about wheezing during exercise. Due to the high rate of recurrence and potential for long-term adverse effects, he or she should also obtain a history of previous concussions. Other issues to be addressed include presence of a single bilateral organ and use of performance-enhancing medication. Finally, physicians should question female athletes regarding their menstrual history and other symptoms or signs of the female athletic triad (eating disorder, amenorrhea, and osteoporosis).

Always carefully review the information provided by the athlete and his or her parents. In 2 separate studies, minimal agreement was found between histories obtained from athletes and parents independently.^19,25 We do not know which source provides the most accurate history; therefore, both the parents and student athlete should be questioned.

TABLE 2
Questions to help discern cardiovascular risk

What should the physical examination include ?

A complete physical examination is not necessary (SOR: D).⁵ The screening physical examination should include vital signs (ie, height, weight, and blood pressure) and visual acuity testing as well as a cardiovascular, pulmonary, abdominal, skin, genital (for males), and musculoskeletal examination. Further examination should be based on issues elicited during the history.

Cardiovascular examination

The cardiovascular examination requires an additional level of detail. Perform auscultation of the heart initially with the patient in both standing and supine position, and during various maneuvers (squat-to-stand, deep inspiration, or Valsalva’s maneuver), as these maneuvers can clarify the type of murmur.

Any systolic murmur grade III/VI or louder, any murmur that disrupts normal heart sounds, any diastolic murmur, or any murmur that intensifies with the previously described maneuvers should be evaluated further through diagnostic studies (echocardiography) or consultation prior to participation. Sinus bradycardia and systolic murmurs are commonly found, occurring in over 50% and between 30% and 50% of athletes, respectively; they do not warrant further evaluation in the asymptomatic athlete.²⁶ Third and fourth heart sounds are also commonly found in asymptomatic athletes without underlying heart disease.^26,27

Noninvasive cardiac testing (eg, electrocardiography, echocardiography, or exercise stress testing) should not be a routine part of the screening preparticipation exam (SOR: B ).⁷ These tests are not cost-effective in a population at relatively low risk for cardiac abnormalities and cannot consistently identify athletes at actual risk.^28-32 For example, a substantial minority of subjects (11%) were found to have a clinically significant increased ventricular wall thickness, which made clinical interpretation of the echocardiographic findings difficult in individual athletes.²⁸ Furthermore, some patients with hypertrophic cardiomyopathy are able to tolerate particularly intense athletic training and competition for many years, and even maintain high levels of achievement without incurring symptoms, disease progression, or sudden death.²⁹

Echocardiography and stress testing are the most commonly recommended diagnostic tests for patients with an abnormal cardiovascular history or examination. With the assistance of clinical information, echocardiography is able to distinguish the nonobstructive hypertrophic cardiomyopathy from the athletic heart syndrome.³³

Musculos keletal examination

A screening musculoskeletal history and examination in combination can be used for asymptomatic athletes with no previous injuries (Table 3) (SOR: A).³⁴ An accurate history is able to detect over 90% of significant musculoskeletal injuries. The screening physical examination is 51% sensitive and 97% specific.³⁴ If the athlete has either a previous injury or other signs or symptoms (ie, pain; tenderness; asymmetries in muscle bulk, strength, or range of motion; any obvious deformity) detected by the general screening examination or history, the general screening should be supplemented with relevant elements of a site-specific examination.

Additional forms of musculoskeletal evaluation are often performed for athletes to determine their general state of flexibility and muscular strength. While various degrees of hyperlaxity, muscular tightness, weakness, asymmetry of strength or flexibility, poor endurance, and abnormal foot configuration may predispose an athlete to increased risk of injury during sports competition, studies have failed to demonstrate conclusively that injuries are prevented by interventions aimed at correcting such abnormalities.^35-37

TABLE 3
The “90-second” musculoskeletal screening examination

Role for lab tests?

Studies do not support the use of routine laboratory or other screening tests such as urinalysis, complete blood count, chemistry profile, lipid profile, ferritin level, or spirometry as part of the exam (SOR: B).^38-41

Determining clearance

Occasionally, an abnormality or condition is found that may limit an athlete’s participation or predispose him or her to further injury. In these cases, the examining physician should review the following questions:⁵

1. Does the problem place the athlete at increased risk for injury?
2. Is another participant at risk for injury because of the problem?
3. Can the athlete safely participate with treatment (ie, medication, rehabilitation, bracing, or padding)?
4. Can limited participation be allowed while treatment is being completed?
5. If clearance is denied only for certain sports or sport categories, in what activities can the athlete safely participate?

Physicians should base clearance to participate in a particular sport on previously published guidelines, such as the recommendations by the American Academy of Pediatrics, the 26th Bethesda Conference, and the American Heart Association.^7,43,44 Participation recommendations are based on the specific diagnosis, though multiple factors such as the classification of the sport and the specific health status of the athlete affect the decision.⁴⁴

Approach to the patient

While current research demonstrates that the preparticipation physical examination has no effect on the overall morbidity and mortality rates in athletes, these exams may fulfill other objectives. Furthermore, no harmful effects of these examinations have been reported, and the exam has become institutionalized in the athletic and sports medicine community. As such, physicians should base their evaluation on the best available evidence using the standard form shown in “Preparticipation physical evaluation for athletics.”⁶ (A copy of the Preparticipation Physical Evaluation form can be found at www.jfponline.com.) This may require that the physician work with local school systems to assure that they understand what constitutes an appropriate examination.

To assist future patient care decisions and research efforts, a standardized preparticipation physical examination with an associated form similar to the evaluation recommended by the Preparticipation Physical Evaluation Task Force should be uniformly implemented throughout the country. The use of consistent clearance criteria as recommended by the Preparticipation Physical Evaluation Task Force or the American Academy of Pediatrics (“Medical conditions and sports participation,” also available at www.jfponline.com) should be used, studied, and revised as needed.^5,44

In addition to the exam, physicians should consider exploring other aspects of sports participation to assist athletes in reducing the risk of injury. Rules, equipment, or other factors may have a greater effect on decreasing the mortality and morbidity associated with athletic participation. A marked decrease in cervical spine injuries occurred following the rule change in football banning deliberate “spearing”—the use of the top of the helmet as the initial point of contact in making a tackle.⁴¹

Is the preparticipation physical examination the best way to determine whether a student athlete can participate fully in his or her chosen sport? This examination has become the standard of care for the over 6 million high school and college students. While most athletes pass the exam without significant medical or orthopedic abnormalities being noted, it often detects conditions that may predispose an athlete to injury or limit full participation in certain activities. We describe an efficient approach to the preparticipation examination.

Although many organizations have adopted the preparticipation exam there has been considerable debate on its content and usefulness.^1-4 Nevertheless, sponsoring institutions continue to require the medical evaluation prior to competition in organized athletics, so family physicians should be knowledgeable about the objectives and limitations of the exam.

The American Academy of Family Physicians, the American Academy of Pediatrics, the American Medical Society for Sports Medicine, the American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine established the Preparticipation Physical Examination Task Force. The recommendations of this task force serve as a guide for the physician conducting these examinations for high school and collegiate athletes.^5,6

Assessing risks of mortality and morbidity

The mortality associated with athletic participation is most often the result of sudden cardiac death, which occurs in about 0.5 per 100,000 high school athletes per academic year and is most commonly due to hypertrophic cardiomyopathy.^7,8 Screening for predisposing conditions is limited by the low prevalence of relevant cardiovascular lesions in the general youth population, the low risk of sudden death even among persons with an unsuspected abnormality, and the large number of school athletes.^7-9

An estimated 200,000 children and adolescents would have to be screened to detect the 500 athletes who are at risk for sudden cardiac death and the 1 person who would actually experience it.¹⁰ Even when cardiac abnormalities are detected, the findings leading to disqualification are most often rhythm and conduction abnormalities, valvular abnormalities, and systemic hypertension, which are not the cardiac abnormalities usually associated with sudden cardiac death in athletes.^11,12

The majority of sudden deaths are associated with 4 sports: football, basketball, track, and soccer. Approximately 90% of athletic-field deaths have occurred in males, mostly high school athletes.^7,13

More frequently than mortality, athletic participation places the individual at risk for acute injury or worsening of an underlying medical condition. These conditions are most commonly musculoskeletal, cardiovascular, or ophthalmologic (Table 1).^5,9,21

Nine studies of the preparticipation exam done between 1980 and 1999 show general agreement on the rates at which it qualifies (84.8% to 96.6%), qualifies with conditions (3.1% to 13.9%), and disqualifies students for sports participation (0.2% to 2.6%).^14-22

TABLE 1
Medical and orthopedic conditions resulting in additional evaluations

What should the medical history include?

The examining physician should obtain a medical history from each participant (strength of recommendation [SOR]: D). A complete medical history will identify approximately 75% of problems that will affect initial athletic participation and serves as the cornerstone of the exam.^14,19 Most conditions requiring further evaluation or restriction will be identified from the medical history. Rifat and colleagues²¹ noted that a complete medical history accounted for 88% of the abnormal findings and 57% of the reasons cited for activity restriction. The Preparticipation Physical Evaluation Task Force has developed a history form that emphasizes the areas of greatest concern.⁵

In particular, examining physicians should ask regarding risk factors and symptoms of cardiovascular disease ( Table 2 ). You should confirm a positive response to any of these questions, and conduct further evaluation if necessary. Unfortunately, most athletes with hypertrophic cardiomyopathy do not report a history of syncope with exercise or a family history of premature sudden cardiac death due to the disease.

Musculoskeletal injury is a common cause for disqualification of an athlete.^14,19,21 The most common injury to restrict participation is a knee injury, with an ankle injury the next most common.²³ The strongest independent predictor of sports injuries is a previous injury (odds ratio [OR]=9.4) and exposure time (OR=6.9).²⁴ DuRant and colleagues²³ found that a previous knee injury or knee surgery was significantly associated with further knee injuries during the subsequent sports season when compared with individuals who did not report previous knee injury or surgery (30.6% vs. 7.2%, P=.0001).

Additional historical information has been recommended for inclusion (SOR: D). For example, the examining physician should question the athlete about wheezing during exercise. Due to the high rate of recurrence and potential for long-term adverse effects, he or she should also obtain a history of previous concussions. Other issues to be addressed include presence of a single bilateral organ and use of performance-enhancing medication. Finally, physicians should question female athletes regarding their menstrual history and other symptoms or signs of the female athletic triad (eating disorder, amenorrhea, and osteoporosis).

Always carefully review the information provided by the athlete and his or her parents. In 2 separate studies, minimal agreement was found between histories obtained from athletes and parents independently.^19,25 We do not know which source provides the most accurate history; therefore, both the parents and student athlete should be questioned.

TABLE 2
Questions to help discern cardiovascular risk

What should the physical examination include ?

A complete physical examination is not necessary (SOR: D).⁵ The screening physical examination should include vital signs (ie, height, weight, and blood pressure) and visual acuity testing as well as a cardiovascular, pulmonary, abdominal, skin, genital (for males), and musculoskeletal examination. Further examination should be based on issues elicited during the history.

Cardiovascular examination

The cardiovascular examination requires an additional level of detail. Perform auscultation of the heart initially with the patient in both standing and supine position, and during various maneuvers (squat-to-stand, deep inspiration, or Valsalva’s maneuver), as these maneuvers can clarify the type of murmur.

Any systolic murmur grade III/VI or louder, any murmur that disrupts normal heart sounds, any diastolic murmur, or any murmur that intensifies with the previously described maneuvers should be evaluated further through diagnostic studies (echocardiography) or consultation prior to participation. Sinus bradycardia and systolic murmurs are commonly found, occurring in over 50% and between 30% and 50% of athletes, respectively; they do not warrant further evaluation in the asymptomatic athlete.²⁶ Third and fourth heart sounds are also commonly found in asymptomatic athletes without underlying heart disease.^26,27

Noninvasive cardiac testing (eg, electrocardiography, echocardiography, or exercise stress testing) should not be a routine part of the screening preparticipation exam (SOR: B ).⁷ These tests are not cost-effective in a population at relatively low risk for cardiac abnormalities and cannot consistently identify athletes at actual risk.^28-32 For example, a substantial minority of subjects (11%) were found to have a clinically significant increased ventricular wall thickness, which made clinical interpretation of the echocardiographic findings difficult in individual athletes.²⁸ Furthermore, some patients with hypertrophic cardiomyopathy are able to tolerate particularly intense athletic training and competition for many years, and even maintain high levels of achievement without incurring symptoms, disease progression, or sudden death.²⁹

Echocardiography and stress testing are the most commonly recommended diagnostic tests for patients with an abnormal cardiovascular history or examination. With the assistance of clinical information, echocardiography is able to distinguish the nonobstructive hypertrophic cardiomyopathy from the athletic heart syndrome.³³

Musculos keletal examination

A screening musculoskeletal history and examination in combination can be used for asymptomatic athletes with no previous injuries (Table 3) (SOR: A).³⁴ An accurate history is able to detect over 90% of significant musculoskeletal injuries. The screening physical examination is 51% sensitive and 97% specific.³⁴ If the athlete has either a previous injury or other signs or symptoms (ie, pain; tenderness; asymmetries in muscle bulk, strength, or range of motion; any obvious deformity) detected by the general screening examination or history, the general screening should be supplemented with relevant elements of a site-specific examination.

Additional forms of musculoskeletal evaluation are often performed for athletes to determine their general state of flexibility and muscular strength. While various degrees of hyperlaxity, muscular tightness, weakness, asymmetry of strength or flexibility, poor endurance, and abnormal foot configuration may predispose an athlete to increased risk of injury during sports competition, studies have failed to demonstrate conclusively that injuries are prevented by interventions aimed at correcting such abnormalities.^35-37

TABLE 3
The “90-second” musculoskeletal screening examination

Role for lab tests?

Studies do not support the use of routine laboratory or other screening tests such as urinalysis, complete blood count, chemistry profile, lipid profile, ferritin level, or spirometry as part of the exam (SOR: B).^38-41

Determining clearance

Occasionally, an abnormality or condition is found that may limit an athlete’s participation or predispose him or her to further injury. In these cases, the examining physician should review the following questions:⁵

1. Does the problem place the athlete at increased risk for injury?
2. Is another participant at risk for injury because of the problem?
3. Can the athlete safely participate with treatment (ie, medication, rehabilitation, bracing, or padding)?
4. Can limited participation be allowed while treatment is being completed?
5. If clearance is denied only for certain sports or sport categories, in what activities can the athlete safely participate?

Physicians should base clearance to participate in a particular sport on previously published guidelines, such as the recommendations by the American Academy of Pediatrics, the 26th Bethesda Conference, and the American Heart Association.^7,43,44 Participation recommendations are based on the specific diagnosis, though multiple factors such as the classification of the sport and the specific health status of the athlete affect the decision.⁴⁴

Approach to the patient

While current research demonstrates that the preparticipation physical examination has no effect on the overall morbidity and mortality rates in athletes, these exams may fulfill other objectives. Furthermore, no harmful effects of these examinations have been reported, and the exam has become institutionalized in the athletic and sports medicine community. As such, physicians should base their evaluation on the best available evidence using the standard form shown in “Preparticipation physical evaluation for athletics.”⁶ (A copy of the Preparticipation Physical Evaluation form can be found at www.jfponline.com.) This may require that the physician work with local school systems to assure that they understand what constitutes an appropriate examination.

To assist future patient care decisions and research efforts, a standardized preparticipation physical examination with an associated form similar to the evaluation recommended by the Preparticipation Physical Evaluation Task Force should be uniformly implemented throughout the country. The use of consistent clearance criteria as recommended by the Preparticipation Physical Evaluation Task Force or the American Academy of Pediatrics (“Medical conditions and sports participation,” also available at www.jfponline.com) should be used, studied, and revised as needed.^5,44

In addition to the exam, physicians should consider exploring other aspects of sports participation to assist athletes in reducing the risk of injury. Rules, equipment, or other factors may have a greater effect on decreasing the mortality and morbidity associated with athletic participation. A marked decrease in cervical spine injuries occurred following the rule change in football banning deliberate “spearing”—the use of the top of the helmet as the initial point of contact in making a tackle.⁴¹

Is the preparticipation physical examination the best way to determine whether a student athlete can participate fully in his or her chosen sport? This examination has become the standard of care for the over 6 million high school and college students. While most athletes pass the exam without significant medical or orthopedic abnormalities being noted, it often detects conditions that may predispose an athlete to injury or limit full participation in certain activities. We describe an efficient approach to the preparticipation examination.

Although many organizations have adopted the preparticipation exam there has been considerable debate on its content and usefulness.^1-4 Nevertheless, sponsoring institutions continue to require the medical evaluation prior to competition in organized athletics, so family physicians should be knowledgeable about the objectives and limitations of the exam.

The American Academy of Family Physicians, the American Academy of Pediatrics, the American Medical Society for Sports Medicine, the American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine established the Preparticipation Physical Examination Task Force. The recommendations of this task force serve as a guide for the physician conducting these examinations for high school and collegiate athletes.^5,6

Assessing risks of mortality and morbidity

The mortality associated with athletic participation is most often the result of sudden cardiac death, which occurs in about 0.5 per 100,000 high school athletes per academic year and is most commonly due to hypertrophic cardiomyopathy.^7,8 Screening for predisposing conditions is limited by the low prevalence of relevant cardiovascular lesions in the general youth population, the low risk of sudden death even among persons with an unsuspected abnormality, and the large number of school athletes.^7-9

An estimated 200,000 children and adolescents would have to be screened to detect the 500 athletes who are at risk for sudden cardiac death and the 1 person who would actually experience it.¹⁰ Even when cardiac abnormalities are detected, the findings leading to disqualification are most often rhythm and conduction abnormalities, valvular abnormalities, and systemic hypertension, which are not the cardiac abnormalities usually associated with sudden cardiac death in athletes.^11,12

The majority of sudden deaths are associated with 4 sports: football, basketball, track, and soccer. Approximately 90% of athletic-field deaths have occurred in males, mostly high school athletes.^7,13

More frequently than mortality, athletic participation places the individual at risk for acute injury or worsening of an underlying medical condition. These conditions are most commonly musculoskeletal, cardiovascular, or ophthalmologic (Table 1).^5,9,21

Nine studies of the preparticipation exam done between 1980 and 1999 show general agreement on the rates at which it qualifies (84.8% to 96.6%), qualifies with conditions (3.1% to 13.9%), and disqualifies students for sports participation (0.2% to 2.6%).^14-22

TABLE 1
Medical and orthopedic conditions resulting in additional evaluations

What should the medical history include?

The examining physician should obtain a medical history from each participant (strength of recommendation [SOR]: D). A complete medical history will identify approximately 75% of problems that will affect initial athletic participation and serves as the cornerstone of the exam.^14,19 Most conditions requiring further evaluation or restriction will be identified from the medical history. Rifat and colleagues²¹ noted that a complete medical history accounted for 88% of the abnormal findings and 57% of the reasons cited for activity restriction. The Preparticipation Physical Evaluation Task Force has developed a history form that emphasizes the areas of greatest concern.⁵

In particular, examining physicians should ask regarding risk factors and symptoms of cardiovascular disease ( Table 2 ). You should confirm a positive response to any of these questions, and conduct further evaluation if necessary. Unfortunately, most athletes with hypertrophic cardiomyopathy do not report a history of syncope with exercise or a family history of premature sudden cardiac death due to the disease.

Musculoskeletal injury is a common cause for disqualification of an athlete.^14,19,21 The most common injury to restrict participation is a knee injury, with an ankle injury the next most common.²³ The strongest independent predictor of sports injuries is a previous injury (odds ratio [OR]=9.4) and exposure time (OR=6.9).²⁴ DuRant and colleagues²³ found that a previous knee injury or knee surgery was significantly associated with further knee injuries during the subsequent sports season when compared with individuals who did not report previous knee injury or surgery (30.6% vs. 7.2%, P=.0001).

Additional historical information has been recommended for inclusion (SOR: D). For example, the examining physician should question the athlete about wheezing during exercise. Due to the high rate of recurrence and potential for long-term adverse effects, he or she should also obtain a history of previous concussions. Other issues to be addressed include presence of a single bilateral organ and use of performance-enhancing medication. Finally, physicians should question female athletes regarding their menstrual history and other symptoms or signs of the female athletic triad (eating disorder, amenorrhea, and osteoporosis).

Always carefully review the information provided by the athlete and his or her parents. In 2 separate studies, minimal agreement was found between histories obtained from athletes and parents independently.^19,25 We do not know which source provides the most accurate history; therefore, both the parents and student athlete should be questioned.

TABLE 2
Questions to help discern cardiovascular risk

What should the physical examination include ?

A complete physical examination is not necessary (SOR: D).⁵ The screening physical examination should include vital signs (ie, height, weight, and blood pressure) and visual acuity testing as well as a cardiovascular, pulmonary, abdominal, skin, genital (for males), and musculoskeletal examination. Further examination should be based on issues elicited during the history.

Cardiovascular examination

The cardiovascular examination requires an additional level of detail. Perform auscultation of the heart initially with the patient in both standing and supine position, and during various maneuvers (squat-to-stand, deep inspiration, or Valsalva’s maneuver), as these maneuvers can clarify the type of murmur.

Any systolic murmur grade III/VI or louder, any murmur that disrupts normal heart sounds, any diastolic murmur, or any murmur that intensifies with the previously described maneuvers should be evaluated further through diagnostic studies (echocardiography) or consultation prior to participation. Sinus bradycardia and systolic murmurs are commonly found, occurring in over 50% and between 30% and 50% of athletes, respectively; they do not warrant further evaluation in the asymptomatic athlete.²⁶ Third and fourth heart sounds are also commonly found in asymptomatic athletes without underlying heart disease.^26,27

Noninvasive cardiac testing (eg, electrocardiography, echocardiography, or exercise stress testing) should not be a routine part of the screening preparticipation exam (SOR: B ).⁷ These tests are not cost-effective in a population at relatively low risk for cardiac abnormalities and cannot consistently identify athletes at actual risk.^28-32 For example, a substantial minority of subjects (11%) were found to have a clinically significant increased ventricular wall thickness, which made clinical interpretation of the echocardiographic findings difficult in individual athletes.²⁸ Furthermore, some patients with hypertrophic cardiomyopathy are able to tolerate particularly intense athletic training and competition for many years, and even maintain high levels of achievement without incurring symptoms, disease progression, or sudden death.²⁹

Echocardiography and stress testing are the most commonly recommended diagnostic tests for patients with an abnormal cardiovascular history or examination. With the assistance of clinical information, echocardiography is able to distinguish the nonobstructive hypertrophic cardiomyopathy from the athletic heart syndrome.³³

Musculos keletal examination

A screening musculoskeletal history and examination in combination can be used for asymptomatic athletes with no previous injuries (Table 3) (SOR: A).³⁴ An accurate history is able to detect over 90% of significant musculoskeletal injuries. The screening physical examination is 51% sensitive and 97% specific.³⁴ If the athlete has either a previous injury or other signs or symptoms (ie, pain; tenderness; asymmetries in muscle bulk, strength, or range of motion; any obvious deformity) detected by the general screening examination or history, the general screening should be supplemented with relevant elements of a site-specific examination.

Additional forms of musculoskeletal evaluation are often performed for athletes to determine their general state of flexibility and muscular strength. While various degrees of hyperlaxity, muscular tightness, weakness, asymmetry of strength or flexibility, poor endurance, and abnormal foot configuration may predispose an athlete to increased risk of injury during sports competition, studies have failed to demonstrate conclusively that injuries are prevented by interventions aimed at correcting such abnormalities.^35-37

TABLE 3
The “90-second” musculoskeletal screening examination

Role for lab tests?

Studies do not support the use of routine laboratory or other screening tests such as urinalysis, complete blood count, chemistry profile, lipid profile, ferritin level, or spirometry as part of the exam (SOR: B).^38-41

Determining clearance

Occasionally, an abnormality or condition is found that may limit an athlete’s participation or predispose him or her to further injury. In these cases, the examining physician should review the following questions:⁵

1. Does the problem place the athlete at increased risk for injury?
2. Is another participant at risk for injury because of the problem?
3. Can the athlete safely participate with treatment (ie, medication, rehabilitation, bracing, or padding)?
4. Can limited participation be allowed while treatment is being completed?
5. If clearance is denied only for certain sports or sport categories, in what activities can the athlete safely participate?

Physicians should base clearance to participate in a particular sport on previously published guidelines, such as the recommendations by the American Academy of Pediatrics, the 26th Bethesda Conference, and the American Heart Association.^7,43,44 Participation recommendations are based on the specific diagnosis, though multiple factors such as the classification of the sport and the specific health status of the athlete affect the decision.⁴⁴

Approach to the patient

While current research demonstrates that the preparticipation physical examination has no effect on the overall morbidity and mortality rates in athletes, these exams may fulfill other objectives. Furthermore, no harmful effects of these examinations have been reported, and the exam has become institutionalized in the athletic and sports medicine community. As such, physicians should base their evaluation on the best available evidence using the standard form shown in “Preparticipation physical evaluation for athletics.”⁶ (A copy of the Preparticipation Physical Evaluation form can be found at www.jfponline.com.) This may require that the physician work with local school systems to assure that they understand what constitutes an appropriate examination.

To assist future patient care decisions and research efforts, a standardized preparticipation physical examination with an associated form similar to the evaluation recommended by the Preparticipation Physical Evaluation Task Force should be uniformly implemented throughout the country. The use of consistent clearance criteria as recommended by the Preparticipation Physical Evaluation Task Force or the American Academy of Pediatrics (“Medical conditions and sports participation,” also available at www.jfponline.com) should be used, studied, and revised as needed.^5,44

In addition to the exam, physicians should consider exploring other aspects of sports participation to assist athletes in reducing the risk of injury. Rules, equipment, or other factors may have a greater effect on decreasing the mortality and morbidity associated with athletic participation. A marked decrease in cervical spine injuries occurred following the rule change in football banning deliberate “spearing”—the use of the top of the helmet as the initial point of contact in making a tackle.⁴¹