RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

RELATED ARTICLE WITH VIDEOS

• Which sling for which SUI patient?
  Mark D. Walters, MD, and Anne M. Weber, MD (Surgical Techniques, May 2012)

3 video clips illustrating midurethral sling procedures

These videos were selected by Dr. Walters and presented courtesy of the International Academy of Pelvic Surgery (IAPS)

When ISD is present, the urethra cannot coaptate and loses its ability to maintain a watertight seal. Women who have this condition often are severely incontinent, leaking urine at low volumes and pressures and with minimal exertion.

In this randomized trial, Schierlitz and colleagues hypothesized that TOT would produce higher objective and subjective failure rates than the TVT. This was confirmed by 6-month data published in 2008.

Details of the trial

Women who had SUI were included in the trial if they had ISD based on urodynamic findings (i.e., maximum urethral closure pressure ≤20 cm H₂O or Valsalva leak-point pressure ≤60 cm H₂O, or both) and were randomly assigned to TVT or TOT. The primary endpoint was symptomatic SUI (confirmed by repeat urodynamic testing) that required a second procedure upon patient request.

Participants were followed for 3 years. If a patient reported symptoms, urodynamic testing was repeated. In addition, the patient was offered another surgery, usually involving placement of a TVT sling.

Schierlitz and colleagues concluded that, if TVT were used in all patients, repeat surgery would be avoided in one in every six patients. The risk of repeat surgery was 15 times greater for TOT, compared with the TVT sling. The median time to failure was 15.6 months for the TOT sling, compared with 43.7 months for the TVT.

Of the 16 patients who underwent repeat surgery, 56% were cured, 25% reported minimal leakage, and 19% remained unchanged.

Quality-of-life scores were similar between groups at the 6-month follow-up.

Why did the TVT outperform the TOT in this population?

Investigators theorized that there is a difference in sling axis, with the TVT placed at a more acute angle than the TOT sling. In addition, the location of the TOT sling is more distal than that of the TVT, based on ultrasonographic imaging. As a result, more effective urethral kinking and support are likely with the TVT sling, improving continence rates.

Strengths and limitations of the trial

The randomization of participants and long-term follow-up bolster the trial’s credibility.

Weaknesses include unblinded participation and postoperative surgical assessment.

Although the sample size was underpowered, there was a significant difference in the primary outcome between the two groups.

We want to hear from you! Tell us what you think.

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. S, a 45-year-old veteran, was diagnosed with posttraumatic stress disorder (PTSD) 18 years ago after a tour of duty in the Persian Gulf. He had combat-related flashbacks triggered by the smell of gasoline or smoke from a fire, was easily startled, and began to isolate himself socially. However, his symptoms improved when he started volunteering at his local Veterans Affairs Medical Center. After he lost his job 3 years ago, Mr. S started experiencing flashbacks. He was irritable, easily startled, and avoided things that reminded him of his time in the Persian Gulf. His psychiatrist prescribed sertraline, titrated to 200 mg/d. The drug reduced the severity of his avoidance and hyperarousal symptoms and improved his mood.

During a clinic visit, Mr. S says he is doing well and can fall asleep at night but is having recurring nightmares about traumatic events that occurred during combat. These nightmares wake him up and have become more frequent, occurring once per night for the past month. Mr. S says he has been watching more news programs about conflicts in Afghanistan and Iraq since the nightmares began. His psychiatrist starts quetiapine, 50 mg at bedtime for 7 nights then 100 mg at bedtime, but after 6 weeks Mr. S says his nightmares continue.

PTSD occurs in approximately 19% of Vietnam war combat veterans¹ and 14% of service members returning from Iraq and Afghanistan.² PTSD symptoms are classified into clusters: intrusive/re-experiencing; avoidant/numbing; and hyperarousal.³ Nightmares are part of the intrusive/re-experiencing cluster, which is Criterion B in DSM-IV-TR. See Table 1 for a description of DSM-IV-TR PTSD criteria. Among PTSD patients, 50% to 70% report PTSD-associated nightmares.⁴ Despite adequate treatment targeted to improve PTSD’s core symptoms, symptoms such as sleep disturbances or nightmares often persist.

Table 1

DSM-IV-TR diagnostic criteria for posttraumatic stress disorder

Nightmares and other sleep disturbances are associated with significant distress and daytime impairment and can interfere with PTSD recovery^4-8 by disrupting sleep-dependent processing of emotional experiences and causing repeated resensitization to trauma cues (Table 2).⁸

Table 2

Psychosocial consequences of sleep disruption in PTSD

Few randomized controlled medication trials specifically address PTSD-related nightmares. Most PTSD studies do not examine sleep outcomes as a primary measure, and comprehensive literature reviews could not offer evidence-based recommendations.^9,10 The American Academy of Sleep Medicine (AASM) also noted a paucity of PTSD studies that identified nightmares as a primary outcome measure.¹¹ See Table 3 for a list of recommended medication options for PTSD-associated nightmares.

Table 3

Recommended medication treatments for PTSD-associated nightmares

CASE CONTINUED: Medication change, improvement

After reviewing AASM’s treatment recommendations, we prescribe prazosin, 1 mg at bedtime for 7 nights, then increase by 1 mg at bedtime each week until Mr. S’s nightmares improve. He reports a substantial improvement in nightmare severity and frequency after a few weeks of treatment with prazosin, 5 mg at bedtime.

Prazosin

Prazosin is an α1-adrenergic receptor antagonist with good CNS penetrability. The rationale for reducing adrenergic activity to address intrusive PTSD symptoms has been well documented.^12,13 In open-label trials,^14-18 a chart review,¹⁹ and placebo-controlled trials,^20-22prazosin reduced trauma nightmares and improved sleep quality and global clinical status more than placebo (Table 4). In these studies, prazosin doses ranged from 1 to 20 mg/d, with an average of 3 mg at bedtime and a starting dose of 1 mg. Prazosin is the only agent recommended in the AASM’s Best Practice Guide for treating PTSD-related nightmares.¹¹

Table 4

RCTs of prazosin for trauma-related nightmares

Atypical antipsychotics

Atypical antipsychotics have been used to reduce nightmares in PTSD; however, most of the evidence from studies evaluated in the AASM’s Best Practice Guide were considered to be low quality.¹¹ Quetiapine and ziprasidone were not included in the AASM review. See (Table 5) for a review of the evidence for atypical antipsychotics for treating PTSD nightmares.

Table 5

Combat-related nightmares: Evidence for atypical antipsychotics

Comparing prazosin and quetiapine. A historical prospective cohort study of 237 veterans with PTSD receiving prazosin or quetiapine for nighttime PTSD symptoms demonstrated that although the 2 drugs have similar efficacy (defined as symptomatic improvement) for short-term, 6-month treatment (61% vs 62%; P=.54), a higher percentage of patients continued prazosin long-term (3 to 6 years) than those taking quetiapine (48% vs 24%; P < .001).²³ Twenty-five percent of patients taking quetiapine switched to prazosin during the study, and approximately one-half of these patients remained on prazosin until the study’s end. Only 8% of prazosin patients switched to quetiapine, and none continued this therapy until study end.²³ Patients in the quetiapine group were more likely to discontinue the drug because of lack of efficacy (13% vs 3%; P=.03) and adverse effects (35% vs 18%; P=.008), specifically sedation (21% vs 2%; P < .001) and metabolic effects (9% vs 0%; P=.014), compared with prazosin. Although this trial may be the only published comparison study of prazosin and quetiapine, its methodological quality has been questioned, which makes it difficult to draw definitive conclusions.

Metabolic syndrome—elevated diastolic blood pressure, increased waist circumference, and low high-density lipoprotein cholesterol—is common among PTSD patients treated with antipsychotics.²⁴ This syndrome may be caused by medications, lifestyle factors, or long-term overactivation of stress-response pathways. A retrospective chart review at a community mental health center revealed that patients taking even low doses of quetiapine for insomnia gained an average of 5 lbs (P=.037).²⁵ Another retrospective chart review at 2 military hospitals reported that patients receiving low-dose quetiapine (≤100 mg/d) gained an average of slightly less than 1 lb per month, which adds up to approximately 10 lbs per year (P < .001).²⁶ The benefit of using atypical antipsychotics may be outweighed by metabolic risks such as obesity, new-onset diabetes, and dyslipidemia.²⁷

Prazosin is considered a first-line treatment for sleep disturbances and nightmares in PTSD because of its superior long-term efficacy and decreased adverse effects compared with quetiapine.

Related Resources

• American Psychiatric Association. Practice guidelines for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2004.
• Veterans Affairs/Department of Defense clinical practice guidelines. Management of traumatic stress disorder and acute stress reaction. www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp.

Drug Brand Names

• Prazosin • Minipress
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Ziprasidone • Geodon

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
Could providing a “curbside” consultation to a colleague leave me medico legally vulnerable if an adverse event leads to a malpractice lawsuit? If so, what can I do to address this risk?—Submitted by “Dr. W”

Medicine is a collaborative profession. Surgeons often combine skills to perform complex operations together, and specialists pool their expertise when they collectively manage patients with several medical problems. Doctors share their knowledge when they give lectures to medical audiences, write reports to referring physicians, or respond verbally to colleagues’ requests for information or advice.¹

Doctors use the phrase “curbside consult” to refer (with humor and self-deprecation) to informal conversations with colleagues about patients’ medical management—advice-seeking that falls short of asking a colleague to make recommendations based on a formal, personal examination. Many physicians seek or provide curbside advice several times a month.² Curbside consults transmit knowledge and cement professional bonds among physicians, making them “an integral part of our medical culture.”³

More than a dozen legal decisions mention curbside consultations. Judges think informal information-sharing improves medical practice and don’t want doctors to stop soliciting ideas or offering suggestions because they fear lawsuits.^4,5 However, courts have found that, under certain conditions, giving advice can create liability for a bad outcome, even though the doctor never met the patient who was harmed.

In this article, we’ll look at:

• when such liability might occur, and
• what you can do to minimize it.

A doctor-patient relationship?

Legally, doctors are obligated to provide competent care for just 1 group of people: their patients. Therefore, to decide if plaintiffs could pursue malpractice claims in cases where doctors offered comments about patients they did not personally examine, courts have asked whether the circumstances, actions undertaken, or nature of information that was exchanged created a professional relationship.

Reynolds v Decatur Memorial Hospital⁴ describes an informal consultation that did not create a physician-patient relationship. In this case, a boy was admitted to a hospital after he had fallen. The treating pediatrician telephoned a neurosurgeon, who asked whether the boy’s neck was stiff, discussed diagnostic possibilities with the pediatrician, and suggested doing a lumbar puncture. The neurosurgeon offered to see the boy if requested, but he never did, and he did not bill for the telephone consultation. Guillain-Barré syndrome was first suspected, but a spinal cord injury was discovered after the boy—who developed quadriplegia—was transferred to another hospital.

In a subsequent lawsuit, the boy’s mother claimed her son’s paralysis resulted from negligence by the first hospital and its doctors, but the trial court dismissed the case against the neurosurgeon. Affirming the trial court’s ruling, an Illinois appeals court explained that the neurosurgeon had not been asked to provide medical services, conduct tests, or interpret test results. “A doctor who gives an informal opinion at the request of a treating physician does not owe a duty of care to the patient whose case was discussed,” the Reynolds court said.

Campbell v Haber⁶ describes circumstances that differed slightly from those described in the Reynolds decision but appeared to create a doctor-patient relationship. Campbell concerned a patient who came to an emergency room (ER) complaining of chest pain. The ER physician’s findings indicated possible heart muscle damage, so he telephoned a cardiologist (whom the ER doctor believed was “on call”) and described the patient’s symptoms and test results. The cardiologist thought the test results were not consistent with a cardiac event. The ER physician told the patient and his wife about the cardiologist’s opinion and, relying on what the cardiologist said, discharged the patient. Shortly after, the patient had a heart attack.

The patient sued not just the ER physician, but the cardiologist, who sought dismissal from the suit because he never saw the patient, had no treatment relationship with him, and never billed for services. However, the trial judge ruled that the patient could sue the cardiologist and the appellate court agreed, saying that a jury had to decide whether the cardiologist had incurred a doctor-patient relationship and might be liable. “An implied physician-patient relationship may arise when a physician gives advice to a patient,” the appeals court said, “even if that advice is communicated through another health care professional.”

Telling the difference

So what differentiates a no-liability curbside consult from a medical discussion that creates a doctor-patient duty and potential for liability for adverse results?

You create a physician-patient relationship when you assume responsibility to diagnose or treat someone.⁷ Although typically this requires an in-person encounter with a patient, it can happen indirectly—electronically (through e-mail), by telephone, or through a family member or another professional. But if you do nothing that implies consent to act for the patient’s benefit, you should have no actual malpractice liability if something goes wrong.^3,8 As a Kansas Supreme Court decision explains, you “cannot be liable for medical malpractice” if you “merely consult with a treating physician and [do] nothing more.”⁵

Several legal cases discuss doctors’ efforts to extricate themselves from lawsuits arising from clinical encounters that the doctors mistakenly thought were just curbside consults. Table 1^8-12 lists situations in which talking about patients goes beyond just being “curbsided.”

Table 1

When it’s not a ‘curbside consultation’

How to respond

Should you decline to provide curbside consultations to keep yourself out of lawsuits? Some authors think so, pointing out that informally transmitted clinical data may be faulty, which means you may give bad advice based on incomplete information or a verbal misunderstanding.^13-16 These authors suggest that if you’re curbsided you should ask to see the patient for a formal consultation, decline to give informal advice, or provide a response that lacks specifics.

Other authors feel that these approaches are needlessly cautious and would harm patients by impeding doctors’ ability to help and learn from each other.^3,17 These authors think the risk of incurring liability from a curbside consult is low. Also, getting advice from a colleague is a valuable risk management strategy; it helps you make sure you’re on the right track, and it shows you are a thoughtful clinician whose patients benefit from your own and your colleagues’ medical expertise.

Even if you’re comfortable soliciting and providing curbside advice, sometimes circumstances make it wise to follow-up an informal initial inquiry with a formal consultation. Table 2^3,17 lists examples of when you should follow-up with a formal consultation.

Table 2

Considerations that favor formal consultation

Documentation

Experts disagree about whether the requesting or receiving physician should document a curbside consultation, and if so, how. On one hand, making a notation in a patient’s record documents the treating doctor’s diligence and may provide a measure of liability protection in a malpractice action. Doing this, however, exposes the identity of the consultant, who might be named among the defendants in a lawsuit.

One commonly recommended strategy is to request the consultant’s permission before identifying him or her in the record,^13,16,17 a position that is defensible on grounds of courtesy alone. But omitting a consultant’s name from record does not guarantee that the consultant’s involvement won’t be discovered in the course of litigation.³ For example, treating doctors who get sued often are asked during their depositions about whether they talked with anyone about the case, and they have to answer honestly.

If a consulted doctor makes written notes, it might suggest that the consultation was more than the sort of informal information-sharing implied by the term “curbside.” However, in the unlikely event that a lawsuit arose and included the consultant as a defendant, documentation of advice given would help the consultant recall and defend what was said.

Related Resources

• Grant-Kels JM, Kels BD. The curbside consultation: legal, moral, and ethical considerations. J Am Acad Dermatol. 2012;66(5):827-829.
• Kreichelt R, Hilbert ML, Shinn D. Minimizing the legal risk with ‘curbside’ consultation. J Healthc Risk Manag. 2008;28(1):27-29.
• Atkinson L. Curbside consults: what is your liability risk? Iowa Med. 2003;93(4):15.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
Could providing a “curbside” consultation to a colleague leave me medico legally vulnerable if an adverse event leads to a malpractice lawsuit? If so, what can I do to address this risk?—Submitted by “Dr. W”

Medicine is a collaborative profession. Surgeons often combine skills to perform complex operations together, and specialists pool their expertise when they collectively manage patients with several medical problems. Doctors share their knowledge when they give lectures to medical audiences, write reports to referring physicians, or respond verbally to colleagues’ requests for information or advice.¹

Doctors use the phrase “curbside consult” to refer (with humor and self-deprecation) to informal conversations with colleagues about patients’ medical management—advice-seeking that falls short of asking a colleague to make recommendations based on a formal, personal examination. Many physicians seek or provide curbside advice several times a month.² Curbside consults transmit knowledge and cement professional bonds among physicians, making them “an integral part of our medical culture.”³

More than a dozen legal decisions mention curbside consultations. Judges think informal information-sharing improves medical practice and don’t want doctors to stop soliciting ideas or offering suggestions because they fear lawsuits.^4,5 However, courts have found that, under certain conditions, giving advice can create liability for a bad outcome, even though the doctor never met the patient who was harmed.

In this article, we’ll look at:

• when such liability might occur, and
• what you can do to minimize it.

A doctor-patient relationship?

Legally, doctors are obligated to provide competent care for just 1 group of people: their patients. Therefore, to decide if plaintiffs could pursue malpractice claims in cases where doctors offered comments about patients they did not personally examine, courts have asked whether the circumstances, actions undertaken, or nature of information that was exchanged created a professional relationship.

Reynolds v Decatur Memorial Hospital⁴ describes an informal consultation that did not create a physician-patient relationship. In this case, a boy was admitted to a hospital after he had fallen. The treating pediatrician telephoned a neurosurgeon, who asked whether the boy’s neck was stiff, discussed diagnostic possibilities with the pediatrician, and suggested doing a lumbar puncture. The neurosurgeon offered to see the boy if requested, but he never did, and he did not bill for the telephone consultation. Guillain-Barré syndrome was first suspected, but a spinal cord injury was discovered after the boy—who developed quadriplegia—was transferred to another hospital.

In a subsequent lawsuit, the boy’s mother claimed her son’s paralysis resulted from negligence by the first hospital and its doctors, but the trial court dismissed the case against the neurosurgeon. Affirming the trial court’s ruling, an Illinois appeals court explained that the neurosurgeon had not been asked to provide medical services, conduct tests, or interpret test results. “A doctor who gives an informal opinion at the request of a treating physician does not owe a duty of care to the patient whose case was discussed,” the Reynolds court said.

Campbell v Haber⁶ describes circumstances that differed slightly from those described in the Reynolds decision but appeared to create a doctor-patient relationship. Campbell concerned a patient who came to an emergency room (ER) complaining of chest pain. The ER physician’s findings indicated possible heart muscle damage, so he telephoned a cardiologist (whom the ER doctor believed was “on call”) and described the patient’s symptoms and test results. The cardiologist thought the test results were not consistent with a cardiac event. The ER physician told the patient and his wife about the cardiologist’s opinion and, relying on what the cardiologist said, discharged the patient. Shortly after, the patient had a heart attack.

The patient sued not just the ER physician, but the cardiologist, who sought dismissal from the suit because he never saw the patient, had no treatment relationship with him, and never billed for services. However, the trial judge ruled that the patient could sue the cardiologist and the appellate court agreed, saying that a jury had to decide whether the cardiologist had incurred a doctor-patient relationship and might be liable. “An implied physician-patient relationship may arise when a physician gives advice to a patient,” the appeals court said, “even if that advice is communicated through another health care professional.”

Telling the difference

So what differentiates a no-liability curbside consult from a medical discussion that creates a doctor-patient duty and potential for liability for adverse results?

You create a physician-patient relationship when you assume responsibility to diagnose or treat someone.⁷ Although typically this requires an in-person encounter with a patient, it can happen indirectly—electronically (through e-mail), by telephone, or through a family member or another professional. But if you do nothing that implies consent to act for the patient’s benefit, you should have no actual malpractice liability if something goes wrong.^3,8 As a Kansas Supreme Court decision explains, you “cannot be liable for medical malpractice” if you “merely consult with a treating physician and [do] nothing more.”⁵

Several legal cases discuss doctors’ efforts to extricate themselves from lawsuits arising from clinical encounters that the doctors mistakenly thought were just curbside consults. Table 1^8-12 lists situations in which talking about patients goes beyond just being “curbsided.”

Table 1

When it’s not a ‘curbside consultation’

How to respond

Should you decline to provide curbside consultations to keep yourself out of lawsuits? Some authors think so, pointing out that informally transmitted clinical data may be faulty, which means you may give bad advice based on incomplete information or a verbal misunderstanding.^13-16 These authors suggest that if you’re curbsided you should ask to see the patient for a formal consultation, decline to give informal advice, or provide a response that lacks specifics.

Other authors feel that these approaches are needlessly cautious and would harm patients by impeding doctors’ ability to help and learn from each other.^3,17 These authors think the risk of incurring liability from a curbside consult is low. Also, getting advice from a colleague is a valuable risk management strategy; it helps you make sure you’re on the right track, and it shows you are a thoughtful clinician whose patients benefit from your own and your colleagues’ medical expertise.

Even if you’re comfortable soliciting and providing curbside advice, sometimes circumstances make it wise to follow-up an informal initial inquiry with a formal consultation. Table 2^3,17 lists examples of when you should follow-up with a formal consultation.

Table 2

Considerations that favor formal consultation

Documentation

Experts disagree about whether the requesting or receiving physician should document a curbside consultation, and if so, how. On one hand, making a notation in a patient’s record documents the treating doctor’s diligence and may provide a measure of liability protection in a malpractice action. Doing this, however, exposes the identity of the consultant, who might be named among the defendants in a lawsuit.

One commonly recommended strategy is to request the consultant’s permission before identifying him or her in the record,^13,16,17 a position that is defensible on grounds of courtesy alone. But omitting a consultant’s name from record does not guarantee that the consultant’s involvement won’t be discovered in the course of litigation.³ For example, treating doctors who get sued often are asked during their depositions about whether they talked with anyone about the case, and they have to answer honestly.

If a consulted doctor makes written notes, it might suggest that the consultation was more than the sort of informal information-sharing implied by the term “curbside.” However, in the unlikely event that a lawsuit arose and included the consultant as a defendant, documentation of advice given would help the consultant recall and defend what was said.

Related Resources

• Grant-Kels JM, Kels BD. The curbside consultation: legal, moral, and ethical considerations. J Am Acad Dermatol. 2012;66(5):827-829.
• Kreichelt R, Hilbert ML, Shinn D. Minimizing the legal risk with ‘curbside’ consultation. J Healthc Risk Manag. 2008;28(1):27-29.
• Atkinson L. Curbside consults: what is your liability risk? Iowa Med. 2003;93(4):15.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
Could providing a “curbside” consultation to a colleague leave me medico legally vulnerable if an adverse event leads to a malpractice lawsuit? If so, what can I do to address this risk?—Submitted by “Dr. W”

Medicine is a collaborative profession. Surgeons often combine skills to perform complex operations together, and specialists pool their expertise when they collectively manage patients with several medical problems. Doctors share their knowledge when they give lectures to medical audiences, write reports to referring physicians, or respond verbally to colleagues’ requests for information or advice.¹

Doctors use the phrase “curbside consult” to refer (with humor and self-deprecation) to informal conversations with colleagues about patients’ medical management—advice-seeking that falls short of asking a colleague to make recommendations based on a formal, personal examination. Many physicians seek or provide curbside advice several times a month.² Curbside consults transmit knowledge and cement professional bonds among physicians, making them “an integral part of our medical culture.”³

More than a dozen legal decisions mention curbside consultations. Judges think informal information-sharing improves medical practice and don’t want doctors to stop soliciting ideas or offering suggestions because they fear lawsuits.^4,5 However, courts have found that, under certain conditions, giving advice can create liability for a bad outcome, even though the doctor never met the patient who was harmed.

In this article, we’ll look at:

• when such liability might occur, and
• what you can do to minimize it.

A doctor-patient relationship?

Legally, doctors are obligated to provide competent care for just 1 group of people: their patients. Therefore, to decide if plaintiffs could pursue malpractice claims in cases where doctors offered comments about patients they did not personally examine, courts have asked whether the circumstances, actions undertaken, or nature of information that was exchanged created a professional relationship.

Reynolds v Decatur Memorial Hospital⁴ describes an informal consultation that did not create a physician-patient relationship. In this case, a boy was admitted to a hospital after he had fallen. The treating pediatrician telephoned a neurosurgeon, who asked whether the boy’s neck was stiff, discussed diagnostic possibilities with the pediatrician, and suggested doing a lumbar puncture. The neurosurgeon offered to see the boy if requested, but he never did, and he did not bill for the telephone consultation. Guillain-Barré syndrome was first suspected, but a spinal cord injury was discovered after the boy—who developed quadriplegia—was transferred to another hospital.

In a subsequent lawsuit, the boy’s mother claimed her son’s paralysis resulted from negligence by the first hospital and its doctors, but the trial court dismissed the case against the neurosurgeon. Affirming the trial court’s ruling, an Illinois appeals court explained that the neurosurgeon had not been asked to provide medical services, conduct tests, or interpret test results. “A doctor who gives an informal opinion at the request of a treating physician does not owe a duty of care to the patient whose case was discussed,” the Reynolds court said.

Campbell v Haber⁶ describes circumstances that differed slightly from those described in the Reynolds decision but appeared to create a doctor-patient relationship. Campbell concerned a patient who came to an emergency room (ER) complaining of chest pain. The ER physician’s findings indicated possible heart muscle damage, so he telephoned a cardiologist (whom the ER doctor believed was “on call”) and described the patient’s symptoms and test results. The cardiologist thought the test results were not consistent with a cardiac event. The ER physician told the patient and his wife about the cardiologist’s opinion and, relying on what the cardiologist said, discharged the patient. Shortly after, the patient had a heart attack.

The patient sued not just the ER physician, but the cardiologist, who sought dismissal from the suit because he never saw the patient, had no treatment relationship with him, and never billed for services. However, the trial judge ruled that the patient could sue the cardiologist and the appellate court agreed, saying that a jury had to decide whether the cardiologist had incurred a doctor-patient relationship and might be liable. “An implied physician-patient relationship may arise when a physician gives advice to a patient,” the appeals court said, “even if that advice is communicated through another health care professional.”

Telling the difference

So what differentiates a no-liability curbside consult from a medical discussion that creates a doctor-patient duty and potential for liability for adverse results?

You create a physician-patient relationship when you assume responsibility to diagnose or treat someone.⁷ Although typically this requires an in-person encounter with a patient, it can happen indirectly—electronically (through e-mail), by telephone, or through a family member or another professional. But if you do nothing that implies consent to act for the patient’s benefit, you should have no actual malpractice liability if something goes wrong.^3,8 As a Kansas Supreme Court decision explains, you “cannot be liable for medical malpractice” if you “merely consult with a treating physician and [do] nothing more.”⁵

Several legal cases discuss doctors’ efforts to extricate themselves from lawsuits arising from clinical encounters that the doctors mistakenly thought were just curbside consults. Table 1^8-12 lists situations in which talking about patients goes beyond just being “curbsided.”

Table 1

When it’s not a ‘curbside consultation’

How to respond

Should you decline to provide curbside consultations to keep yourself out of lawsuits? Some authors think so, pointing out that informally transmitted clinical data may be faulty, which means you may give bad advice based on incomplete information or a verbal misunderstanding.^13-16 These authors suggest that if you’re curbsided you should ask to see the patient for a formal consultation, decline to give informal advice, or provide a response that lacks specifics.

Other authors feel that these approaches are needlessly cautious and would harm patients by impeding doctors’ ability to help and learn from each other.^3,17 These authors think the risk of incurring liability from a curbside consult is low. Also, getting advice from a colleague is a valuable risk management strategy; it helps you make sure you’re on the right track, and it shows you are a thoughtful clinician whose patients benefit from your own and your colleagues’ medical expertise.

Even if you’re comfortable soliciting and providing curbside advice, sometimes circumstances make it wise to follow-up an informal initial inquiry with a formal consultation. Table 2^3,17 lists examples of when you should follow-up with a formal consultation.

Table 2

Considerations that favor formal consultation

Documentation

Experts disagree about whether the requesting or receiving physician should document a curbside consultation, and if so, how. On one hand, making a notation in a patient’s record documents the treating doctor’s diligence and may provide a measure of liability protection in a malpractice action. Doing this, however, exposes the identity of the consultant, who might be named among the defendants in a lawsuit.

One commonly recommended strategy is to request the consultant’s permission before identifying him or her in the record,^13,16,17 a position that is defensible on grounds of courtesy alone. But omitting a consultant’s name from record does not guarantee that the consultant’s involvement won’t be discovered in the course of litigation.³ For example, treating doctors who get sued often are asked during their depositions about whether they talked with anyone about the case, and they have to answer honestly.

If a consulted doctor makes written notes, it might suggest that the consultation was more than the sort of informal information-sharing implied by the term “curbside.” However, in the unlikely event that a lawsuit arose and included the consultant as a defendant, documentation of advice given would help the consultant recall and defend what was said.

Related Resources

• Grant-Kels JM, Kels BD. The curbside consultation: legal, moral, and ethical considerations. J Am Acad Dermatol. 2012;66(5):827-829.
• Kreichelt R, Hilbert ML, Shinn D. Minimizing the legal risk with ‘curbside’ consultation. J Healthc Risk Manag. 2008;28(1):27-29.
• Atkinson L. Curbside consults: what is your liability risk? Iowa Med. 2003;93(4):15.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although cholinesterase inhibitors (ChEIs) and memantine at standard doses may slow the progression of Alzheimer’s disease (AD) as assessed by cognitive, functional, and global measures, this effect is relatively modest. For the estimated 5.4 million Americans with AD¹—more than one-half of whom have moderate to severe disease²—there is a great need for new approaches to slow AD progression.

High doses of donepezil or memantine may be the next step in achieving better results than standard pharmacologic treatments for AD. This article presents the possible benefits and indications for high doses of donepezil (23 mg/d) and memantine (28 mg/d) for managing moderate to severe AD and their safety and tolerability profiles.

Current treatments offer modest benefits

AD treatments comprise 2 categories: ChEIs (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Table 1).^3,4 All ChEIs are FDA-approved for mild to moderate AD; donepezil also is approved for severe AD. Memantine is approved for moderate to severe AD, either alone or in combination with ChEIs. Until recently, the maximum FDA-approved doses were donepezil, 10 mg/d, and memantine, 20 mg/d. However, these dosages are associated with only modest beneficial effects in managing cognitive deterioration in patients with moderate to severe dementia.^5,6 Studies have reported that combining a ChEI, such as donepezil, and memantine is well tolerated and may result in synergistic benefits by affecting different neurotransmitters in patients with moderate to severe AD.^7,8

Recently, the FDA approved higher daily doses of donepezil (23 mg) and memantine (28 mg) for moderate to severe AD on the basis of positive phase III trial results.^9-11 Donepezil, 23 mg/d, currently is marketed in the United States; the availability date for memantine, 28 mg/d, was undetermined at press time.

Table 1

FDA-approved treatments for Alzheimer’s disease

High-dose donepezil (23 mg/d)

Cognitive decline with AD has been associated with increasing loss of cholinergic neurons and cholinergic activities, particularly in areas associated with memory/cognition and learning, including cortical areas involving the temporal lobe, hippocampus, and nucleus basalis of Meynert.^12-14 In addition, evidence suggests that increasing levels of acetylcholine by using ChEIs can enhance cognitive function.^13,15

Donepezil is a selective, reversible ChEI believed to enhance central cholinergic function.¹⁵ Randomized clinical trials assessing dose-response with donepezil, 5 mg/d and 10 mg/d, have demonstrated more benefit in cognition with either dose than placebo. The 10 mg/d dose was more effective than 5 mg/d in patients with mild to moderate and severe AD.^16-18 In patients with advanced AD who are stable on 5 mg/d, increasing to 10 mg/d could slow the progression of cognitive decline.¹⁸

Rationale for higher doses. Positron emission tomography studies have shown that at stable doses of donepezil, 5 mg/d or 10 mg/d, average cortical acetylcholinesterase (AChE) inhibition was <30%.^19,20 Based on these findings, researchers thought that cortical AChE inhibition may be suboptimal with donepezil, 10 mg/d, and that higher doses of ChEI may be required in patients with more advanced AD—and therefore more cholinergic loss—for adequate cholinesterase inhibition. In a pilot study of patients with mild to moderate AD, higher doses of donepezil (15 mg/d and 20 mg/d) were reported to be safe and well tolerated.²¹

The 23-mg/d donepezil formulation was developed to provide a higher dose administered once daily without a sharp rise in peak concentration. The FDA approved donepezil, 23 mg/d, for patients with moderate to severe AD on the basis of phase III trial results.^9,22 In a randomized, double-blind, multicenter, head-to-head clinical trial, >1,400 patients with moderate to severe AD (Mini-Mental State Exam [MMSE]: 0 to 20) on a stable dose of donepezil, 10 mg/d, for ≥3 months were randomly assigned to receive high-dose donepezil (23 mg/d) or standard-dose donepezil (10 mg/d) for 24 weeks.^9,22 Patients in the 23-mg/d group showed a statistically significant improvement in cognition compared with the 10-mg/d group. The difference between groups on a measure of global improvement was not significant.^9,22 However, in a post-hoc analysis, it was demonstrated that a subgroup of patients with more severe cognitive impairment (baseline MMSE: 0 to 16), showed significant improvement in cognition as well as global functioning.⁹

Overall, treatment-emergent adverse events (TEAEs) during the study were higher in patients receiving 23 mg/d (74%) than those receiving 10 mg/d (64%). The most common TEAEs in the 23-mg/d and 10-mg/d groups were nausea (12% vs 3%, respectively), vomiting (9% vs 3%), and diarrhea (8% vs 5%) (Table 2).²² These gastrointestinal adverse effects were more frequent during the first month of treatment and were relatively infrequent beyond 1 month. Serious TEAEs, such as falls, urinary tract infection, pneumonia, syncope, aggression, and confusional state, were noted in a similar proportion of patients in the 23-mg/d and 10-mg/d groups; most of these were considered unrelated to treatment. No drug-related deaths occurred during the study. High-dose (23 mg/d) donepezil generally was well tolerated, with a typical ChEI safety profile but superior efficacy.

A recent commentary discussed the issue of effect size and whether a 2.2-point difference on a 100-point scale (the Severe Impairment Battery [SIB]) is clinically meaningful.²³ As with all anti-dementia therapies, in any cohort some patients will gain considerably more than 2.2 points on the SIB, which is clinically significant. A 6-month trial is recommended to identify these optimal responders.

Table 2

High-dose vs standard-dose donepezil: Treatment-emergent adverse events

High-dose memantine

Memantine is an NMDA receptor antagonist, which works on glutamate, an ubiquitous neurotransmitter in the brain that serves many functions. For reasons that are not fully understood, in AD glutamate becomes excitotoxic and causes neuronal death.

Some researchers have hypothesized that if safe and well tolerated, a memantine dose >20 mg/d may have better efficacy than a lower dose. Memantine’s manufacturer has developed an extended-release (ER), once-daily formulation of memantine, 28 mg/d, to improve adherence and possibly increase efficacy.^10,11 Because of memantine ER’s relatively slow absorption rate and longer median T_max, of 12 hours, there is minimal fluctuation in plasma levels during steady-state dosing intervals compared with the immediate-release (IR) formulation.¹⁰

In a phase I study of 24 healthy volunteers that investigated the safety, tolerability, and pharmacokinetics of memantine ER, 28 mg/d, TEAEs were mild; the most common were headache, somnolence, and dizziness.¹⁰ During memantine treatment, there were no serious adverse events, potential significant changes in patients’ vital signs, or deaths.

Memantine ER plus ChEI. A multicenter, multinational, randomized, double-blind study compared memantine ER, 28 mg/d, and placebo in patients with moderate to severe AD (MMSE: 3 to 14).¹¹ All patients were receiving concurrent, stable ChEI treatment (donepezil, rivastigmine, or galantamine) for ≥3 months before the study. Patients treated with memantine ER, 28 mg/d, and ChEI (n = 342) showed a significant improvement compared with the placebo/ChEI group (n = 335) in cognition and global functioning. Patients receiving memantine/ChEI also showed statistically significant benefits on behavior and verbal fluency testing compared with patients receiving placebo/ChEI. Memantine was well tolerated; most adverse events were mild or moderate. The most common adverse events in the memantine/ChEI group that occurred at a higher rate relative to the placebo/ChEI group were headache (5.6% vs 5.1%, respectively), diarrhea (5.0% vs 3.9%), and dizziness (4.7% vs 1.5%). There were no deaths related to memantine (Table 3).¹¹

Memantine ER, 28 mg/d, may be tolerated better than the IR formulation because of less plasma level fluctuation during the steady-state dosing interval. Also, memantine ER, 28 mg/d, may offer better efficacy over memantine IR, 20 mg/d, because of dose-dependent cognitive, global, and behavioral effects. In addition, once-daily dosing of memantine ER may improve adherence compared with the IR formulation.²⁴

In patients with severe renal impairment, dosage of memantine IR should be reduced from 20 mg/d to 10 mg/d.²⁵ However, there is no available information regarding the dosing, safety, and tolerability of memantine ER, 28 mg/d, in patients with renal disease.

Table3

High-dose memantine: Treatment-emergent adverse events^a

Recommendations

Because there are few FDA-approved treatments for AD, higher doses of donepezil or memantine may be an option for patients who have “maxed out” on their AD therapy or no longer respond to lower doses. Higher doses of donepezil (23 mg/d) and memantine (28 mg/d) could improve medication adherence because both are once-daily preparations. In clinical trials, donepezil, 23 mg/d, was more effective than donepezil, 10 mg/d.⁹ Whether memantine ER, 28 mg/d, is superior to memantine IR, 20 mg/d, needs to be investigated in head-to-head, double-blind, controlled studies.

For patients with moderate to severe AD, donepezil, 23 mg, is associated with greater benefits in cognition compared with donepezil, 10 mg/d.⁹ Similarly, because of potentially superior efficacy because of a higher dose, memantine ER, 28 mg, might best help patients with moderate to severe AD, specifically those who either don’t respond or lose response to memantine IR, 20 mg/d. Combining a ChEI, such as donepezil, with memantine is associated with slower cognitive decline and short and long-term benefits on measures of cognition, activities of daily living, global outcome, and behavior.^7,26 However, additional clinical trials are needed to assess the safety, tolerability, and efficacy of combination therapy with higher doses of donepezil and memantine ER.

Related Resources

• Alzheimer’s Disease Education and Referral Center. www.nia.nih.gov/Alzheimers.
• Lleó A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med. 2006;57:513-533.

Drug Brand Names

• Donepezil • Aricept
• Galantamine • Razadyne
• Memantine • Namenda
• Rivastigmine • Exelon
• Tacrine • Cognex

Disclosures

Dr. Grossberg’s academic department has received research funding from Forest Pharmaceuticals and Pfizer Inc. Dr. Grossberg has received grant/research support from Baxter BioScience, Forest Pharmaceuticals, Janssen, the National Institutes of Health, Novartis, and Pfizer, Inc.; is a consultant to Baxter BioScience, Forest Pharmaceuticals, Merck, Novartis, and Otsuka; and is on the Safety Monitoring Committee for Merck.

Dr. Singh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although cholinesterase inhibitors (ChEIs) and memantine at standard doses may slow the progression of Alzheimer’s disease (AD) as assessed by cognitive, functional, and global measures, this effect is relatively modest. For the estimated 5.4 million Americans with AD¹—more than one-half of whom have moderate to severe disease²—there is a great need for new approaches to slow AD progression.

High doses of donepezil or memantine may be the next step in achieving better results than standard pharmacologic treatments for AD. This article presents the possible benefits and indications for high doses of donepezil (23 mg/d) and memantine (28 mg/d) for managing moderate to severe AD and their safety and tolerability profiles.

Current treatments offer modest benefits

AD treatments comprise 2 categories: ChEIs (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Table 1).^3,4 All ChEIs are FDA-approved for mild to moderate AD; donepezil also is approved for severe AD. Memantine is approved for moderate to severe AD, either alone or in combination with ChEIs. Until recently, the maximum FDA-approved doses were donepezil, 10 mg/d, and memantine, 20 mg/d. However, these dosages are associated with only modest beneficial effects in managing cognitive deterioration in patients with moderate to severe dementia.^5,6 Studies have reported that combining a ChEI, such as donepezil, and memantine is well tolerated and may result in synergistic benefits by affecting different neurotransmitters in patients with moderate to severe AD.^7,8

Recently, the FDA approved higher daily doses of donepezil (23 mg) and memantine (28 mg) for moderate to severe AD on the basis of positive phase III trial results.^9-11 Donepezil, 23 mg/d, currently is marketed in the United States; the availability date for memantine, 28 mg/d, was undetermined at press time.

Table 1

FDA-approved treatments for Alzheimer’s disease

High-dose donepezil (23 mg/d)

Cognitive decline with AD has been associated with increasing loss of cholinergic neurons and cholinergic activities, particularly in areas associated with memory/cognition and learning, including cortical areas involving the temporal lobe, hippocampus, and nucleus basalis of Meynert.^12-14 In addition, evidence suggests that increasing levels of acetylcholine by using ChEIs can enhance cognitive function.^13,15

Donepezil is a selective, reversible ChEI believed to enhance central cholinergic function.¹⁵ Randomized clinical trials assessing dose-response with donepezil, 5 mg/d and 10 mg/d, have demonstrated more benefit in cognition with either dose than placebo. The 10 mg/d dose was more effective than 5 mg/d in patients with mild to moderate and severe AD.^16-18 In patients with advanced AD who are stable on 5 mg/d, increasing to 10 mg/d could slow the progression of cognitive decline.¹⁸

Rationale for higher doses. Positron emission tomography studies have shown that at stable doses of donepezil, 5 mg/d or 10 mg/d, average cortical acetylcholinesterase (AChE) inhibition was <30%.^19,20 Based on these findings, researchers thought that cortical AChE inhibition may be suboptimal with donepezil, 10 mg/d, and that higher doses of ChEI may be required in patients with more advanced AD—and therefore more cholinergic loss—for adequate cholinesterase inhibition. In a pilot study of patients with mild to moderate AD, higher doses of donepezil (15 mg/d and 20 mg/d) were reported to be safe and well tolerated.²¹

The 23-mg/d donepezil formulation was developed to provide a higher dose administered once daily without a sharp rise in peak concentration. The FDA approved donepezil, 23 mg/d, for patients with moderate to severe AD on the basis of phase III trial results.^9,22 In a randomized, double-blind, multicenter, head-to-head clinical trial, >1,400 patients with moderate to severe AD (Mini-Mental State Exam [MMSE]: 0 to 20) on a stable dose of donepezil, 10 mg/d, for ≥3 months were randomly assigned to receive high-dose donepezil (23 mg/d) or standard-dose donepezil (10 mg/d) for 24 weeks.^9,22 Patients in the 23-mg/d group showed a statistically significant improvement in cognition compared with the 10-mg/d group. The difference between groups on a measure of global improvement was not significant.^9,22 However, in a post-hoc analysis, it was demonstrated that a subgroup of patients with more severe cognitive impairment (baseline MMSE: 0 to 16), showed significant improvement in cognition as well as global functioning.⁹

Overall, treatment-emergent adverse events (TEAEs) during the study were higher in patients receiving 23 mg/d (74%) than those receiving 10 mg/d (64%). The most common TEAEs in the 23-mg/d and 10-mg/d groups were nausea (12% vs 3%, respectively), vomiting (9% vs 3%), and diarrhea (8% vs 5%) (Table 2).²² These gastrointestinal adverse effects were more frequent during the first month of treatment and were relatively infrequent beyond 1 month. Serious TEAEs, such as falls, urinary tract infection, pneumonia, syncope, aggression, and confusional state, were noted in a similar proportion of patients in the 23-mg/d and 10-mg/d groups; most of these were considered unrelated to treatment. No drug-related deaths occurred during the study. High-dose (23 mg/d) donepezil generally was well tolerated, with a typical ChEI safety profile but superior efficacy.

A recent commentary discussed the issue of effect size and whether a 2.2-point difference on a 100-point scale (the Severe Impairment Battery [SIB]) is clinically meaningful.²³ As with all anti-dementia therapies, in any cohort some patients will gain considerably more than 2.2 points on the SIB, which is clinically significant. A 6-month trial is recommended to identify these optimal responders.

Table 2

High-dose vs standard-dose donepezil: Treatment-emergent adverse events

High-dose memantine

Memantine is an NMDA receptor antagonist, which works on glutamate, an ubiquitous neurotransmitter in the brain that serves many functions. For reasons that are not fully understood, in AD glutamate becomes excitotoxic and causes neuronal death.

Some researchers have hypothesized that if safe and well tolerated, a memantine dose >20 mg/d may have better efficacy than a lower dose. Memantine’s manufacturer has developed an extended-release (ER), once-daily formulation of memantine, 28 mg/d, to improve adherence and possibly increase efficacy.^10,11 Because of memantine ER’s relatively slow absorption rate and longer median T_max, of 12 hours, there is minimal fluctuation in plasma levels during steady-state dosing intervals compared with the immediate-release (IR) formulation.¹⁰

In a phase I study of 24 healthy volunteers that investigated the safety, tolerability, and pharmacokinetics of memantine ER, 28 mg/d, TEAEs were mild; the most common were headache, somnolence, and dizziness.¹⁰ During memantine treatment, there were no serious adverse events, potential significant changes in patients’ vital signs, or deaths.

Memantine ER plus ChEI. A multicenter, multinational, randomized, double-blind study compared memantine ER, 28 mg/d, and placebo in patients with moderate to severe AD (MMSE: 3 to 14).¹¹ All patients were receiving concurrent, stable ChEI treatment (donepezil, rivastigmine, or galantamine) for ≥3 months before the study. Patients treated with memantine ER, 28 mg/d, and ChEI (n = 342) showed a significant improvement compared with the placebo/ChEI group (n = 335) in cognition and global functioning. Patients receiving memantine/ChEI also showed statistically significant benefits on behavior and verbal fluency testing compared with patients receiving placebo/ChEI. Memantine was well tolerated; most adverse events were mild or moderate. The most common adverse events in the memantine/ChEI group that occurred at a higher rate relative to the placebo/ChEI group were headache (5.6% vs 5.1%, respectively), diarrhea (5.0% vs 3.9%), and dizziness (4.7% vs 1.5%). There were no deaths related to memantine (Table 3).¹¹

Memantine ER, 28 mg/d, may be tolerated better than the IR formulation because of less plasma level fluctuation during the steady-state dosing interval. Also, memantine ER, 28 mg/d, may offer better efficacy over memantine IR, 20 mg/d, because of dose-dependent cognitive, global, and behavioral effects. In addition, once-daily dosing of memantine ER may improve adherence compared with the IR formulation.²⁴

In patients with severe renal impairment, dosage of memantine IR should be reduced from 20 mg/d to 10 mg/d.²⁵ However, there is no available information regarding the dosing, safety, and tolerability of memantine ER, 28 mg/d, in patients with renal disease.

Table3

High-dose memantine: Treatment-emergent adverse events^a

Recommendations

Because there are few FDA-approved treatments for AD, higher doses of donepezil or memantine may be an option for patients who have “maxed out” on their AD therapy or no longer respond to lower doses. Higher doses of donepezil (23 mg/d) and memantine (28 mg/d) could improve medication adherence because both are once-daily preparations. In clinical trials, donepezil, 23 mg/d, was more effective than donepezil, 10 mg/d.⁹ Whether memantine ER, 28 mg/d, is superior to memantine IR, 20 mg/d, needs to be investigated in head-to-head, double-blind, controlled studies.

For patients with moderate to severe AD, donepezil, 23 mg, is associated with greater benefits in cognition compared with donepezil, 10 mg/d.⁹ Similarly, because of potentially superior efficacy because of a higher dose, memantine ER, 28 mg, might best help patients with moderate to severe AD, specifically those who either don’t respond or lose response to memantine IR, 20 mg/d. Combining a ChEI, such as donepezil, with memantine is associated with slower cognitive decline and short and long-term benefits on measures of cognition, activities of daily living, global outcome, and behavior.^7,26 However, additional clinical trials are needed to assess the safety, tolerability, and efficacy of combination therapy with higher doses of donepezil and memantine ER.

Related Resources

• Alzheimer’s Disease Education and Referral Center. www.nia.nih.gov/Alzheimers.
• Lleó A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med. 2006;57:513-533.

Drug Brand Names

• Donepezil • Aricept
• Galantamine • Razadyne
• Memantine • Namenda
• Rivastigmine • Exelon
• Tacrine • Cognex

Disclosures

Dr. Grossberg’s academic department has received research funding from Forest Pharmaceuticals and Pfizer Inc. Dr. Grossberg has received grant/research support from Baxter BioScience, Forest Pharmaceuticals, Janssen, the National Institutes of Health, Novartis, and Pfizer, Inc.; is a consultant to Baxter BioScience, Forest Pharmaceuticals, Merck, Novartis, and Otsuka; and is on the Safety Monitoring Committee for Merck.

Dr. Singh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Although cholinesterase inhibitors (ChEIs) and memantine at standard doses may slow the progression of Alzheimer’s disease (AD) as assessed by cognitive, functional, and global measures, this effect is relatively modest. For the estimated 5.4 million Americans with AD¹—more than one-half of whom have moderate to severe disease²—there is a great need for new approaches to slow AD progression.

High doses of donepezil or memantine may be the next step in achieving better results than standard pharmacologic treatments for AD. This article presents the possible benefits and indications for high doses of donepezil (23 mg/d) and memantine (28 mg/d) for managing moderate to severe AD and their safety and tolerability profiles.

Current treatments offer modest benefits

AD treatments comprise 2 categories: ChEIs (donepezil, rivastigmine, and galantamine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Table 1).^3,4 All ChEIs are FDA-approved for mild to moderate AD; donepezil also is approved for severe AD. Memantine is approved for moderate to severe AD, either alone or in combination with ChEIs. Until recently, the maximum FDA-approved doses were donepezil, 10 mg/d, and memantine, 20 mg/d. However, these dosages are associated with only modest beneficial effects in managing cognitive deterioration in patients with moderate to severe dementia.^5,6 Studies have reported that combining a ChEI, such as donepezil, and memantine is well tolerated and may result in synergistic benefits by affecting different neurotransmitters in patients with moderate to severe AD.^7,8

Recently, the FDA approved higher daily doses of donepezil (23 mg) and memantine (28 mg) for moderate to severe AD on the basis of positive phase III trial results.^9-11 Donepezil, 23 mg/d, currently is marketed in the United States; the availability date for memantine, 28 mg/d, was undetermined at press time.

Table 1

FDA-approved treatments for Alzheimer’s disease

High-dose donepezil (23 mg/d)

Cognitive decline with AD has been associated with increasing loss of cholinergic neurons and cholinergic activities, particularly in areas associated with memory/cognition and learning, including cortical areas involving the temporal lobe, hippocampus, and nucleus basalis of Meynert.^12-14 In addition, evidence suggests that increasing levels of acetylcholine by using ChEIs can enhance cognitive function.^13,15

Donepezil is a selective, reversible ChEI believed to enhance central cholinergic function.¹⁵ Randomized clinical trials assessing dose-response with donepezil, 5 mg/d and 10 mg/d, have demonstrated more benefit in cognition with either dose than placebo. The 10 mg/d dose was more effective than 5 mg/d in patients with mild to moderate and severe AD.^16-18 In patients with advanced AD who are stable on 5 mg/d, increasing to 10 mg/d could slow the progression of cognitive decline.¹⁸

Rationale for higher doses. Positron emission tomography studies have shown that at stable doses of donepezil, 5 mg/d or 10 mg/d, average cortical acetylcholinesterase (AChE) inhibition was <30%.^19,20 Based on these findings, researchers thought that cortical AChE inhibition may be suboptimal with donepezil, 10 mg/d, and that higher doses of ChEI may be required in patients with more advanced AD—and therefore more cholinergic loss—for adequate cholinesterase inhibition. In a pilot study of patients with mild to moderate AD, higher doses of donepezil (15 mg/d and 20 mg/d) were reported to be safe and well tolerated.²¹

The 23-mg/d donepezil formulation was developed to provide a higher dose administered once daily without a sharp rise in peak concentration. The FDA approved donepezil, 23 mg/d, for patients with moderate to severe AD on the basis of phase III trial results.^9,22 In a randomized, double-blind, multicenter, head-to-head clinical trial, >1,400 patients with moderate to severe AD (Mini-Mental State Exam [MMSE]: 0 to 20) on a stable dose of donepezil, 10 mg/d, for ≥3 months were randomly assigned to receive high-dose donepezil (23 mg/d) or standard-dose donepezil (10 mg/d) for 24 weeks.^9,22 Patients in the 23-mg/d group showed a statistically significant improvement in cognition compared with the 10-mg/d group. The difference between groups on a measure of global improvement was not significant.^9,22 However, in a post-hoc analysis, it was demonstrated that a subgroup of patients with more severe cognitive impairment (baseline MMSE: 0 to 16), showed significant improvement in cognition as well as global functioning.⁹

Overall, treatment-emergent adverse events (TEAEs) during the study were higher in patients receiving 23 mg/d (74%) than those receiving 10 mg/d (64%). The most common TEAEs in the 23-mg/d and 10-mg/d groups were nausea (12% vs 3%, respectively), vomiting (9% vs 3%), and diarrhea (8% vs 5%) (Table 2).²² These gastrointestinal adverse effects were more frequent during the first month of treatment and were relatively infrequent beyond 1 month. Serious TEAEs, such as falls, urinary tract infection, pneumonia, syncope, aggression, and confusional state, were noted in a similar proportion of patients in the 23-mg/d and 10-mg/d groups; most of these were considered unrelated to treatment. No drug-related deaths occurred during the study. High-dose (23 mg/d) donepezil generally was well tolerated, with a typical ChEI safety profile but superior efficacy.

A recent commentary discussed the issue of effect size and whether a 2.2-point difference on a 100-point scale (the Severe Impairment Battery [SIB]) is clinically meaningful.²³ As with all anti-dementia therapies, in any cohort some patients will gain considerably more than 2.2 points on the SIB, which is clinically significant. A 6-month trial is recommended to identify these optimal responders.

Table 2

High-dose vs standard-dose donepezil: Treatment-emergent adverse events

High-dose memantine

Memantine is an NMDA receptor antagonist, which works on glutamate, an ubiquitous neurotransmitter in the brain that serves many functions. For reasons that are not fully understood, in AD glutamate becomes excitotoxic and causes neuronal death.

Some researchers have hypothesized that if safe and well tolerated, a memantine dose >20 mg/d may have better efficacy than a lower dose. Memantine’s manufacturer has developed an extended-release (ER), once-daily formulation of memantine, 28 mg/d, to improve adherence and possibly increase efficacy.^10,11 Because of memantine ER’s relatively slow absorption rate and longer median T_max, of 12 hours, there is minimal fluctuation in plasma levels during steady-state dosing intervals compared with the immediate-release (IR) formulation.¹⁰

In a phase I study of 24 healthy volunteers that investigated the safety, tolerability, and pharmacokinetics of memantine ER, 28 mg/d, TEAEs were mild; the most common were headache, somnolence, and dizziness.¹⁰ During memantine treatment, there were no serious adverse events, potential significant changes in patients’ vital signs, or deaths.

Memantine ER plus ChEI. A multicenter, multinational, randomized, double-blind study compared memantine ER, 28 mg/d, and placebo in patients with moderate to severe AD (MMSE: 3 to 14).¹¹ All patients were receiving concurrent, stable ChEI treatment (donepezil, rivastigmine, or galantamine) for ≥3 months before the study. Patients treated with memantine ER, 28 mg/d, and ChEI (n = 342) showed a significant improvement compared with the placebo/ChEI group (n = 335) in cognition and global functioning. Patients receiving memantine/ChEI also showed statistically significant benefits on behavior and verbal fluency testing compared with patients receiving placebo/ChEI. Memantine was well tolerated; most adverse events were mild or moderate. The most common adverse events in the memantine/ChEI group that occurred at a higher rate relative to the placebo/ChEI group were headache (5.6% vs 5.1%, respectively), diarrhea (5.0% vs 3.9%), and dizziness (4.7% vs 1.5%). There were no deaths related to memantine (Table 3).¹¹

Memantine ER, 28 mg/d, may be tolerated better than the IR formulation because of less plasma level fluctuation during the steady-state dosing interval. Also, memantine ER, 28 mg/d, may offer better efficacy over memantine IR, 20 mg/d, because of dose-dependent cognitive, global, and behavioral effects. In addition, once-daily dosing of memantine ER may improve adherence compared with the IR formulation.²⁴

In patients with severe renal impairment, dosage of memantine IR should be reduced from 20 mg/d to 10 mg/d.²⁵ However, there is no available information regarding the dosing, safety, and tolerability of memantine ER, 28 mg/d, in patients with renal disease.

Table3

High-dose memantine: Treatment-emergent adverse events^a

Recommendations

Because there are few FDA-approved treatments for AD, higher doses of donepezil or memantine may be an option for patients who have “maxed out” on their AD therapy or no longer respond to lower doses. Higher doses of donepezil (23 mg/d) and memantine (28 mg/d) could improve medication adherence because both are once-daily preparations. In clinical trials, donepezil, 23 mg/d, was more effective than donepezil, 10 mg/d.⁹ Whether memantine ER, 28 mg/d, is superior to memantine IR, 20 mg/d, needs to be investigated in head-to-head, double-blind, controlled studies.

For patients with moderate to severe AD, donepezil, 23 mg, is associated with greater benefits in cognition compared with donepezil, 10 mg/d.⁹ Similarly, because of potentially superior efficacy because of a higher dose, memantine ER, 28 mg, might best help patients with moderate to severe AD, specifically those who either don’t respond or lose response to memantine IR, 20 mg/d. Combining a ChEI, such as donepezil, with memantine is associated with slower cognitive decline and short and long-term benefits on measures of cognition, activities of daily living, global outcome, and behavior.^7,26 However, additional clinical trials are needed to assess the safety, tolerability, and efficacy of combination therapy with higher doses of donepezil and memantine ER.

Related Resources

• Alzheimer’s Disease Education and Referral Center. www.nia.nih.gov/Alzheimers.
• Lleó A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med. 2006;57:513-533.

Drug Brand Names

• Donepezil • Aricept
• Galantamine • Razadyne
• Memantine • Namenda
• Rivastigmine • Exelon
• Tacrine • Cognex

Disclosures

Dr. Grossberg’s academic department has received research funding from Forest Pharmaceuticals and Pfizer Inc. Dr. Grossberg has received grant/research support from Baxter BioScience, Forest Pharmaceuticals, Janssen, the National Institutes of Health, Novartis, and Pfizer, Inc.; is a consultant to Baxter BioScience, Forest Pharmaceuticals, Merck, Novartis, and Otsuka; and is on the Safety Monitoring Committee for Merck.

Dr. Singh reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

For many clinicians, bupropion is the “go-to” medication for treating depressed patients who smoke, have concerns about sexual dysfunction side effects, and/or worry about weight gain. Bupropion is FDA-approved for preventing seasonal major depressive episodes in patients with seasonal affective disorder and is indicated as a smoking cessation aid.

“Anxious depression”—defined as depression with high levels of anxiety—is associated with poorer outcomes than “non-anxious” depression.¹ Prescribing medications for these patients can be challenging. Some clinicians believe that bupropion exacerbates anxiety and should not be used to treat patients who experience both anxiety and depression.

Reports from our patients and our cumulative clinical experience are key factors in developing expertise in selecting appropriate medications. When informing our patients about what to expect from medications, however, it can be useful to combine anecdotal evidence with knowledge of the facts or lack thereof. Are there data to support or contradict the idea that bupropion can cause anxiety while treating depression?

What the research shows

The drug manufacturer reports a “substantial proportion of patients treated with Wellbutrin experience some degree of increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment.”²

In 2001, Rush et al³ published the results of a 16-week study (n=248) assessing pre-treatment anxiety levels and response to sertraline or bupropion. The authors concluded that anxious and depressed patients who received sertraline didn’t experience a superior anxiolytic or antidepressant response compared with bupropion.³ The same authors came to similar conclusions in a retrospective analysis of a pair of 8-week randomized, controlled, double-blind trials of selective serotonin reuptake inhibitors (SSRIs) and bupropion.⁴

In 2001, Nieuwstraten et al⁵ compared bupropion with SSRIs for treating depression by reviewing several randomized, double-blind, controlled trials. The relative risk of developing “anxiety/agitation” was 1.32 (95% confidence interval, 0.85 to 2.04), which was not statistically significant.

In a 2008 meta-analysis, Papakostas et al⁶ pooled individual patient data from 10 randomized, double-blind, placebo-controlled trials. Their aim was to compare the efficacy of bupropion to SSRIs in treating “anxious depression.” They found no difference in timing or degree of improvement in anxiety symptoms between groups based on Hamilton Anxiety Scale or Hamilton Depression Rating Scale—Anxiety-Somatization (HDRS-AS) scores. The authors recommended that antidepressant choice should not be based on concerns about worsening anxiety symptoms in depressed patients.⁶

Another meta-analysis by Papakostas et al⁷ of the same 10 randomized, double-blind, placebo-controlled trials suggested SSRIs may confer an advantage over bupropion in treating a subset of patients with “anxious depression,” which they defined as a HDRS-AS score ≥7. The authors noted the advantage was statistically significant, although “modest.”

Other smaller studies suggest that bupropion does not increase anxiety.^8,9 A pilot study (N = 24, no placebo control) concluded that bupropion XL was comparable to escitalopram in treating anxiety in outpatients with generalized anxiety disorder.⁸

Because designing and executing drug trials can be expensive, it is not surprising that most of the evidence cited above derives from pharmaceutical company-sponsored or industry-affiliated work. As such, we should evaluate available evidence within the context of what we hear from and observe in our patients.

Our opinion

When assessing patients with depression and anxiety, we must carefully evaluate symptoms to distinguish between depression with associated anxiety symptoms and depression with a comorbid anxiety disorder.

If a patient suffers from depression with associated anxiety symptoms (“anxious depression”), keep in mind that although some data demonstrate a superior response to SSRIs, other studies show no difference in effect. Some research—albeit smaller, less compelling studies—suggests that bupropion may decrease anxiety.

If your patient suffers from comorbid depression and an anxiety disorder, bupropion would not be a first-line choice because it is not FDA-approved to treat anxiety disorders. Although it is possible that anxiety/agitation could result from bupropion use, there is not sufficient data to support its reputation as ”anxiogenic.”

What is your experience?

Do you agree with the authors? Send comments to [email protected] or share your thoughts on http://www.facebook.com/CurrentPsychiatry.

Related Resource

• American Psychiatric Association. Mixed anxiety-depressive disorder. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:780-781.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Escitalopram • Lexapro
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

For many clinicians, bupropion is the “go-to” medication for treating depressed patients who smoke, have concerns about sexual dysfunction side effects, and/or worry about weight gain. Bupropion is FDA-approved for preventing seasonal major depressive episodes in patients with seasonal affective disorder and is indicated as a smoking cessation aid.

“Anxious depression”—defined as depression with high levels of anxiety—is associated with poorer outcomes than “non-anxious” depression.¹ Prescribing medications for these patients can be challenging. Some clinicians believe that bupropion exacerbates anxiety and should not be used to treat patients who experience both anxiety and depression.

Reports from our patients and our cumulative clinical experience are key factors in developing expertise in selecting appropriate medications. When informing our patients about what to expect from medications, however, it can be useful to combine anecdotal evidence with knowledge of the facts or lack thereof. Are there data to support or contradict the idea that bupropion can cause anxiety while treating depression?

What the research shows

The drug manufacturer reports a “substantial proportion of patients treated with Wellbutrin experience some degree of increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment.”²

In 2001, Rush et al³ published the results of a 16-week study (n=248) assessing pre-treatment anxiety levels and response to sertraline or bupropion. The authors concluded that anxious and depressed patients who received sertraline didn’t experience a superior anxiolytic or antidepressant response compared with bupropion.³ The same authors came to similar conclusions in a retrospective analysis of a pair of 8-week randomized, controlled, double-blind trials of selective serotonin reuptake inhibitors (SSRIs) and bupropion.⁴

In 2001, Nieuwstraten et al⁵ compared bupropion with SSRIs for treating depression by reviewing several randomized, double-blind, controlled trials. The relative risk of developing “anxiety/agitation” was 1.32 (95% confidence interval, 0.85 to 2.04), which was not statistically significant.

In a 2008 meta-analysis, Papakostas et al⁶ pooled individual patient data from 10 randomized, double-blind, placebo-controlled trials. Their aim was to compare the efficacy of bupropion to SSRIs in treating “anxious depression.” They found no difference in timing or degree of improvement in anxiety symptoms between groups based on Hamilton Anxiety Scale or Hamilton Depression Rating Scale—Anxiety-Somatization (HDRS-AS) scores. The authors recommended that antidepressant choice should not be based on concerns about worsening anxiety symptoms in depressed patients.⁶

Another meta-analysis by Papakostas et al⁷ of the same 10 randomized, double-blind, placebo-controlled trials suggested SSRIs may confer an advantage over bupropion in treating a subset of patients with “anxious depression,” which they defined as a HDRS-AS score ≥7. The authors noted the advantage was statistically significant, although “modest.”

Other smaller studies suggest that bupropion does not increase anxiety.^8,9 A pilot study (N = 24, no placebo control) concluded that bupropion XL was comparable to escitalopram in treating anxiety in outpatients with generalized anxiety disorder.⁸

Because designing and executing drug trials can be expensive, it is not surprising that most of the evidence cited above derives from pharmaceutical company-sponsored or industry-affiliated work. As such, we should evaluate available evidence within the context of what we hear from and observe in our patients.

Our opinion

When assessing patients with depression and anxiety, we must carefully evaluate symptoms to distinguish between depression with associated anxiety symptoms and depression with a comorbid anxiety disorder.

If a patient suffers from depression with associated anxiety symptoms (“anxious depression”), keep in mind that although some data demonstrate a superior response to SSRIs, other studies show no difference in effect. Some research—albeit smaller, less compelling studies—suggests that bupropion may decrease anxiety.

If your patient suffers from comorbid depression and an anxiety disorder, bupropion would not be a first-line choice because it is not FDA-approved to treat anxiety disorders. Although it is possible that anxiety/agitation could result from bupropion use, there is not sufficient data to support its reputation as ”anxiogenic.”

What is your experience?

Do you agree with the authors? Send comments to [email protected] or share your thoughts on http://www.facebook.com/CurrentPsychiatry.

Related Resource

• American Psychiatric Association. Mixed anxiety-depressive disorder. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:780-781.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Escitalopram • Lexapro
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

For many clinicians, bupropion is the “go-to” medication for treating depressed patients who smoke, have concerns about sexual dysfunction side effects, and/or worry about weight gain. Bupropion is FDA-approved for preventing seasonal major depressive episodes in patients with seasonal affective disorder and is indicated as a smoking cessation aid.

“Anxious depression”—defined as depression with high levels of anxiety—is associated with poorer outcomes than “non-anxious” depression.¹ Prescribing medications for these patients can be challenging. Some clinicians believe that bupropion exacerbates anxiety and should not be used to treat patients who experience both anxiety and depression.

Reports from our patients and our cumulative clinical experience are key factors in developing expertise in selecting appropriate medications. When informing our patients about what to expect from medications, however, it can be useful to combine anecdotal evidence with knowledge of the facts or lack thereof. Are there data to support or contradict the idea that bupropion can cause anxiety while treating depression?

What the research shows

The drug manufacturer reports a “substantial proportion of patients treated with Wellbutrin experience some degree of increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment.”²

In 2001, Rush et al³ published the results of a 16-week study (n=248) assessing pre-treatment anxiety levels and response to sertraline or bupropion. The authors concluded that anxious and depressed patients who received sertraline didn’t experience a superior anxiolytic or antidepressant response compared with bupropion.³ The same authors came to similar conclusions in a retrospective analysis of a pair of 8-week randomized, controlled, double-blind trials of selective serotonin reuptake inhibitors (SSRIs) and bupropion.⁴

In 2001, Nieuwstraten et al⁵ compared bupropion with SSRIs for treating depression by reviewing several randomized, double-blind, controlled trials. The relative risk of developing “anxiety/agitation” was 1.32 (95% confidence interval, 0.85 to 2.04), which was not statistically significant.

In a 2008 meta-analysis, Papakostas et al⁶ pooled individual patient data from 10 randomized, double-blind, placebo-controlled trials. Their aim was to compare the efficacy of bupropion to SSRIs in treating “anxious depression.” They found no difference in timing or degree of improvement in anxiety symptoms between groups based on Hamilton Anxiety Scale or Hamilton Depression Rating Scale—Anxiety-Somatization (HDRS-AS) scores. The authors recommended that antidepressant choice should not be based on concerns about worsening anxiety symptoms in depressed patients.⁶

Another meta-analysis by Papakostas et al⁷ of the same 10 randomized, double-blind, placebo-controlled trials suggested SSRIs may confer an advantage over bupropion in treating a subset of patients with “anxious depression,” which they defined as a HDRS-AS score ≥7. The authors noted the advantage was statistically significant, although “modest.”

Other smaller studies suggest that bupropion does not increase anxiety.^8,9 A pilot study (N = 24, no placebo control) concluded that bupropion XL was comparable to escitalopram in treating anxiety in outpatients with generalized anxiety disorder.⁸

Because designing and executing drug trials can be expensive, it is not surprising that most of the evidence cited above derives from pharmaceutical company-sponsored or industry-affiliated work. As such, we should evaluate available evidence within the context of what we hear from and observe in our patients.

Our opinion

When assessing patients with depression and anxiety, we must carefully evaluate symptoms to distinguish between depression with associated anxiety symptoms and depression with a comorbid anxiety disorder.

If a patient suffers from depression with associated anxiety symptoms (“anxious depression”), keep in mind that although some data demonstrate a superior response to SSRIs, other studies show no difference in effect. Some research—albeit smaller, less compelling studies—suggests that bupropion may decrease anxiety.

If your patient suffers from comorbid depression and an anxiety disorder, bupropion would not be a first-line choice because it is not FDA-approved to treat anxiety disorders. Although it is possible that anxiety/agitation could result from bupropion use, there is not sufficient data to support its reputation as ”anxiogenic.”

What is your experience?

Do you agree with the authors? Send comments to [email protected] or share your thoughts on http://www.facebook.com/CurrentPsychiatry.

Related Resource

• American Psychiatric Association. Mixed anxiety-depressive disorder. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000:780-781.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Escitalopram • Lexapro
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

The prevalence of type 2 diabetes mellitus (T2DM) is similar in men and women (11.8% vs 10.8%, respectively), however there are gender differences that should be considered when developing a treatment plan (eg, cardiovascular risk, psychosocial factors, coping strategies, and the perception of benefit from self-care) when managing those diagnosed with this disease and those at risk for developing it.¹ This article describes these differences in the context of two patients—one at risk for T2DM being seen by his health care provider for a routine physical examination, and one who has been treated for several years for T2DM and is being seen for a follow-up office visit. For each patient, the implications for treatment are discussed.

Men at Risk for Type 2 Diabetes Mellitus

Key Risk Factors for Type 2 Diabetes Mellitus in Men

This case is not an uncommon presentation of a middle-aged male who has several risk factors for diabetes (see Case Study 1 continued ). JW also has key risk factors for T2DM in men. The Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg surveys identified 128 men and 85 women with T2DM.² Increasing age and BMI, positive parental history of T2DM, and a low high-density lipoprotein cholesterol (HDL-C) level were independent risk factors predicting the development of T2DM in both men and women. However, several other factors posed a higher risk in men relative to women, including systolic BP (hazard ratio [HR], 1.16 per 10-mm Hg increase), regular smoking (HR, 1.75), and alcohol intake ≥ 40 g/d (HR, 1.95). (Note: 1 fluid ounce 80 proof alcohol ≈ 11 g ethanol; 12 fluid ounces beer [~5% alcohol] ≈ 14 g ethanol). After adjusting for these factors, a separate analysis (4424 men, 4380 women) showed that men who lived alone were more likely to develop T2DM than either men or women who did not live alone (HR, 1.69 in men vs 0.85 in women; P = .006).³ While the number of people with T2DM in MONICA was small, the results suggest that measuring BP, particularly systolic BP, and taking a smoking and alcohol history may be especially important in men.

With respect to alcohol intake, epidemiologic and randomized clinical trials have generally demonstrated an inverse relationship between moderate alcohol consumption (20 to 30 g/d) and the long-term risk of T2DM.^2,4-7 Differences among studies in how patients were grouped preclude determination of the daily alcohol consumption that confers the greatest risk benefit, although one recent study conducted over 4 years indicates that the greatest benefit in diabetes risk reduction may occur when men who previously consumed 8

Other nutrition and lifestyle patterns also seem to be particularly beneficial in reducing the risk of T2DM in men. Survey data involving 22,921 Japanese men and 29,759 Japanese women followed over 5 years showed that fish and seafood intake was significantly associated with a decreased risk of T2DM in men but not in women.⁹ The odds ratio of developing T2DM for the highest quartile versus the lowest quartile of fish and seafood intake was 0.73 (P = .04 for trend). Additional analysis did not identify any significant association with the fat content of fish.

Results of the Health Professionals Follow-up Study provide evidence of benefit in lowering the risk of T2DM in men who consume high amounts of low-fat dairy products, whole grains, and magnesium ( TABLE 1 ). With respect to dairy food consumption, after 12 years of follow-up involving 1243 incident cases of T2DM, the relative risk (RR) of developing T2DM in men in the top quintile of dairy intake was 0.77 compared with those in the lowest quintile (P = .003 for trend).¹⁰ Men in the highest quintile consumed 4.1 servings of dairy food per day compared with 0.5 servings per day in the lowest quintile. Each serving-per-day increase in total dairy intake was associated with a 9% lower risk for T2DM, with a lower risk seen with consumption of low-fat vs high-fat dairy food. With respect to whole-grain intake, the RR of developing T2DM was 0.58 in men in the upper vs lower quintiles (3.2 vs 0.4 servings/d), although the effect was attenuated with BMI (P = .0006 for trend).¹¹ Similar observations were made with respect to magnesium consumption; a RR of 0.76 for T2DM was observed in men with a median magnesium consumption of 457 mg/d compared with those who consumed 270 mg/d.¹²

TABLE 1

Suggestions for Men Who Are at Risk of or Have Been Diagnosed with Type 2 Diabetes Mellitus (T2DM)*

Working with men to avoid the development of T2DM is an important objective for family physicians. It is essential to identify men who are at increased risk, including those with prediabetes, provide education about the disease and its risk factors, and implement appropriate risk reduction strategies. Risk reduction strategies should focus on modifiable factors, such as body weight, physical activity, BP, blood lipids, blood glucose, and smoking. With JW, his motivation to “get back into shape” will help move the conversation toward achievable goals that can be set and modified over time. Other strategies that may be helpful in reducing the risk of developing T2DM in men include a moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium ( TABLE 1 ).

Once diagnosed with T2DM, there are risk management strategies that can be particularly helpful in men. These include strategies that target cardiovascular health, as well as those that consider the psychosocial and coping behaviors of men.

Risk of Complications in Men With Type 2 Diabetes Mellitus

In people diagnosed with T2DM, there are differences between men and women with respect to risk for cardiovascular and other comorbid diseases, as well as in their psychosocial well-being and coping strategies.

Risk for Cardiovascular Disease in Type 2 Diabetes Mellitus

A systematic literature review shows that men with T2DM generally fare better than women with T2DM regarding their risk for CVD. Men with T2DM have a 2- to 3-fold increase in the risk of developing coronary heart disease (CHD) compared with men without T2DM, whereas women with T2DM have a 4- to 6-fold increase in risk compared with women without T2DM.¹⁵ Compared with women with T2DM, men with T2DM also have a better prognosis after myocardial infarction (MI) and a lower risk of death overall from CVD. Possible reasons for these differences include a lower risk of hypertension, a less severe form of dyslipidemia, and a lower prevalence of obesity in men with T2DM compared with women with T2DM.¹⁵ These same reasons for observed differences between men and women were seen in a meta-analysis of 29 studies, where the RR of fatal MI in men with T2DM compared with women with T2DM was 0.68.¹⁶ Similar findings were seen in the Skaraborg Project, which involved 1116 Swedish patients with hypertension and/or T2DM.¹⁷ Compared with a healthy population, the age-adjusted HR for fatal MI was 1.9 for men with T2DM and 5.0 for women with T2DM over 8.1 years of follow-up (RR, 0.38 for men vs women). Analysis of the data indicated that these results were not explained by the more favorable survival rate in women without T2DM than in men without T2DM.¹⁷

Somewhat different results have been reported by the Italian Diabetes and Informatics Study Group in a slightly different T2DM population. This investigation involved men and women with T2DM (N = 11,644) who could have microvascular but not macrovascular disease.¹⁸ After 4 years of follow-up, the age-adjusted incident rates for first CHD event (composite of acute MI, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) were 28.8 per 1000 person-years in men and 23.3 per 1000 person-years in women. Incident rates (per 1000 person-years) of acute MI (10.3 vs 4.7), major CHD events (13.1 vs 5.8), and fatal CHD (2.6 vs 0.6) were all significantly more frequent in men than in women, respectively. Multivariate analysis showed that hypertension and A1C were additional risk factors for CHD in men; for each 20% increment above the A1C upper limit of normal, there was a 14% risk increase for CHD. The presence of microvascular complications increased risk by 20% in men and 35% in women. In this analysis, glycemic control and hypertension were found to be the predominant risk factors in men, while high triglyceride levels, low HDL-C levels, and microangiopathy were predominant in women.

Additional multivariate analyses provide greater insight into specific factors that affect the risk of CVD and outcomes in men with T2DM. One investigation compared men and women with T2DM who were normotensive without evidence of CVD but with microalbuminuria. After 4.7 years of follow-up, men were found to be at lower risk (RR, 0.12) for a composite of death, acute MI, unstable angina, coronary interventions, heart failure, cerebral ischemic stroke or transient ischemic attack, and peripheral artery disease.¹⁹ Other investigators have reported a lower risk of stroke, including fatal stroke, in men with T2DM compared with women with T2DM.^20,21 For example, analysis of the General Practice Research Database identified 22,178 men and 19,621 women with T2DM between the ages of 35 and 89 years.²⁰ The stroke rate per 1000 person-years across all ages was 10.82 (95% confidence interval (CI), 10.17-11.51) in men and 13.16 (95% CI, 12.40-13.97) in women. In men, the rate per 1000 person-years rose from 1.81 in the 35 to 44 year age group to 28.35 in men 85 years of age or older. Although the rate of stroke per 1000 person-years was lower in women than men in the 35 to 44 year age group (1.53 vs 1.81), the rate in women exceeded that of men in the 85 years of age or older group (32.20 vs 28.35).

Other Chronic Complications

Kidney disease is affected by blood lipids, specifically HDL-C, in men with T2DM. An investigation in men and women with T2DM with normoalbuminuria or microalbuminuria at baseline showed that a low HDL-C level was an independent predictor of progression to a more advanced stage of albuminuria over 4.3 years of follow-up (HR, 0.391 for men with normal HDL-C compared with men with low HDL-C). In women, no lipid parameters were associated with progression of albuminuria.²²

While these investigations do not provide a clear picture of the differences regarding cardiovascular risk between men and women with T2DM, they suggest that men with T2DM have a lower risk of nonfatal and fatal CVD and stroke than do women with T2DM. However, the lower risk seen in men may be affected by the cardiovascular endpoints measured and the presence of microvascular disease. Possible independent risk factors for CVD in men with T2DM include hypertension, poor glycemic control, and low HDL-C.

Psychosocial Well-Being, Benefit of Self-Care, and Coping Strategies

Type 2 diabetes mellitus is a chronic disease with glycemic control largely determined by patient self-management, and the attitudes and beliefs of patients with T2DM are important factors to consider from diagnosis onward.²³ There are important differences between men and women with T2DM regarding attitudes and beliefs. Published investigations provide some, although not entirely consistent, insight into these psychosocial differences between men and women with T2DM. These differences are summarized in TABLE 2 .^24-32 Taking these differences into account when planning treatment and when communicating with and educating the patient is essential for improved patient self-management.

TABLE 2

Psychosocial and Coping Characteristics of Men with Type 2 Diabetes Mellitus (T2DM)^24-32

Summary

The growing epidemic of T2DM requires intervention to assist patients who have been diagnosed to better manage the disease, to reduce the risk of developing the disease in those who have not yet been diagnosed, and to manage the associated complications. In addition to individualizing interventions based on a patient’s needs, concerns, and capabilities, taking gender into account is necessary. In otherwise healthy people, several independent factors appear to pose a higher risk of T2DM in men relative to women, including systolic hypertension, regular smoking, and alcohol intake ≥ 40 g/d. At the same time, men achieve greater risk reduction from moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium.

Once diagnosed with T2DM, men generally fare better than women regarding the risk for CVD; they also have a better prognosis after MI and a lower risk of death overall from CVD. Possible independent risk factors for CVD in men with T2DM that are especially important may include hypertension, poor glycemic control, and low HDL-C levels. Psychosocial complications, such as depression, are less likely in men with T2DM. However, men expend less effort coping, are less likely to utilize healthcare services, and are less informed about treatment options. Although men have a lower expectation of the benefit of self-management, they find support from family and friends more helpful than do women, but they are fearful of losing control of their disease.

Taking these gender differences into account should prove helpful as family care physicians work with men to reduce their risk of developing T2DM and in helping men diagnosed with T2DM to better self-manage their disease.

The prevalence of type 2 diabetes mellitus (T2DM) is similar in men and women (11.8% vs 10.8%, respectively), however there are gender differences that should be considered when developing a treatment plan (eg, cardiovascular risk, psychosocial factors, coping strategies, and the perception of benefit from self-care) when managing those diagnosed with this disease and those at risk for developing it.¹ This article describes these differences in the context of two patients—one at risk for T2DM being seen by his health care provider for a routine physical examination, and one who has been treated for several years for T2DM and is being seen for a follow-up office visit. For each patient, the implications for treatment are discussed.

Men at Risk for Type 2 Diabetes Mellitus

Key Risk Factors for Type 2 Diabetes Mellitus in Men

This case is not an uncommon presentation of a middle-aged male who has several risk factors for diabetes (see Case Study 1 continued ). JW also has key risk factors for T2DM in men. The Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg surveys identified 128 men and 85 women with T2DM.² Increasing age and BMI, positive parental history of T2DM, and a low high-density lipoprotein cholesterol (HDL-C) level were independent risk factors predicting the development of T2DM in both men and women. However, several other factors posed a higher risk in men relative to women, including systolic BP (hazard ratio [HR], 1.16 per 10-mm Hg increase), regular smoking (HR, 1.75), and alcohol intake ≥ 40 g/d (HR, 1.95). (Note: 1 fluid ounce 80 proof alcohol ≈ 11 g ethanol; 12 fluid ounces beer [~5% alcohol] ≈ 14 g ethanol). After adjusting for these factors, a separate analysis (4424 men, 4380 women) showed that men who lived alone were more likely to develop T2DM than either men or women who did not live alone (HR, 1.69 in men vs 0.85 in women; P = .006).³ While the number of people with T2DM in MONICA was small, the results suggest that measuring BP, particularly systolic BP, and taking a smoking and alcohol history may be especially important in men.

With respect to alcohol intake, epidemiologic and randomized clinical trials have generally demonstrated an inverse relationship between moderate alcohol consumption (20 to 30 g/d) and the long-term risk of T2DM.^2,4-7 Differences among studies in how patients were grouped preclude determination of the daily alcohol consumption that confers the greatest risk benefit, although one recent study conducted over 4 years indicates that the greatest benefit in diabetes risk reduction may occur when men who previously consumed 8

Other nutrition and lifestyle patterns also seem to be particularly beneficial in reducing the risk of T2DM in men. Survey data involving 22,921 Japanese men and 29,759 Japanese women followed over 5 years showed that fish and seafood intake was significantly associated with a decreased risk of T2DM in men but not in women.⁹ The odds ratio of developing T2DM for the highest quartile versus the lowest quartile of fish and seafood intake was 0.73 (P = .04 for trend). Additional analysis did not identify any significant association with the fat content of fish.

Results of the Health Professionals Follow-up Study provide evidence of benefit in lowering the risk of T2DM in men who consume high amounts of low-fat dairy products, whole grains, and magnesium ( TABLE 1 ). With respect to dairy food consumption, after 12 years of follow-up involving 1243 incident cases of T2DM, the relative risk (RR) of developing T2DM in men in the top quintile of dairy intake was 0.77 compared with those in the lowest quintile (P = .003 for trend).¹⁰ Men in the highest quintile consumed 4.1 servings of dairy food per day compared with 0.5 servings per day in the lowest quintile. Each serving-per-day increase in total dairy intake was associated with a 9% lower risk for T2DM, with a lower risk seen with consumption of low-fat vs high-fat dairy food. With respect to whole-grain intake, the RR of developing T2DM was 0.58 in men in the upper vs lower quintiles (3.2 vs 0.4 servings/d), although the effect was attenuated with BMI (P = .0006 for trend).¹¹ Similar observations were made with respect to magnesium consumption; a RR of 0.76 for T2DM was observed in men with a median magnesium consumption of 457 mg/d compared with those who consumed 270 mg/d.¹²

TABLE 1

Suggestions for Men Who Are at Risk of or Have Been Diagnosed with Type 2 Diabetes Mellitus (T2DM)*

Working with men to avoid the development of T2DM is an important objective for family physicians. It is essential to identify men who are at increased risk, including those with prediabetes, provide education about the disease and its risk factors, and implement appropriate risk reduction strategies. Risk reduction strategies should focus on modifiable factors, such as body weight, physical activity, BP, blood lipids, blood glucose, and smoking. With JW, his motivation to “get back into shape” will help move the conversation toward achievable goals that can be set and modified over time. Other strategies that may be helpful in reducing the risk of developing T2DM in men include a moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium ( TABLE 1 ).

Once diagnosed with T2DM, there are risk management strategies that can be particularly helpful in men. These include strategies that target cardiovascular health, as well as those that consider the psychosocial and coping behaviors of men.

Risk of Complications in Men With Type 2 Diabetes Mellitus

In people diagnosed with T2DM, there are differences between men and women with respect to risk for cardiovascular and other comorbid diseases, as well as in their psychosocial well-being and coping strategies.

Risk for Cardiovascular Disease in Type 2 Diabetes Mellitus

A systematic literature review shows that men with T2DM generally fare better than women with T2DM regarding their risk for CVD. Men with T2DM have a 2- to 3-fold increase in the risk of developing coronary heart disease (CHD) compared with men without T2DM, whereas women with T2DM have a 4- to 6-fold increase in risk compared with women without T2DM.¹⁵ Compared with women with T2DM, men with T2DM also have a better prognosis after myocardial infarction (MI) and a lower risk of death overall from CVD. Possible reasons for these differences include a lower risk of hypertension, a less severe form of dyslipidemia, and a lower prevalence of obesity in men with T2DM compared with women with T2DM.¹⁵ These same reasons for observed differences between men and women were seen in a meta-analysis of 29 studies, where the RR of fatal MI in men with T2DM compared with women with T2DM was 0.68.¹⁶ Similar findings were seen in the Skaraborg Project, which involved 1116 Swedish patients with hypertension and/or T2DM.¹⁷ Compared with a healthy population, the age-adjusted HR for fatal MI was 1.9 for men with T2DM and 5.0 for women with T2DM over 8.1 years of follow-up (RR, 0.38 for men vs women). Analysis of the data indicated that these results were not explained by the more favorable survival rate in women without T2DM than in men without T2DM.¹⁷

Somewhat different results have been reported by the Italian Diabetes and Informatics Study Group in a slightly different T2DM population. This investigation involved men and women with T2DM (N = 11,644) who could have microvascular but not macrovascular disease.¹⁸ After 4 years of follow-up, the age-adjusted incident rates for first CHD event (composite of acute MI, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) were 28.8 per 1000 person-years in men and 23.3 per 1000 person-years in women. Incident rates (per 1000 person-years) of acute MI (10.3 vs 4.7), major CHD events (13.1 vs 5.8), and fatal CHD (2.6 vs 0.6) were all significantly more frequent in men than in women, respectively. Multivariate analysis showed that hypertension and A1C were additional risk factors for CHD in men; for each 20% increment above the A1C upper limit of normal, there was a 14% risk increase for CHD. The presence of microvascular complications increased risk by 20% in men and 35% in women. In this analysis, glycemic control and hypertension were found to be the predominant risk factors in men, while high triglyceride levels, low HDL-C levels, and microangiopathy were predominant in women.

Additional multivariate analyses provide greater insight into specific factors that affect the risk of CVD and outcomes in men with T2DM. One investigation compared men and women with T2DM who were normotensive without evidence of CVD but with microalbuminuria. After 4.7 years of follow-up, men were found to be at lower risk (RR, 0.12) for a composite of death, acute MI, unstable angina, coronary interventions, heart failure, cerebral ischemic stroke or transient ischemic attack, and peripheral artery disease.¹⁹ Other investigators have reported a lower risk of stroke, including fatal stroke, in men with T2DM compared with women with T2DM.^20,21 For example, analysis of the General Practice Research Database identified 22,178 men and 19,621 women with T2DM between the ages of 35 and 89 years.²⁰ The stroke rate per 1000 person-years across all ages was 10.82 (95% confidence interval (CI), 10.17-11.51) in men and 13.16 (95% CI, 12.40-13.97) in women. In men, the rate per 1000 person-years rose from 1.81 in the 35 to 44 year age group to 28.35 in men 85 years of age or older. Although the rate of stroke per 1000 person-years was lower in women than men in the 35 to 44 year age group (1.53 vs 1.81), the rate in women exceeded that of men in the 85 years of age or older group (32.20 vs 28.35).

Other Chronic Complications

Kidney disease is affected by blood lipids, specifically HDL-C, in men with T2DM. An investigation in men and women with T2DM with normoalbuminuria or microalbuminuria at baseline showed that a low HDL-C level was an independent predictor of progression to a more advanced stage of albuminuria over 4.3 years of follow-up (HR, 0.391 for men with normal HDL-C compared with men with low HDL-C). In women, no lipid parameters were associated with progression of albuminuria.²²

While these investigations do not provide a clear picture of the differences regarding cardiovascular risk between men and women with T2DM, they suggest that men with T2DM have a lower risk of nonfatal and fatal CVD and stroke than do women with T2DM. However, the lower risk seen in men may be affected by the cardiovascular endpoints measured and the presence of microvascular disease. Possible independent risk factors for CVD in men with T2DM include hypertension, poor glycemic control, and low HDL-C.

Psychosocial Well-Being, Benefit of Self-Care, and Coping Strategies

Type 2 diabetes mellitus is a chronic disease with glycemic control largely determined by patient self-management, and the attitudes and beliefs of patients with T2DM are important factors to consider from diagnosis onward.²³ There are important differences between men and women with T2DM regarding attitudes and beliefs. Published investigations provide some, although not entirely consistent, insight into these psychosocial differences between men and women with T2DM. These differences are summarized in TABLE 2 .^24-32 Taking these differences into account when planning treatment and when communicating with and educating the patient is essential for improved patient self-management.

TABLE 2

Psychosocial and Coping Characteristics of Men with Type 2 Diabetes Mellitus (T2DM)^24-32

Summary

The growing epidemic of T2DM requires intervention to assist patients who have been diagnosed to better manage the disease, to reduce the risk of developing the disease in those who have not yet been diagnosed, and to manage the associated complications. In addition to individualizing interventions based on a patient’s needs, concerns, and capabilities, taking gender into account is necessary. In otherwise healthy people, several independent factors appear to pose a higher risk of T2DM in men relative to women, including systolic hypertension, regular smoking, and alcohol intake ≥ 40 g/d. At the same time, men achieve greater risk reduction from moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium.

Once diagnosed with T2DM, men generally fare better than women regarding the risk for CVD; they also have a better prognosis after MI and a lower risk of death overall from CVD. Possible independent risk factors for CVD in men with T2DM that are especially important may include hypertension, poor glycemic control, and low HDL-C levels. Psychosocial complications, such as depression, are less likely in men with T2DM. However, men expend less effort coping, are less likely to utilize healthcare services, and are less informed about treatment options. Although men have a lower expectation of the benefit of self-management, they find support from family and friends more helpful than do women, but they are fearful of losing control of their disease.

Taking these gender differences into account should prove helpful as family care physicians work with men to reduce their risk of developing T2DM and in helping men diagnosed with T2DM to better self-manage their disease.

The prevalence of type 2 diabetes mellitus (T2DM) is similar in men and women (11.8% vs 10.8%, respectively), however there are gender differences that should be considered when developing a treatment plan (eg, cardiovascular risk, psychosocial factors, coping strategies, and the perception of benefit from self-care) when managing those diagnosed with this disease and those at risk for developing it.¹ This article describes these differences in the context of two patients—one at risk for T2DM being seen by his health care provider for a routine physical examination, and one who has been treated for several years for T2DM and is being seen for a follow-up office visit. For each patient, the implications for treatment are discussed.

Men at Risk for Type 2 Diabetes Mellitus

Key Risk Factors for Type 2 Diabetes Mellitus in Men

This case is not an uncommon presentation of a middle-aged male who has several risk factors for diabetes (see Case Study 1 continued ). JW also has key risk factors for T2DM in men. The Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg surveys identified 128 men and 85 women with T2DM.² Increasing age and BMI, positive parental history of T2DM, and a low high-density lipoprotein cholesterol (HDL-C) level were independent risk factors predicting the development of T2DM in both men and women. However, several other factors posed a higher risk in men relative to women, including systolic BP (hazard ratio [HR], 1.16 per 10-mm Hg increase), regular smoking (HR, 1.75), and alcohol intake ≥ 40 g/d (HR, 1.95). (Note: 1 fluid ounce 80 proof alcohol ≈ 11 g ethanol; 12 fluid ounces beer [~5% alcohol] ≈ 14 g ethanol). After adjusting for these factors, a separate analysis (4424 men, 4380 women) showed that men who lived alone were more likely to develop T2DM than either men or women who did not live alone (HR, 1.69 in men vs 0.85 in women; P = .006).³ While the number of people with T2DM in MONICA was small, the results suggest that measuring BP, particularly systolic BP, and taking a smoking and alcohol history may be especially important in men.

With respect to alcohol intake, epidemiologic and randomized clinical trials have generally demonstrated an inverse relationship between moderate alcohol consumption (20 to 30 g/d) and the long-term risk of T2DM.^2,4-7 Differences among studies in how patients were grouped preclude determination of the daily alcohol consumption that confers the greatest risk benefit, although one recent study conducted over 4 years indicates that the greatest benefit in diabetes risk reduction may occur when men who previously consumed 8

Other nutrition and lifestyle patterns also seem to be particularly beneficial in reducing the risk of T2DM in men. Survey data involving 22,921 Japanese men and 29,759 Japanese women followed over 5 years showed that fish and seafood intake was significantly associated with a decreased risk of T2DM in men but not in women.⁹ The odds ratio of developing T2DM for the highest quartile versus the lowest quartile of fish and seafood intake was 0.73 (P = .04 for trend). Additional analysis did not identify any significant association with the fat content of fish.

Results of the Health Professionals Follow-up Study provide evidence of benefit in lowering the risk of T2DM in men who consume high amounts of low-fat dairy products, whole grains, and magnesium ( TABLE 1 ). With respect to dairy food consumption, after 12 years of follow-up involving 1243 incident cases of T2DM, the relative risk (RR) of developing T2DM in men in the top quintile of dairy intake was 0.77 compared with those in the lowest quintile (P = .003 for trend).¹⁰ Men in the highest quintile consumed 4.1 servings of dairy food per day compared with 0.5 servings per day in the lowest quintile. Each serving-per-day increase in total dairy intake was associated with a 9% lower risk for T2DM, with a lower risk seen with consumption of low-fat vs high-fat dairy food. With respect to whole-grain intake, the RR of developing T2DM was 0.58 in men in the upper vs lower quintiles (3.2 vs 0.4 servings/d), although the effect was attenuated with BMI (P = .0006 for trend).¹¹ Similar observations were made with respect to magnesium consumption; a RR of 0.76 for T2DM was observed in men with a median magnesium consumption of 457 mg/d compared with those who consumed 270 mg/d.¹²

TABLE 1

Suggestions for Men Who Are at Risk of or Have Been Diagnosed with Type 2 Diabetes Mellitus (T2DM)*

Working with men to avoid the development of T2DM is an important objective for family physicians. It is essential to identify men who are at increased risk, including those with prediabetes, provide education about the disease and its risk factors, and implement appropriate risk reduction strategies. Risk reduction strategies should focus on modifiable factors, such as body weight, physical activity, BP, blood lipids, blood glucose, and smoking. With JW, his motivation to “get back into shape” will help move the conversation toward achievable goals that can be set and modified over time. Other strategies that may be helpful in reducing the risk of developing T2DM in men include a moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium ( TABLE 1 ).

Once diagnosed with T2DM, there are risk management strategies that can be particularly helpful in men. These include strategies that target cardiovascular health, as well as those that consider the psychosocial and coping behaviors of men.

Risk of Complications in Men With Type 2 Diabetes Mellitus

In people diagnosed with T2DM, there are differences between men and women with respect to risk for cardiovascular and other comorbid diseases, as well as in their psychosocial well-being and coping strategies.

Risk for Cardiovascular Disease in Type 2 Diabetes Mellitus

A systematic literature review shows that men with T2DM generally fare better than women with T2DM regarding their risk for CVD. Men with T2DM have a 2- to 3-fold increase in the risk of developing coronary heart disease (CHD) compared with men without T2DM, whereas women with T2DM have a 4- to 6-fold increase in risk compared with women without T2DM.¹⁵ Compared with women with T2DM, men with T2DM also have a better prognosis after myocardial infarction (MI) and a lower risk of death overall from CVD. Possible reasons for these differences include a lower risk of hypertension, a less severe form of dyslipidemia, and a lower prevalence of obesity in men with T2DM compared with women with T2DM.¹⁵ These same reasons for observed differences between men and women were seen in a meta-analysis of 29 studies, where the RR of fatal MI in men with T2DM compared with women with T2DM was 0.68.¹⁶ Similar findings were seen in the Skaraborg Project, which involved 1116 Swedish patients with hypertension and/or T2DM.¹⁷ Compared with a healthy population, the age-adjusted HR for fatal MI was 1.9 for men with T2DM and 5.0 for women with T2DM over 8.1 years of follow-up (RR, 0.38 for men vs women). Analysis of the data indicated that these results were not explained by the more favorable survival rate in women without T2DM than in men without T2DM.¹⁷

Somewhat different results have been reported by the Italian Diabetes and Informatics Study Group in a slightly different T2DM population. This investigation involved men and women with T2DM (N = 11,644) who could have microvascular but not macrovascular disease.¹⁸ After 4 years of follow-up, the age-adjusted incident rates for first CHD event (composite of acute MI, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) were 28.8 per 1000 person-years in men and 23.3 per 1000 person-years in women. Incident rates (per 1000 person-years) of acute MI (10.3 vs 4.7), major CHD events (13.1 vs 5.8), and fatal CHD (2.6 vs 0.6) were all significantly more frequent in men than in women, respectively. Multivariate analysis showed that hypertension and A1C were additional risk factors for CHD in men; for each 20% increment above the A1C upper limit of normal, there was a 14% risk increase for CHD. The presence of microvascular complications increased risk by 20% in men and 35% in women. In this analysis, glycemic control and hypertension were found to be the predominant risk factors in men, while high triglyceride levels, low HDL-C levels, and microangiopathy were predominant in women.

Additional multivariate analyses provide greater insight into specific factors that affect the risk of CVD and outcomes in men with T2DM. One investigation compared men and women with T2DM who were normotensive without evidence of CVD but with microalbuminuria. After 4.7 years of follow-up, men were found to be at lower risk (RR, 0.12) for a composite of death, acute MI, unstable angina, coronary interventions, heart failure, cerebral ischemic stroke or transient ischemic attack, and peripheral artery disease.¹⁹ Other investigators have reported a lower risk of stroke, including fatal stroke, in men with T2DM compared with women with T2DM.^20,21 For example, analysis of the General Practice Research Database identified 22,178 men and 19,621 women with T2DM between the ages of 35 and 89 years.²⁰ The stroke rate per 1000 person-years across all ages was 10.82 (95% confidence interval (CI), 10.17-11.51) in men and 13.16 (95% CI, 12.40-13.97) in women. In men, the rate per 1000 person-years rose from 1.81 in the 35 to 44 year age group to 28.35 in men 85 years of age or older. Although the rate of stroke per 1000 person-years was lower in women than men in the 35 to 44 year age group (1.53 vs 1.81), the rate in women exceeded that of men in the 85 years of age or older group (32.20 vs 28.35).

Other Chronic Complications

Kidney disease is affected by blood lipids, specifically HDL-C, in men with T2DM. An investigation in men and women with T2DM with normoalbuminuria or microalbuminuria at baseline showed that a low HDL-C level was an independent predictor of progression to a more advanced stage of albuminuria over 4.3 years of follow-up (HR, 0.391 for men with normal HDL-C compared with men with low HDL-C). In women, no lipid parameters were associated with progression of albuminuria.²²

While these investigations do not provide a clear picture of the differences regarding cardiovascular risk between men and women with T2DM, they suggest that men with T2DM have a lower risk of nonfatal and fatal CVD and stroke than do women with T2DM. However, the lower risk seen in men may be affected by the cardiovascular endpoints measured and the presence of microvascular disease. Possible independent risk factors for CVD in men with T2DM include hypertension, poor glycemic control, and low HDL-C.

Psychosocial Well-Being, Benefit of Self-Care, and Coping Strategies

Type 2 diabetes mellitus is a chronic disease with glycemic control largely determined by patient self-management, and the attitudes and beliefs of patients with T2DM are important factors to consider from diagnosis onward.²³ There are important differences between men and women with T2DM regarding attitudes and beliefs. Published investigations provide some, although not entirely consistent, insight into these psychosocial differences between men and women with T2DM. These differences are summarized in TABLE 2 .^24-32 Taking these differences into account when planning treatment and when communicating with and educating the patient is essential for improved patient self-management.

TABLE 2

Psychosocial and Coping Characteristics of Men with Type 2 Diabetes Mellitus (T2DM)^24-32

Summary

The growing epidemic of T2DM requires intervention to assist patients who have been diagnosed to better manage the disease, to reduce the risk of developing the disease in those who have not yet been diagnosed, and to manage the associated complications. In addition to individualizing interventions based on a patient’s needs, concerns, and capabilities, taking gender into account is necessary. In otherwise healthy people, several independent factors appear to pose a higher risk of T2DM in men relative to women, including systolic hypertension, regular smoking, and alcohol intake ≥ 40 g/d. At the same time, men achieve greater risk reduction from moderate daily alcohol intake and a diet high in fish and seafood, low-fat dairy products, whole grains, and magnesium.

Once diagnosed with T2DM, men generally fare better than women regarding the risk for CVD; they also have a better prognosis after MI and a lower risk of death overall from CVD. Possible independent risk factors for CVD in men with T2DM that are especially important may include hypertension, poor glycemic control, and low HDL-C levels. Psychosocial complications, such as depression, are less likely in men with T2DM. However, men expend less effort coping, are less likely to utilize healthcare services, and are less informed about treatment options. Although men have a lower expectation of the benefit of self-management, they find support from family and friends more helpful than do women, but they are fearful of losing control of their disease.

Taking these gender differences into account should prove helpful as family care physicians work with men to reduce their risk of developing T2DM and in helping men diagnosed with T2DM to better self-manage their disease.

A decade ago, the World Health Organization suggested that “increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.”¹ A recent survey found that medication adherence rates over the course of 1 year were 24% for patients with depression, 36% with diabetes, 54% with epilepsy, 32% with dyslipidemia, and 42% with hypertension.² Poor adherence rates such as these contribute to the low rates of disease control in patients with diabetes, dyslipidemia, hypertension, and other chronic diseases.^3,4 Since chronic diseases are largely self-managed, effective patient self-management is critical to good health-related outcomes. To help patients self-manage their diseases, the family physician must work collaboratively with each patient to select, initiate, and modify therapy based upon the patient’s needs, interests, and capabilities. Just as there are important differences between children and adults, men and women often manifest diseases differently. In addition, men and women often deal with and manage their diseases in different ways. While “Men’s Health” is often considered to be a focus on the urogenital tract, we have sought to also focus on diseases that have a high prevalence in men, or where treatment in men may be different compared with women.

The first 2 articles in this supplement on men’s health concern 2 diseases increasingly encountered by men as they age. Dr. Martin Miner provides his thoughts about screening for and diagnosing benign prostatic hyperplasia, including strategies to promote patient report of symptoms and the role of the prostate specific antigen test. A case study is utilized to illustrate key considerations when selecting therapy and promoting patient self-management of benign prostatic hyperplasia. Dr. Gary Ruoff follows a patient from initial diagnosis of gout through selection of treatment for the acute flare and chronic treatment with urate-lowering therapy. A treatment plan is presented at each management step. In the next article, Dr. Richard Aguilar takes a case study approach to describe key risk factors for type 2 diabetes mellitus in men. He also discusses how men self-manage type 2 diabetes differently than women and provides insight as to how to address common psychosocial issues in men. Drs. Louis Kuritzky and José Díez review clinical experience with the two newest antiplatelet agents, prasugrel and ticagrelor. Answers are also provided to common questions and problems encountered with the use of antiplatelet agents in primary care. The next 2 articles focus on major modifiable risk factors contributing to cardiovascular disease. In the first, Dr. Michael Cobble focuses on patient assessment and treatment strategies to help men modify abnormal lipid levels and blood pressure for primary prevention of coronary heart disease. Finally, a more in-depth discussion of dyslipidemia is provided by Dr. Peter Toth, who begins by providing a brief overview of the current evidence regarding the long-term benefits of statin therapy, as well as his clinical perspective on the newest statin, pitavastatin. Dr. Toth also provides answers to many problems frequently encountered in the primary care management of patients with dyslipidemia using statin therapy.

It is my hope that the insights provided by these authors will be helpful to family physicians in managing their male patients with these common chronic diseases.

A decade ago, the World Health Organization suggested that “increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.”¹ A recent survey found that medication adherence rates over the course of 1 year were 24% for patients with depression, 36% with diabetes, 54% with epilepsy, 32% with dyslipidemia, and 42% with hypertension.² Poor adherence rates such as these contribute to the low rates of disease control in patients with diabetes, dyslipidemia, hypertension, and other chronic diseases.^3,4 Since chronic diseases are largely self-managed, effective patient self-management is critical to good health-related outcomes. To help patients self-manage their diseases, the family physician must work collaboratively with each patient to select, initiate, and modify therapy based upon the patient’s needs, interests, and capabilities. Just as there are important differences between children and adults, men and women often manifest diseases differently. In addition, men and women often deal with and manage their diseases in different ways. While “Men’s Health” is often considered to be a focus on the urogenital tract, we have sought to also focus on diseases that have a high prevalence in men, or where treatment in men may be different compared with women.

The first 2 articles in this supplement on men’s health concern 2 diseases increasingly encountered by men as they age. Dr. Martin Miner provides his thoughts about screening for and diagnosing benign prostatic hyperplasia, including strategies to promote patient report of symptoms and the role of the prostate specific antigen test. A case study is utilized to illustrate key considerations when selecting therapy and promoting patient self-management of benign prostatic hyperplasia. Dr. Gary Ruoff follows a patient from initial diagnosis of gout through selection of treatment for the acute flare and chronic treatment with urate-lowering therapy. A treatment plan is presented at each management step. In the next article, Dr. Richard Aguilar takes a case study approach to describe key risk factors for type 2 diabetes mellitus in men. He also discusses how men self-manage type 2 diabetes differently than women and provides insight as to how to address common psychosocial issues in men. Drs. Louis Kuritzky and José Díez review clinical experience with the two newest antiplatelet agents, prasugrel and ticagrelor. Answers are also provided to common questions and problems encountered with the use of antiplatelet agents in primary care. The next 2 articles focus on major modifiable risk factors contributing to cardiovascular disease. In the first, Dr. Michael Cobble focuses on patient assessment and treatment strategies to help men modify abnormal lipid levels and blood pressure for primary prevention of coronary heart disease. Finally, a more in-depth discussion of dyslipidemia is provided by Dr. Peter Toth, who begins by providing a brief overview of the current evidence regarding the long-term benefits of statin therapy, as well as his clinical perspective on the newest statin, pitavastatin. Dr. Toth also provides answers to many problems frequently encountered in the primary care management of patients with dyslipidemia using statin therapy.

It is my hope that the insights provided by these authors will be helpful to family physicians in managing their male patients with these common chronic diseases.

A decade ago, the World Health Organization suggested that “increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments.”¹ A recent survey found that medication adherence rates over the course of 1 year were 24% for patients with depression, 36% with diabetes, 54% with epilepsy, 32% with dyslipidemia, and 42% with hypertension.² Poor adherence rates such as these contribute to the low rates of disease control in patients with diabetes, dyslipidemia, hypertension, and other chronic diseases.^3,4 Since chronic diseases are largely self-managed, effective patient self-management is critical to good health-related outcomes. To help patients self-manage their diseases, the family physician must work collaboratively with each patient to select, initiate, and modify therapy based upon the patient’s needs, interests, and capabilities. Just as there are important differences between children and adults, men and women often manifest diseases differently. In addition, men and women often deal with and manage their diseases in different ways. While “Men’s Health” is often considered to be a focus on the urogenital tract, we have sought to also focus on diseases that have a high prevalence in men, or where treatment in men may be different compared with women.

The first 2 articles in this supplement on men’s health concern 2 diseases increasingly encountered by men as they age. Dr. Martin Miner provides his thoughts about screening for and diagnosing benign prostatic hyperplasia, including strategies to promote patient report of symptoms and the role of the prostate specific antigen test. A case study is utilized to illustrate key considerations when selecting therapy and promoting patient self-management of benign prostatic hyperplasia. Dr. Gary Ruoff follows a patient from initial diagnosis of gout through selection of treatment for the acute flare and chronic treatment with urate-lowering therapy. A treatment plan is presented at each management step. In the next article, Dr. Richard Aguilar takes a case study approach to describe key risk factors for type 2 diabetes mellitus in men. He also discusses how men self-manage type 2 diabetes differently than women and provides insight as to how to address common psychosocial issues in men. Drs. Louis Kuritzky and José Díez review clinical experience with the two newest antiplatelet agents, prasugrel and ticagrelor. Answers are also provided to common questions and problems encountered with the use of antiplatelet agents in primary care. The next 2 articles focus on major modifiable risk factors contributing to cardiovascular disease. In the first, Dr. Michael Cobble focuses on patient assessment and treatment strategies to help men modify abnormal lipid levels and blood pressure for primary prevention of coronary heart disease. Finally, a more in-depth discussion of dyslipidemia is provided by Dr. Peter Toth, who begins by providing a brief overview of the current evidence regarding the long-term benefits of statin therapy, as well as his clinical perspective on the newest statin, pitavastatin. Dr. Toth also provides answers to many problems frequently encountered in the primary care management of patients with dyslipidemia using statin therapy.

It is my hope that the insights provided by these authors will be helpful to family physicians in managing their male patients with these common chronic diseases.

CASE KD is an 18-year-old high school basketball player who was knocked backwards during a game, hitting her head on the floor. She had immediate head and neck pain but no loss of consciousness; she was transported by EMS to the local emergency department (ED) for further evaluation. Results of head and neck CT scans were normal, and she was discharged home. Four days later, KD’s parents brought her to our office because she was experiencing ongoing headache, phonophobia, nausea, light-headedness, poor balance, increased sleepiness, and irritability.

The Centers for Disease Control and Prevention estimate that approximately 300,000 sports concussions occur yearly in the United States,¹ and that 135,000 of these cases are treated in EDs.² These numbers have not gone unnoticed in the consumer press. Over the past 18 months, Sports Illustrated, Newsweek, and Time^3-5 have published stories on sports-related concussion, helping to raise public awareness of its risks.

Recommendations for practitioners have changed. In 1997, the American Academy of Neurology⁶ published one-size-fits-all guidelines on managing concussion, using levels of symptomatology and loss of consciousness to grade the severity of concussion from 1 to 3. These guidelines were similar to the Cantu and Colorado guidelines of the early 1990s.^7,8 Since then, however, the diagnostic criteria and expert opinion about treatment and return to physical activity have changed. Indeed, several medical organizations^9-12 now recommend a more individualized approach to evaluation and management, which we describe here.

It begins with a definition

While there is no single agreed-upon characterization of “concussion,” the 3rd International Conference on Concussion in Sport (ICCS)¹² provides this definition:

Concussion is defined as a complex pathophysiological process affecting the brain, induced by traumatic biomechanical forces. Several common features that incorporate clinical, pathologic, and biomechanical injury constructs that may be utilized in defining the nature of a concussive head injury include:

1. Concussion may be caused either by a direct blow to the head, face, or neck or a blow elsewhere on the body with an ‘‘impulsive’’ force transmitted to the head.
2. Concussion typically results in the rapid onset of short-lived impairment of neurologic function that resolves spontaneously.
3. Concussion may result in neuropathological changes but the acute clinical symptoms largely reflect a functional disturbance rather than a structural injury.
4. Concussion results in a graded set of clinical symptoms that may or may not involve loss of consciousness. Resolution of the clinical and cognitive symptoms typically follows a sequential course.… In a small percentage of cases, however, postconcussive symptoms may be prolonged.
5. No abnormality on standard structural neuroimaging studies is seen in concussion.

Office evaluation
Obtain a thorough history and conduct a neurologic evaluation and musculoskeletal examination of the head and neck.

Clues to expected length of recovery

A patient with a concussion may lose consciousness after the impact, or have a brief convulsion that is not a seizure.¹³ In the periodimmediately after the injury, the patient may exhibit a constellation of such signs and symptoms as headache, confusion, a dazed look, dilated pupils, amnesia, poor balance, nausea, or vomiting. These features typically resolve over time, but may persist for weeks or months. Anterograde or retrograde amnesia may also occur. TABLE 1 details a more complete list of concussion symptoms. If the patient is a child or young adult, it is useful to have a parent present at the office visit to describe the patient’s mood, sleep, appetite, and overall health after the injury.

Factors that may portend a longer recovery include a previous concussion, retrograde or anterograde amnesia, younger age, and female sex.¹⁴

Dire problems beyond concussion. Complaints or historical elements inconsistent with concussion that should be considered red flags include any focal neurologic complaints, vomiting or headache that worsens after a period of improvement, or obtundation or disorientation that has worsened since the injury. With such findings, consider more serious head injuries and arrange for a more complete immediate neurologic work-up.

CASE Our neurologic examination yielded normal results. However, our patient was unable to balance correctly on one leg. The cognitive exam revealed a deficit in short-term memory. We diagnosed a concussion, advised her to refrain from sports, and prescribed cognitive rest. A return to school for half days would be considered once her symptoms began to resolve.

TABLE 1
Signs and symptoms commonly associated with concussion

Options for the neurologic exam
With a simple concussion, expect a normal neurologic examination, with the possible exception of the ability to balance. Head imaging is not necessary in the setting of suspected concussion, because results of computed tomography (CT) and magnetic resonance imaging (MRI) will likely be normal.¹²

Balance testing can assist in the diagnosis of concussion and the monitoring of recovery from injury.^15-17 The Balance Error Scoring System (BESS)¹⁵ is a validated and simple test that can be done in the office. The test involves 3 consecutive stances: (a) normal stance with feet comfortably apart and hands on hips, (b) with feet aligned heel to toe with the dominant leg in front, and (c) standing on the nondominant leg with the dominant leg flexed 30 degrees at the hip. Have the patient repeat each version of the test for 20 seconds with eyes closed, on a stable and then unstable surface (eg, foam mat).

It’s recommended that another staff member be present to spot the patient in case of a fall. A link to a complete description of the test and scoring details is provided in the Web resources box.

Assess cognitive function. One tool for assessing cognitive function is the Sports Concussion Assessment Tool 2 (SCAT2).¹² SCAT2 includes newer, as yet unvalidated sections and several sections that have been independently studied and proven useful in diagnosing concussion. Validated sections are the Maddocks questions, used only at the time and place of injury¹⁸ ; the modified BESS¹⁵ ; and the Standardized Assessment of Concussion (SAC).¹⁹ The SCAT2 and the SAC (which may be used separately) include questions that assist in evaluating short-term memory and attention, and are useful in the physician’s office.

Do computer-based tools help? Another option for cognitive assessment is computer-based neuropsychologic testing developed specifically for use with suspected concussion. Any of these programs can be used in the office by a trained practitioner. Schools may also use the programs under the supervision of an athletic trainer or team physician. Available programs are ImPACT, developed by the University of Pittsburgh (http://impacttest.com); the Cognitive Stability Index (CSI), by HeadMinder (http://www.headminder.com/site/csi/home.html); and the Computerized Cognitive Assessment Tool (CCAT), by CogState/Axon Sports (http://www.axonsports.com). Multiple studies have shown such programs to be useful in diagnosing and monitoring recovery from sports concussion.^20-23

However, among sports medicine practitioners, there seems to be a consensus that computer-based neuropsychologic testing is most useful when a baseline score exists. Baseline testing is usually done preseason on athletes in a healthy state. If a baseline score is not available, a patient’s postinjury score is compared with normative data produced by the developer of the individual test.

Few, if any, outcome studies have been conducted to determine whether computer-basedneuropsychologic testing provides any meaningful improvement in the care of athletes who have suffered concussions. There is also concern that few studies by independent sources have replicated the data disseminated by developers of the tests.^24,25 The most recent guidelines by the 3rd ICCS recommend using neuropsychologic testing only as an aid to an overall medical evaluation, not as the sole determinant of recovery from concussion.¹² Numerous studies now underway may help clarify the role of neuropsychologic testing in concussion.

CASE By the time of our follow-up exam 7 days later (11 days from injury), KD had returned to school for half days, but her phonophobia and headaches worsened at school and she had difficulty focusing on academic tasks. Neurologic, balance, and cognitive exams were all normal. We advised her to gradually return to school full time while abstaining from sporting activity.

At 16 days’ follow-up (20 days from injury), KD had returned to school full time and said she felt more like herself, although she continued to have daily headaches and phonophobia. All exam results were normal. Sports were still off limits, and we told her to expect at least 7 more days of respite before any return to exercise would be allowed.

At 23 days’ follow-up (27 days from injury), KD’s symptoms had completely resolved, and all exam results were normal. We prescribed a stepwise return to athletic activity over the next 10 days and discussed this plan with the school’s athletic trainer, who would supervise her return to play.

Individualize management

The one-size-fits-all approach previously recommended⁶ is no longer the standard of care. In your initial encounter with the patient (and parents, as appropriate), explain the nature of the injury, expected course of recovery, and requirements for a return to play. Also discuss the possibility of postconcussive syndrome and the risk of rare sequelae such as second impact syndrome.

If the patient is symptomatic or exhibits examination findings consistent with concussion, recommend immediate cessation of sports activity.^9-12 With a school-aged athlete, if symptoms reported by the patient or parents are significant, consider prescribing cognitive rest, which can be provided through quiet accommodations at school or perhaps even time off from school or exams.^12,24 In the early period of recovery, increased cognitive or physical activity can cause symptoms to worsen. With improvement, the patient may return to school half time to lessen the chance of a significant return of symptoms. If half days are tolerated, the patient may transition to full days. Make sure the diagnosis and expectations for recovery are communicated to the appropriate school officials so that necessary accommodationscan be made. If symptoms after the initial office visit are mild, a one-week return to school is appropriate to evaluate the patient’s recovery.

Allowing a return to sports. Once the patient is asymptomatic, and physical and cognitive test results are normal, discuss a return-to-play protocol with the patient (and with parents and athletic trainer or coach, as appropriate). Multiple sources^10,11,26 now recommend a stepwise return to play, as detailed by the 3rd ICCS ( TABLE 2 ).¹² Increase or decrease the length of the protocol depending on the patient and the specifics of the case.

There is little science to guide the treatment of children with concussion. However, given that their brains are still developing, it’s prudent to be more conservative than with older adolescents or adults. Multiple sources apart from the 3rd ICCS agree with this recommendation. Several authors suggest more cognitive rest and a longer return-to-play protocol in all cases.^10,27 In fact, the ICCS committee additionally recommends observing a symptom-free waiting period for pediatric athletes before even starting a return-to-play protocol.

McCrory et al²⁶ suggest that children under age 15 be treated more conservatively than those 15 and older. They suggest treating those 15 and older with the protocol for older adolescents. Specifying an age at which one should always make a decision for or against conservative care can be problematic. However, based on the recommendations above, it would seem reasonable to provide conservative treatment for children younger than high school age and perhaps even those in the early years of high school.

Consider legal implications. Become familiar with state laws that require certain steps in managing sports concussion. The Web site http://www.sportsconcussions.org/laws.html²⁸ lists states with sports concussion statutes, as well as states with bills working their way through the legislative system. Currently, 29 states are listed with laws; 14 more and the District of Columbia have pending legislation.

TABLE 2
Stepwise protocol for return to play

Anticipate complications
Most patients with concussions who are managed appropriately do well. However, complications can occur. The most serious complication is second impact syndrome, which usually occurs when concussion is unrecognized or not well managed. While not well understood, this condition is thought to result from a sudden increase in intracranial pressure after a second head injury in an athlete already suffering from concussion symptoms. The injury typically results in serious long-term neurologic deficits, or even fatality.²⁹ Second impact syndrome has been documented as occurring in the same game after an initial injury, as well as in subsequent games.²⁹

A more common, but less serious, complication is postconcussion syndrome.³⁰ This is an ill-defined condition in which the patient suffers from concussive symptoms for an extended period of time, generally for more than 3 months.³⁰ As with acute concussion, the constellation of symptoms ranges from headache to cognitive impairment. In cases of postconcussion syndrome, it is appropriate to consult with neuropsychologists, psychiatrists, or neurologists for assistance with symptoms and associated mood disorders. Similar to acute concussion management, it is generally recommended that athletes not be cleared to resume play while struggling with the symptoms of postconcussion syndrome.³⁰

There have also been recent reports of late-life sequelae in those who have sustained multiple concussions. Depression and dementia have been suggested in surveys of retired NFL players.^31,32 There have also been studies both suggesting¹⁴ and questioning^33,34 whether multiple concussions result in long-term cognitive deficits. While the evidence available at this time is not firm, there seems to be an increasing belief that multiple concussions can affect long-term cognitive abilities. For these reasons, use caution in making return-to-play decisions for patients with multiple concussions or concussions with long-lasting symptoms.

CORRESPONDENCE Aaron M. Lear, MD, 224 West Exchange Street, Suite 440, Akron, OH 44302; [email protected]