Total knee arthroplasty (TKA) is a good surgical option to relieve pain and improve function in patients with osteoarthritis. The goal of surgery is to achieve a well-aligned prosthesis with well-balanced ligaments in order to minimize wear and improve implant survival. Overall, 82% to 89% of patients are satisfied with their outcomes after TKA, with good 10- to 15-year implant survivorship; however, there is still a subset of patients that are unsatisfied. In many cases, patient dissatisfaction is attributed to improper component alignment.^1-3 Over the past decade, computer navigation and robotics have been introduced to control surgical variables so as to gain greater consistency in implant placement and postoperative component alignment.

Computer-assisted navigation tools were introduced not only to improve implant alignment but, more importantly, to optimize clinical outcomes. Most studies have demonstrated that the use of navigation is associated with fewer radiographic outliers after TKA.⁴ Various studies have compared radiographic results of navigated TKA with results of TKA using standard instrumentation.^4-7 While long-term studies are necessary, short-term follow-up has shown that computer-assisted TKA can improve alignment, especially in patients with severe deformity.^8-10 Currently, there is no definitive consensus that computer-assisted TKA leads to significantly better component alignment or postoperative outcomes due to the fact that many studies are limited by study design or small cohorts. However, the currently published articles support better component alignment and clinical outcomes with computer-assisted TKA. While some argue that the use of computer-assisted surgery is dependent on the user’s experience, computer-assisted surgery can assist less-experienced surgeons to reliably achieve good midterm outcomes with a low complication rate.^8,11 Various studies have looked at computer-assisted TKA at midterm follow-up, with no significant differences in clinical outcome between navigated and traditional techniques. However, long-term studies showing the benefits of computer navigation are beginning to emerge. For example, de Steiger and colleagues¹² recently found that computer-assisted TKA reduced the overall revision rate for loosening after TKA in patients less than 65 years of age.

While surgical navigation helps improve implant planning, robotic tools have emerged as a tool to help refine surgical execution. Coupled with surgical navigation tools, robotic control of surgical gestures may further enhance precision in implant placement and/or enable novel implant design features. At present, robotic techniques are increasingly used in unicompartmental knee arthroplasty (UKA) and TKA.¹³ Studies have demonstrated that the robotic tool is 3 times more accurate with 3 times less variability than conventional techniques in UKA.¹⁴ The utility of robotic tools for TKA remains unclear. Robotic-driven automatic cutting guides have been shown to reduce time and improve accuracy compared with navigation guides in femoral TKA cutting procedures in a cadaveric model.¹⁵ However, robotic-enabled TKA procedures are poorly described at present, and the clinical implications of their proposed improved precision remain unclear.

Computer navigation and robotic tools in TKA hold the promise of enhanced control of surgical variables that influence clinical outcome. The variables that may be impacted by these advanced tools include implant positioning, lower limb alignment, soft-tissue balance, and, potentially, implant design and fixation. At present, these tools have primarily been shown to improve lower limb alignment in TKA. The clinical impact of the enhanced control of this single surgical variable (lower limb alignment) has been muted in short-term and midterm studies. Future studies should be directed at understanding which surgical variable, or combination of variables, it is most essential to precisely control so as to positively impact clinical outcomes. ◾

Total knee arthroplasty (TKA) is a good surgical option to relieve pain and improve function in patients with osteoarthritis. The goal of surgery is to achieve a well-aligned prosthesis with well-balanced ligaments in order to minimize wear and improve implant survival. Overall, 82% to 89% of patients are satisfied with their outcomes after TKA, with good 10- to 15-year implant survivorship; however, there is still a subset of patients that are unsatisfied. In many cases, patient dissatisfaction is attributed to improper component alignment.^1-3 Over the past decade, computer navigation and robotics have been introduced to control surgical variables so as to gain greater consistency in implant placement and postoperative component alignment.

Computer-assisted navigation tools were introduced not only to improve implant alignment but, more importantly, to optimize clinical outcomes. Most studies have demonstrated that the use of navigation is associated with fewer radiographic outliers after TKA.⁴ Various studies have compared radiographic results of navigated TKA with results of TKA using standard instrumentation.^4-7 While long-term studies are necessary, short-term follow-up has shown that computer-assisted TKA can improve alignment, especially in patients with severe deformity.^8-10 Currently, there is no definitive consensus that computer-assisted TKA leads to significantly better component alignment or postoperative outcomes due to the fact that many studies are limited by study design or small cohorts. However, the currently published articles support better component alignment and clinical outcomes with computer-assisted TKA. While some argue that the use of computer-assisted surgery is dependent on the user’s experience, computer-assisted surgery can assist less-experienced surgeons to reliably achieve good midterm outcomes with a low complication rate.^8,11 Various studies have looked at computer-assisted TKA at midterm follow-up, with no significant differences in clinical outcome between navigated and traditional techniques. However, long-term studies showing the benefits of computer navigation are beginning to emerge. For example, de Steiger and colleagues¹² recently found that computer-assisted TKA reduced the overall revision rate for loosening after TKA in patients less than 65 years of age.

While surgical navigation helps improve implant planning, robotic tools have emerged as a tool to help refine surgical execution. Coupled with surgical navigation tools, robotic control of surgical gestures may further enhance precision in implant placement and/or enable novel implant design features. At present, robotic techniques are increasingly used in unicompartmental knee arthroplasty (UKA) and TKA.¹³ Studies have demonstrated that the robotic tool is 3 times more accurate with 3 times less variability than conventional techniques in UKA.¹⁴ The utility of robotic tools for TKA remains unclear. Robotic-driven automatic cutting guides have been shown to reduce time and improve accuracy compared with navigation guides in femoral TKA cutting procedures in a cadaveric model.¹⁵ However, robotic-enabled TKA procedures are poorly described at present, and the clinical implications of their proposed improved precision remain unclear.

Computer navigation and robotic tools in TKA hold the promise of enhanced control of surgical variables that influence clinical outcome. The variables that may be impacted by these advanced tools include implant positioning, lower limb alignment, soft-tissue balance, and, potentially, implant design and fixation. At present, these tools have primarily been shown to improve lower limb alignment in TKA. The clinical impact of the enhanced control of this single surgical variable (lower limb alignment) has been muted in short-term and midterm studies. Future studies should be directed at understanding which surgical variable, or combination of variables, it is most essential to precisely control so as to positively impact clinical outcomes. ◾

Total knee arthroplasty (TKA) is a good surgical option to relieve pain and improve function in patients with osteoarthritis. The goal of surgery is to achieve a well-aligned prosthesis with well-balanced ligaments in order to minimize wear and improve implant survival. Overall, 82% to 89% of patients are satisfied with their outcomes after TKA, with good 10- to 15-year implant survivorship; however, there is still a subset of patients that are unsatisfied. In many cases, patient dissatisfaction is attributed to improper component alignment.^1-3 Over the past decade, computer navigation and robotics have been introduced to control surgical variables so as to gain greater consistency in implant placement and postoperative component alignment.

Computer-assisted navigation tools were introduced not only to improve implant alignment but, more importantly, to optimize clinical outcomes. Most studies have demonstrated that the use of navigation is associated with fewer radiographic outliers after TKA.⁴ Various studies have compared radiographic results of navigated TKA with results of TKA using standard instrumentation.^4-7 While long-term studies are necessary, short-term follow-up has shown that computer-assisted TKA can improve alignment, especially in patients with severe deformity.^8-10 Currently, there is no definitive consensus that computer-assisted TKA leads to significantly better component alignment or postoperative outcomes due to the fact that many studies are limited by study design or small cohorts. However, the currently published articles support better component alignment and clinical outcomes with computer-assisted TKA. While some argue that the use of computer-assisted surgery is dependent on the user’s experience, computer-assisted surgery can assist less-experienced surgeons to reliably achieve good midterm outcomes with a low complication rate.^8,11 Various studies have looked at computer-assisted TKA at midterm follow-up, with no significant differences in clinical outcome between navigated and traditional techniques. However, long-term studies showing the benefits of computer navigation are beginning to emerge. For example, de Steiger and colleagues¹² recently found that computer-assisted TKA reduced the overall revision rate for loosening after TKA in patients less than 65 years of age.

While surgical navigation helps improve implant planning, robotic tools have emerged as a tool to help refine surgical execution. Coupled with surgical navigation tools, robotic control of surgical gestures may further enhance precision in implant placement and/or enable novel implant design features. At present, robotic techniques are increasingly used in unicompartmental knee arthroplasty (UKA) and TKA.¹³ Studies have demonstrated that the robotic tool is 3 times more accurate with 3 times less variability than conventional techniques in UKA.¹⁴ The utility of robotic tools for TKA remains unclear. Robotic-driven automatic cutting guides have been shown to reduce time and improve accuracy compared with navigation guides in femoral TKA cutting procedures in a cadaveric model.¹⁵ However, robotic-enabled TKA procedures are poorly described at present, and the clinical implications of their proposed improved precision remain unclear.

Computer navigation and robotic tools in TKA hold the promise of enhanced control of surgical variables that influence clinical outcome. The variables that may be impacted by these advanced tools include implant positioning, lower limb alignment, soft-tissue balance, and, potentially, implant design and fixation. At present, these tools have primarily been shown to improve lower limb alignment in TKA. The clinical impact of the enhanced control of this single surgical variable (lower limb alignment) has been muted in short-term and midterm studies. Future studies should be directed at understanding which surgical variable, or combination of variables, it is most essential to precisely control so as to positively impact clinical outcomes. ◾

WASHINGTON – Early resumption of antiplatelet agents or anticoagulants after a major gastrointestinal bleeding event is clearly associated with an increased risk of rebleeding, but a decreased risk of death, results from an observational study show.

Furthermore, anticoagulant treatment “is associated with a higher risk of rebleeding and death compared with antiplatelet treatment after a previous GI event,” Dr. Angel Lanas said to an overflow crowd at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

In a separate case-control study, Dr. Lanas and his associates recently reported that the risk of GI bleeding was twofold higher for anticoagulants than for low-dose aspirin in patients hospitalized for GI bleeding (Clin. Gastroenterol. Hepatol. 2015 May;13:906-12.e2. [doi:10.1016/j.cgh.2014.11.007])

The current study examined adverse events in a cohort of 160 patients who developed a major gastrointestinal bleed (GIB) while using anticoagulants and/or antiplatelet therapy between March 2008 and July 2013. Long-term interruption or short-term resumption of these treatments has important clinical implications and differences in the intrinsic risks between antiplatelet or anticoagulant users after drug resumption are not well established, said Dr. Lanas of the University of Zaragoza, Spain.

Drug use information was prospectively collected during the GIB event, with data during the follow-up period obtained from two different Spanish databases.

Treatment during the index bleeding event was continued without interruption in 11 patients and interrupted in 149 patients (93%). Among those whose therapy was interrupted, 21 (14%) never resumed therapy and 128 (86%) resumed therapy (118 patients within 15 days and 10 patients after 15 days). The 86% treatment resumption rate is much higher than the 40%-66% rates reported in previous studies, indicating that Spanish physicians restarted treatment quite early, Dr. Lanas observed.

Patrice Wendling/Frontline Medical News

The mean age at baseline was 76.6 years, 61.3% of patients were men, and half had a Charlson index score > 4. Median follow-up was 21.5 months (range 1-63 months).

Ischemic events did not differ between patients who did or did not restart anticoagulants or antiplatelets (16.4% vs. 14.3%; P value = .806). However, rebleeding occurred in 32% of patients who resumed therapy versus none who did not (P = .002), but deaths were higher in those who did not restart therapy (38.1% vs. 12.5%; P = .003), Dr. Lanas said.

These differences remain significant in Kaplan-Meier survival curves for death (P = .021) and rebleeding (P = .004).

A comparison of early therapy resumption (≤ 15 days) vs. delayed (mean delay 62 days) or no resumption revealed similar results. Early resumption was associated with a higher rate of rebleeding (32.2% vs. 9.7%; P = .012), but a lower rate of death (11% vs. 35.5%; P = .001), with no difference in ischemic events (17% vs. 13%; P = .586), Dr. Lanas said.

Again, the differences remain significant in Kaplan-Meier survival curves for death (P = .011) and rebleeding (P = .013).

When the investigators looked at rebleeding according to drug use, patients receiving anticoagulants vs. antiplatelets had significantly higher rates of rebleeding (34.7% vs. 20.5%; P = .043), death (22.2% vs. 10.2%; P = .038), and any event (68.1% vs. 52.3%; P = .043).

After adjustment for gender, age, Charlson index, diabetes, and arterial hypertension, the risk of rebleeding was more than threefold higher for dual antiplatelet and anticoagulant users than for antiplatelet-alone users (odds ratio, 3.45; P = .025) and was twofold higher for anticoagulant vs. antiplatelet users (OR, 2.07; P = .045), Dr. Lanas said.

Finally, an analysis of the cause of bleeding suggests the cause of rebleeding may be different from the original event and that there is a shift toward the lower GI tract, he added.

The index bleeding event was caused largely by an upper GI peptic ulcer in 48% of all 160 patients, with 43.7% of events due to lower GI diverticulosis, vascular lesions, ischemic, or other lesions. In contrast, peptic ulcers accounted for only 7% of rebleeding events, while lower GI events accounted for 72%. Proton pump inhibition use was evenly distributed in upper and lower GI bleeding, although effective endoscopic treatment may have influenced upper GI bleeds, Dr. Lanas said.

“The importance of this is that we may have very good therapy tools for the upper GI, but still we have problems controlling the bleeding from the lower GI,” he added.

During a discussion of the study, an audience member asked how many days clinicians should wait to restart anticoagulants or antiplatelets.

“In those patients with peptic ulcer bleeding, it’s better to just give the antiplatelet therapy soon after the bleeding event or just to not interrupt the aspirin because the morality at 30 days was higher in those who were interrupted,” Dr. Lanas advised. “...I think for the cutoff point to show differences for patients with a worse outcome versus those with a better outcome, you shouldn’t restart anticoagulant therapy before day 15 after the bleeding event.”

Dr. Lanas received consulting fees, speaking and teaching fees, other financial support, and grant and research support from Bayer.

[email protected]

On Twitter @pwendl

WASHINGTON – Early resumption of antiplatelet agents or anticoagulants after a major gastrointestinal bleeding event is clearly associated with an increased risk of rebleeding, but a decreased risk of death, results from an observational study show.

Furthermore, anticoagulant treatment “is associated with a higher risk of rebleeding and death compared with antiplatelet treatment after a previous GI event,” Dr. Angel Lanas said to an overflow crowd at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

In a separate case-control study, Dr. Lanas and his associates recently reported that the risk of GI bleeding was twofold higher for anticoagulants than for low-dose aspirin in patients hospitalized for GI bleeding (Clin. Gastroenterol. Hepatol. 2015 May;13:906-12.e2. [doi:10.1016/j.cgh.2014.11.007])

The current study examined adverse events in a cohort of 160 patients who developed a major gastrointestinal bleed (GIB) while using anticoagulants and/or antiplatelet therapy between March 2008 and July 2013. Long-term interruption or short-term resumption of these treatments has important clinical implications and differences in the intrinsic risks between antiplatelet or anticoagulant users after drug resumption are not well established, said Dr. Lanas of the University of Zaragoza, Spain.

Drug use information was prospectively collected during the GIB event, with data during the follow-up period obtained from two different Spanish databases.

Treatment during the index bleeding event was continued without interruption in 11 patients and interrupted in 149 patients (93%). Among those whose therapy was interrupted, 21 (14%) never resumed therapy and 128 (86%) resumed therapy (118 patients within 15 days and 10 patients after 15 days). The 86% treatment resumption rate is much higher than the 40%-66% rates reported in previous studies, indicating that Spanish physicians restarted treatment quite early, Dr. Lanas observed.

Patrice Wendling/Frontline Medical News

The mean age at baseline was 76.6 years, 61.3% of patients were men, and half had a Charlson index score > 4. Median follow-up was 21.5 months (range 1-63 months).

Ischemic events did not differ between patients who did or did not restart anticoagulants or antiplatelets (16.4% vs. 14.3%; P value = .806). However, rebleeding occurred in 32% of patients who resumed therapy versus none who did not (P = .002), but deaths were higher in those who did not restart therapy (38.1% vs. 12.5%; P = .003), Dr. Lanas said.

These differences remain significant in Kaplan-Meier survival curves for death (P = .021) and rebleeding (P = .004).

A comparison of early therapy resumption (≤ 15 days) vs. delayed (mean delay 62 days) or no resumption revealed similar results. Early resumption was associated with a higher rate of rebleeding (32.2% vs. 9.7%; P = .012), but a lower rate of death (11% vs. 35.5%; P = .001), with no difference in ischemic events (17% vs. 13%; P = .586), Dr. Lanas said.

Again, the differences remain significant in Kaplan-Meier survival curves for death (P = .011) and rebleeding (P = .013).

When the investigators looked at rebleeding according to drug use, patients receiving anticoagulants vs. antiplatelets had significantly higher rates of rebleeding (34.7% vs. 20.5%; P = .043), death (22.2% vs. 10.2%; P = .038), and any event (68.1% vs. 52.3%; P = .043).

After adjustment for gender, age, Charlson index, diabetes, and arterial hypertension, the risk of rebleeding was more than threefold higher for dual antiplatelet and anticoagulant users than for antiplatelet-alone users (odds ratio, 3.45; P = .025) and was twofold higher for anticoagulant vs. antiplatelet users (OR, 2.07; P = .045), Dr. Lanas said.

Finally, an analysis of the cause of bleeding suggests the cause of rebleeding may be different from the original event and that there is a shift toward the lower GI tract, he added.

The index bleeding event was caused largely by an upper GI peptic ulcer in 48% of all 160 patients, with 43.7% of events due to lower GI diverticulosis, vascular lesions, ischemic, or other lesions. In contrast, peptic ulcers accounted for only 7% of rebleeding events, while lower GI events accounted for 72%. Proton pump inhibition use was evenly distributed in upper and lower GI bleeding, although effective endoscopic treatment may have influenced upper GI bleeds, Dr. Lanas said.

“The importance of this is that we may have very good therapy tools for the upper GI, but still we have problems controlling the bleeding from the lower GI,” he added.

During a discussion of the study, an audience member asked how many days clinicians should wait to restart anticoagulants or antiplatelets.

“In those patients with peptic ulcer bleeding, it’s better to just give the antiplatelet therapy soon after the bleeding event or just to not interrupt the aspirin because the morality at 30 days was higher in those who were interrupted,” Dr. Lanas advised. “...I think for the cutoff point to show differences for patients with a worse outcome versus those with a better outcome, you shouldn’t restart anticoagulant therapy before day 15 after the bleeding event.”

Dr. Lanas received consulting fees, speaking and teaching fees, other financial support, and grant and research support from Bayer.

[email protected]

On Twitter @pwendl

WASHINGTON – Early resumption of antiplatelet agents or anticoagulants after a major gastrointestinal bleeding event is clearly associated with an increased risk of rebleeding, but a decreased risk of death, results from an observational study show.

Furthermore, anticoagulant treatment “is associated with a higher risk of rebleeding and death compared with antiplatelet treatment after a previous GI event,” Dr. Angel Lanas said to an overflow crowd at the annual Digestive Disease Week.

Patrice Wendling/Frontline Medical News

In a separate case-control study, Dr. Lanas and his associates recently reported that the risk of GI bleeding was twofold higher for anticoagulants than for low-dose aspirin in patients hospitalized for GI bleeding (Clin. Gastroenterol. Hepatol. 2015 May;13:906-12.e2. [doi:10.1016/j.cgh.2014.11.007])

The current study examined adverse events in a cohort of 160 patients who developed a major gastrointestinal bleed (GIB) while using anticoagulants and/or antiplatelet therapy between March 2008 and July 2013. Long-term interruption or short-term resumption of these treatments has important clinical implications and differences in the intrinsic risks between antiplatelet or anticoagulant users after drug resumption are not well established, said Dr. Lanas of the University of Zaragoza, Spain.

Drug use information was prospectively collected during the GIB event, with data during the follow-up period obtained from two different Spanish databases.

Treatment during the index bleeding event was continued without interruption in 11 patients and interrupted in 149 patients (93%). Among those whose therapy was interrupted, 21 (14%) never resumed therapy and 128 (86%) resumed therapy (118 patients within 15 days and 10 patients after 15 days). The 86% treatment resumption rate is much higher than the 40%-66% rates reported in previous studies, indicating that Spanish physicians restarted treatment quite early, Dr. Lanas observed.

Patrice Wendling/Frontline Medical News

The mean age at baseline was 76.6 years, 61.3% of patients were men, and half had a Charlson index score > 4. Median follow-up was 21.5 months (range 1-63 months).

Ischemic events did not differ between patients who did or did not restart anticoagulants or antiplatelets (16.4% vs. 14.3%; P value = .806). However, rebleeding occurred in 32% of patients who resumed therapy versus none who did not (P = .002), but deaths were higher in those who did not restart therapy (38.1% vs. 12.5%; P = .003), Dr. Lanas said.

These differences remain significant in Kaplan-Meier survival curves for death (P = .021) and rebleeding (P = .004).

A comparison of early therapy resumption (≤ 15 days) vs. delayed (mean delay 62 days) or no resumption revealed similar results. Early resumption was associated with a higher rate of rebleeding (32.2% vs. 9.7%; P = .012), but a lower rate of death (11% vs. 35.5%; P = .001), with no difference in ischemic events (17% vs. 13%; P = .586), Dr. Lanas said.

Again, the differences remain significant in Kaplan-Meier survival curves for death (P = .011) and rebleeding (P = .013).

When the investigators looked at rebleeding according to drug use, patients receiving anticoagulants vs. antiplatelets had significantly higher rates of rebleeding (34.7% vs. 20.5%; P = .043), death (22.2% vs. 10.2%; P = .038), and any event (68.1% vs. 52.3%; P = .043).

After adjustment for gender, age, Charlson index, diabetes, and arterial hypertension, the risk of rebleeding was more than threefold higher for dual antiplatelet and anticoagulant users than for antiplatelet-alone users (odds ratio, 3.45; P = .025) and was twofold higher for anticoagulant vs. antiplatelet users (OR, 2.07; P = .045), Dr. Lanas said.

Finally, an analysis of the cause of bleeding suggests the cause of rebleeding may be different from the original event and that there is a shift toward the lower GI tract, he added.

The index bleeding event was caused largely by an upper GI peptic ulcer in 48% of all 160 patients, with 43.7% of events due to lower GI diverticulosis, vascular lesions, ischemic, or other lesions. In contrast, peptic ulcers accounted for only 7% of rebleeding events, while lower GI events accounted for 72%. Proton pump inhibition use was evenly distributed in upper and lower GI bleeding, although effective endoscopic treatment may have influenced upper GI bleeds, Dr. Lanas said.

“The importance of this is that we may have very good therapy tools for the upper GI, but still we have problems controlling the bleeding from the lower GI,” he added.

During a discussion of the study, an audience member asked how many days clinicians should wait to restart anticoagulants or antiplatelets.

“In those patients with peptic ulcer bleeding, it’s better to just give the antiplatelet therapy soon after the bleeding event or just to not interrupt the aspirin because the morality at 30 days was higher in those who were interrupted,” Dr. Lanas advised. “...I think for the cutoff point to show differences for patients with a worse outcome versus those with a better outcome, you shouldn’t restart anticoagulant therapy before day 15 after the bleeding event.”

Dr. Lanas received consulting fees, speaking and teaching fees, other financial support, and grant and research support from Bayer.

[email protected]

On Twitter @pwendl

CASE Feeling hopeless
Dr. D, age 33, a white, male physician, presents with worsening depression, suicidal ideation, and somatic complaints. Dr. D says his per­sonal life has become increasingly unhappy. He describes the pressures of a busy practice and conflict with his wife about his availabil­ity to her. He is feeling financial pressure and general disappointment about practicing medicine. Lack of recreational activities and close friends and absent spiritual life has led to feelings of isolation and depression.

Dr. D reports difficulty falling asleep, wak­ing up early, and feeling fatigued. He describes obsessive, negative thoughts about his work and his personal life; he is anxious and tense. Dissatisfied and exhausted, he says he feels hopeless and empty and has become preoc­cupied with thoughts of death.

Dr. D describes musculoskeletal tension in the neck, shoulders, and face, with pain in the back of the neck. When the depressive symp­toms or pain are particularly severe, he admits that his attention to critical information lapses. When interacting with his patients, he has missed important nuances about medica­tion side effects, for example, frustrating his patients and himself.

Dr. D and his wife do not have children. His mother and paternal grandfather had depres­sion, but Dr. D has no family history of suicide or drug or alcohol abuse. He has no signifi­cant medical conditions, and is not taking any medications. Dr. D drinks 1 or 2 cups of caf­feinated coffee a day. He does not smoke, use recreational drugs, or drink alcohol regularly.

What would be your next step in treating Dr. D?
   a) alert the state medical board about his suicidal ideation
   b) recommend inpatient treatment
   c) refer Dr. D to a clinician who has experi­ence treating physicians
   d) formulate a suicide risk assessment

The authors’ observation
Assessment of the suicidal physician is complex. It requires patience and ability to understand the source and the extent of the physician’s desperation and suffering. Not all psychiatrists are well suited to working with patients who also are peers. An expe­rienced clinician, who has confronted the challenges of practice and treated individu­als from many professions, could be better equipped than a recent graduate. Physician− patients might not be forthcoming about the extent of their suicidal thinking, because they fear involuntary hospitalization and jeopardizing their career.¹

The evaluating clinician must be thor­ough and clear, and able to facilitate a trusting relationship. The ill physician should be encouraged to express sui­cidal ideation freely—without judgments, restrictions, or threats—to a trusted psy­chiatrist. Questions should be clear with­out possibility of misinterpretation. Ask:
   • “Do you have thoughts of death, dying, or wanting to be dead?”
   • “Do you think about suicide?”
   • “Do you feel you might act on those thoughts?”
   • “What keeps you safe?”

Physicians and other health profes­sional have a higher relative risk of sui­cide (Table 1).2 Hospitalization should be considered and the decision based on the severity of the illness and the associ­ated risk. Dr. D has several risk factors for suicide, including marital discord, pain, professional demands, and access to lethal means (Table 2).1,3,4

Dr. D’s depressive symptoms became worse when he discovered his wife was hav­ing an affair. The depression became so debili­tating that he requested, and was granted, an 8-week medical leave. Once away from the daily pressures of work, his depression improved somewhat, but conflict with his wife intensified and thoughts of suicide became more frequent. Soon afterward, Dr. D and his wife separated and he moved out. His supervi­sor recommended that Dr. D obtain treatment, but it was only after the separation that Dr. D decided to seek psychiatric care.

What type of psychotherapy is recommended for physicians with suicidal ideation?
   a) psychodynamic psychotherapy
   b) person-centered therapy
   c) cognitive-behavioral therapy (CBT)
   d) dialectical behavior therapy (DBT)

The authors’ observation
Reassure your physician−patients that it is safe and reasonable to take personal time off from work to recover from any ill­ness, whether physical or mental. Consider the best treatment approaches to ensure patient’s safety, comfort, and rapid recov­ery. A critical part of treatment is exploring and identifying changes needed to achieve a life that is compatible with the ideal self, the patient’s view of himself, his beliefs, goals, and life’s meaning.

Physicians are at particular risk of losing the ideal self.⁵ Loss of the ideal self is com­mon, and can be life threatening. Person-centered psychotherapy, CBT, supportive psychotherapy, DBT, and pharmacotherapy are used to lessen emotional distress and promote adaptive coping strategies, but approaches are different. Short-term coun­seling can reduce the effects of job stress,⁶ but a longer-term intervention likely is nec­essary for a mood disorder with thoughts of self-harm.

CBT emphasizes helping physicians rec­ognize cognitive distortions and finding solutions. The behavioral aspects of CBT pro­mote physical and mental relaxation, which is helpful in easing muscle tension, lowering heart rate, and decreasing the tendency to hyperventilate during stress.⁷ Mindfulness-based stress reduction programs can provide physical and mental benefits.⁸ DBT, a type of behavioral therapy, combines mindfulness, acceptance of the current state, skills to regu­late emotion, and positive interpersonal rela­tionship strategies.⁹

Pharmacotherapy should be focused on improving sleep, anxiety, appetite, and mood. Your patient may have other symp­toms that need to be addressed: Ask what symptom bothers your patient the most, then work to provide solutions. Some interventions could promote adaptive cop­ing strategies to identify ways to increase perceived control over the work day.¹⁰

TREATMENT Self-exploration
The treatment team instructs Dr. D to take a personal inventory of the elements of his ideal self, along the lines suggested in person-centered therapy.^11,12 How did Dr. D envision his practice when he was in residency? What other domains of life were important to him? When Dr. D comes back with his list, the need for change is discussed and the process for incorporating these elements into his life begins. He begins to realize that returning to the elements of his ideal self brought oppor­tunities, friendship, love, and faith back into his life.^13,14

Maintaining balance between work respon­sibilities and pleasurable activities is part of achieving the ideal self. Recreation, social sup­port, and exercise decrease the experience of stress and promote wellness.^15,16

An important discussion centers on Dr. D’s risk of losing meaning in life after distancing himself from his original motivation to help people though practicing medicine. Dr. D understands that the distance between his expectations and dreams as a student and his current reality contributed to his depression.¹⁷ These conversations and changes in behavior brings Dr. D’s actual life closer to this ideal self, reducing self-discrepancy and lessening neg­ative mood.¹⁸

The treating psychiatrist is aware of the reporting requirements to the state medi­cal board, which are discussed with Dr. D. No report is deemed necessary.

The authors’ observation
Dr. D’s treatment course was challenging and required a multi-component approach. Establishing trust, while defining the limits of confidentiality, formed the foundation for the therapeutic relationship. The treatment provider asked for names of colleagues or friends to be contacted in case of an emer­gency. Dr. D chose his physician supervisor and agreed that the psychiatrist could con­tact the supervisor and vice versa.

Medication was prescribed at the end of the first session to begin to address anxiety and sleep problems. The initial medication was fluvoxamine, 50 mg/d, for anxiety and depression, clonazepam, 0.5 mg/d for anxiety, and zolpidem, 10 mg/d, for sleep. Adjustments were made in the dosage of antidepressant and responses monitored closely until the therapeutic dosage was reached with minimal side effects. Sleep improved, irritability lessened, and Dr. D’s obsessive, negative thinking and depres­sion improved. Deeper, restorative sleep also began to reduce physical tension and pain. Improved sleep and decreased mea­sures of depression are associated with sig­nificantly reduced risk of suicide.¹⁹

A treating psychiatrist should be aware of the state medical board requirements. In Ohio, where this case unfolded, reporting is required when the physician−patient is deemed unable to practice medicine according to acceptable and prevailing standards of care.²⁰

Relieving tension and somatic complaints
An important part of the treatment plan consisted of managing chronic muscle ten­sion and pain. We decided to front-load treatment, addressing the severe depres­sion, anxiety, and pain simultaneously. Even moderate pain relief would give Dr. D a greater sense of control and improve his mood.

Dr. D understood that a return to nor­mal biorhythms was necessary to form the foundation for the next step of therapy.²¹ The treatment team introduced mindful breathing, but Dr. D questioned how some­thing so simple could lift severe depres­sion. Focused, mindful breathing was not a cure, but a first step in regaining control over the current disarray of physical and emotional variations. We encouraged daily practice and he agreed to 5 practice ses­sions per week.

Next, the treatment team introduced progressive relaxation. Again, the simplic­ity of this process of tensing and relaxing groups of muscles was met with disbe­lief. Our therapist explained that volun­tarily producing muscle tension facilitates the relaxation response of both the mind and the body. The mind first commands the muscles to do what it does easily— “tense”; then is asked to elicit what is more difficult—“relax.” Repetition of the simple commands “tense—relax” in the arms, legs, back, abdomen, shoulders, neck, and face establishes a calming rhythm, again increasing the sense of control.22 We strongly encouraged daily practice of this exercise and Dr. D committed to the mind­ful breathing and relaxation exercise.

OUTCOME Recovery, maintenance
Dr. D and his psychotherapist address his anger, all-or-nothing thinking, and loneliness. Grief over his failed marriage was identified, giving them an opportunity to explore this loss and past, perceived losses of his parents’  affection in the context of the therapeutic relationship. Supportive therapy promoted ways to fulfill his ideal self.

Treatment lasted 2 years. Dr. D’s prior depressive episode indicates a need for maintenance medication. The antidepres­sant is continued and, with help from sup­portive psychotherapy, stress management, 8 weeks away from work, and the life changes mentioned above, our patient has not had a relapse.

Bottom Line
Depression and thoughts of suicide are common among physicians. Grant time off from work and reassure the physician that he (she) is entitled to seek medical treatment without repercussions. Adapt the type of psychotherapy to the physician’s specific concerns. Because physicians are at particular risk for loss of the ideal self, first consider person-centered therapy.

Related Resources
• Vanderbilt Center for Professional Health. www.mc.vanderbilt.edu/cph.
• Federation of State Physician Health Programs, Inc. www.fsphp.org.

Drug Brand Names
Clonazepam • Klonopin       Fluvoxamine • Luvox      Zolpidem • Ambien

AcknowledgementThe authors wish to acknowledge the contribution of Rachel Sieke, BS, Research Assistant, Department of Psychiatry, University of Toledo Medical Center, Toledo, Ohio.

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

CASE Feeling hopeless
Dr. D, age 33, a white, male physician, presents with worsening depression, suicidal ideation, and somatic complaints. Dr. D says his per­sonal life has become increasingly unhappy. He describes the pressures of a busy practice and conflict with his wife about his availabil­ity to her. He is feeling financial pressure and general disappointment about practicing medicine. Lack of recreational activities and close friends and absent spiritual life has led to feelings of isolation and depression.

Dr. D reports difficulty falling asleep, wak­ing up early, and feeling fatigued. He describes obsessive, negative thoughts about his work and his personal life; he is anxious and tense. Dissatisfied and exhausted, he says he feels hopeless and empty and has become preoc­cupied with thoughts of death.

Dr. D describes musculoskeletal tension in the neck, shoulders, and face, with pain in the back of the neck. When the depressive symp­toms or pain are particularly severe, he admits that his attention to critical information lapses. When interacting with his patients, he has missed important nuances about medica­tion side effects, for example, frustrating his patients and himself.

Dr. D and his wife do not have children. His mother and paternal grandfather had depres­sion, but Dr. D has no family history of suicide or drug or alcohol abuse. He has no signifi­cant medical conditions, and is not taking any medications. Dr. D drinks 1 or 2 cups of caf­feinated coffee a day. He does not smoke, use recreational drugs, or drink alcohol regularly.

What would be your next step in treating Dr. D?
   a) alert the state medical board about his suicidal ideation
   b) recommend inpatient treatment
   c) refer Dr. D to a clinician who has experi­ence treating physicians
   d) formulate a suicide risk assessment

The authors’ observation
Assessment of the suicidal physician is complex. It requires patience and ability to understand the source and the extent of the physician’s desperation and suffering. Not all psychiatrists are well suited to working with patients who also are peers. An expe­rienced clinician, who has confronted the challenges of practice and treated individu­als from many professions, could be better equipped than a recent graduate. Physician− patients might not be forthcoming about the extent of their suicidal thinking, because they fear involuntary hospitalization and jeopardizing their career.¹

The evaluating clinician must be thor­ough and clear, and able to facilitate a trusting relationship. The ill physician should be encouraged to express sui­cidal ideation freely—without judgments, restrictions, or threats—to a trusted psy­chiatrist. Questions should be clear with­out possibility of misinterpretation. Ask:
   • “Do you have thoughts of death, dying, or wanting to be dead?”
   • “Do you think about suicide?”
   • “Do you feel you might act on those thoughts?”
   • “What keeps you safe?”

Physicians and other health profes­sional have a higher relative risk of sui­cide (Table 1).2 Hospitalization should be considered and the decision based on the severity of the illness and the associ­ated risk. Dr. D has several risk factors for suicide, including marital discord, pain, professional demands, and access to lethal means (Table 2).1,3,4

Dr. D’s depressive symptoms became worse when he discovered his wife was hav­ing an affair. The depression became so debili­tating that he requested, and was granted, an 8-week medical leave. Once away from the daily pressures of work, his depression improved somewhat, but conflict with his wife intensified and thoughts of suicide became more frequent. Soon afterward, Dr. D and his wife separated and he moved out. His supervi­sor recommended that Dr. D obtain treatment, but it was only after the separation that Dr. D decided to seek psychiatric care.

What type of psychotherapy is recommended for physicians with suicidal ideation?
   a) psychodynamic psychotherapy
   b) person-centered therapy
   c) cognitive-behavioral therapy (CBT)
   d) dialectical behavior therapy (DBT)

The authors’ observation
Reassure your physician−patients that it is safe and reasonable to take personal time off from work to recover from any ill­ness, whether physical or mental. Consider the best treatment approaches to ensure patient’s safety, comfort, and rapid recov­ery. A critical part of treatment is exploring and identifying changes needed to achieve a life that is compatible with the ideal self, the patient’s view of himself, his beliefs, goals, and life’s meaning.

Physicians are at particular risk of losing the ideal self.⁵ Loss of the ideal self is com­mon, and can be life threatening. Person-centered psychotherapy, CBT, supportive psychotherapy, DBT, and pharmacotherapy are used to lessen emotional distress and promote adaptive coping strategies, but approaches are different. Short-term coun­seling can reduce the effects of job stress,⁶ but a longer-term intervention likely is nec­essary for a mood disorder with thoughts of self-harm.

CBT emphasizes helping physicians rec­ognize cognitive distortions and finding solutions. The behavioral aspects of CBT pro­mote physical and mental relaxation, which is helpful in easing muscle tension, lowering heart rate, and decreasing the tendency to hyperventilate during stress.⁷ Mindfulness-based stress reduction programs can provide physical and mental benefits.⁸ DBT, a type of behavioral therapy, combines mindfulness, acceptance of the current state, skills to regu­late emotion, and positive interpersonal rela­tionship strategies.⁹

Pharmacotherapy should be focused on improving sleep, anxiety, appetite, and mood. Your patient may have other symp­toms that need to be addressed: Ask what symptom bothers your patient the most, then work to provide solutions. Some interventions could promote adaptive cop­ing strategies to identify ways to increase perceived control over the work day.¹⁰

TREATMENT Self-exploration
The treatment team instructs Dr. D to take a personal inventory of the elements of his ideal self, along the lines suggested in person-centered therapy.^11,12 How did Dr. D envision his practice when he was in residency? What other domains of life were important to him? When Dr. D comes back with his list, the need for change is discussed and the process for incorporating these elements into his life begins. He begins to realize that returning to the elements of his ideal self brought oppor­tunities, friendship, love, and faith back into his life.^13,14

Maintaining balance between work respon­sibilities and pleasurable activities is part of achieving the ideal self. Recreation, social sup­port, and exercise decrease the experience of stress and promote wellness.^15,16

An important discussion centers on Dr. D’s risk of losing meaning in life after distancing himself from his original motivation to help people though practicing medicine. Dr. D understands that the distance between his expectations and dreams as a student and his current reality contributed to his depression.¹⁷ These conversations and changes in behavior brings Dr. D’s actual life closer to this ideal self, reducing self-discrepancy and lessening neg­ative mood.¹⁸

The treating psychiatrist is aware of the reporting requirements to the state medi­cal board, which are discussed with Dr. D. No report is deemed necessary.

The authors’ observation
Dr. D’s treatment course was challenging and required a multi-component approach. Establishing trust, while defining the limits of confidentiality, formed the foundation for the therapeutic relationship. The treatment provider asked for names of colleagues or friends to be contacted in case of an emer­gency. Dr. D chose his physician supervisor and agreed that the psychiatrist could con­tact the supervisor and vice versa.

Medication was prescribed at the end of the first session to begin to address anxiety and sleep problems. The initial medication was fluvoxamine, 50 mg/d, for anxiety and depression, clonazepam, 0.5 mg/d for anxiety, and zolpidem, 10 mg/d, for sleep. Adjustments were made in the dosage of antidepressant and responses monitored closely until the therapeutic dosage was reached with minimal side effects. Sleep improved, irritability lessened, and Dr. D’s obsessive, negative thinking and depres­sion improved. Deeper, restorative sleep also began to reduce physical tension and pain. Improved sleep and decreased mea­sures of depression are associated with sig­nificantly reduced risk of suicide.¹⁹

A treating psychiatrist should be aware of the state medical board requirements. In Ohio, where this case unfolded, reporting is required when the physician−patient is deemed unable to practice medicine according to acceptable and prevailing standards of care.²⁰

Relieving tension and somatic complaints
An important part of the treatment plan consisted of managing chronic muscle ten­sion and pain. We decided to front-load treatment, addressing the severe depres­sion, anxiety, and pain simultaneously. Even moderate pain relief would give Dr. D a greater sense of control and improve his mood.

Dr. D understood that a return to nor­mal biorhythms was necessary to form the foundation for the next step of therapy.²¹ The treatment team introduced mindful breathing, but Dr. D questioned how some­thing so simple could lift severe depres­sion. Focused, mindful breathing was not a cure, but a first step in regaining control over the current disarray of physical and emotional variations. We encouraged daily practice and he agreed to 5 practice ses­sions per week.

Next, the treatment team introduced progressive relaxation. Again, the simplic­ity of this process of tensing and relaxing groups of muscles was met with disbe­lief. Our therapist explained that volun­tarily producing muscle tension facilitates the relaxation response of both the mind and the body. The mind first commands the muscles to do what it does easily— “tense”; then is asked to elicit what is more difficult—“relax.” Repetition of the simple commands “tense—relax” in the arms, legs, back, abdomen, shoulders, neck, and face establishes a calming rhythm, again increasing the sense of control.22 We strongly encouraged daily practice of this exercise and Dr. D committed to the mind­ful breathing and relaxation exercise.

OUTCOME Recovery, maintenance
Dr. D and his psychotherapist address his anger, all-or-nothing thinking, and loneliness. Grief over his failed marriage was identified, giving them an opportunity to explore this loss and past, perceived losses of his parents’  affection in the context of the therapeutic relationship. Supportive therapy promoted ways to fulfill his ideal self.

Treatment lasted 2 years. Dr. D’s prior depressive episode indicates a need for maintenance medication. The antidepres­sant is continued and, with help from sup­portive psychotherapy, stress management, 8 weeks away from work, and the life changes mentioned above, our patient has not had a relapse.

Bottom Line
Depression and thoughts of suicide are common among physicians. Grant time off from work and reassure the physician that he (she) is entitled to seek medical treatment without repercussions. Adapt the type of psychotherapy to the physician’s specific concerns. Because physicians are at particular risk for loss of the ideal self, first consider person-centered therapy.

Related Resources
• Vanderbilt Center for Professional Health. www.mc.vanderbilt.edu/cph.
• Federation of State Physician Health Programs, Inc. www.fsphp.org.

Drug Brand Names
Clonazepam • Klonopin       Fluvoxamine • Luvox      Zolpidem • Ambien

AcknowledgementThe authors wish to acknowledge the contribution of Rachel Sieke, BS, Research Assistant, Department of Psychiatry, University of Toledo Medical Center, Toledo, Ohio.

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

CASE Feeling hopeless
Dr. D, age 33, a white, male physician, presents with worsening depression, suicidal ideation, and somatic complaints. Dr. D says his per­sonal life has become increasingly unhappy. He describes the pressures of a busy practice and conflict with his wife about his availabil­ity to her. He is feeling financial pressure and general disappointment about practicing medicine. Lack of recreational activities and close friends and absent spiritual life has led to feelings of isolation and depression.

Dr. D reports difficulty falling asleep, wak­ing up early, and feeling fatigued. He describes obsessive, negative thoughts about his work and his personal life; he is anxious and tense. Dissatisfied and exhausted, he says he feels hopeless and empty and has become preoc­cupied with thoughts of death.

Dr. D describes musculoskeletal tension in the neck, shoulders, and face, with pain in the back of the neck. When the depressive symp­toms or pain are particularly severe, he admits that his attention to critical information lapses. When interacting with his patients, he has missed important nuances about medica­tion side effects, for example, frustrating his patients and himself.

Dr. D and his wife do not have children. His mother and paternal grandfather had depres­sion, but Dr. D has no family history of suicide or drug or alcohol abuse. He has no signifi­cant medical conditions, and is not taking any medications. Dr. D drinks 1 or 2 cups of caf­feinated coffee a day. He does not smoke, use recreational drugs, or drink alcohol regularly.

What would be your next step in treating Dr. D?
   a) alert the state medical board about his suicidal ideation
   b) recommend inpatient treatment
   c) refer Dr. D to a clinician who has experi­ence treating physicians
   d) formulate a suicide risk assessment

The authors’ observation
Assessment of the suicidal physician is complex. It requires patience and ability to understand the source and the extent of the physician’s desperation and suffering. Not all psychiatrists are well suited to working with patients who also are peers. An expe­rienced clinician, who has confronted the challenges of practice and treated individu­als from many professions, could be better equipped than a recent graduate. Physician− patients might not be forthcoming about the extent of their suicidal thinking, because they fear involuntary hospitalization and jeopardizing their career.¹

The evaluating clinician must be thor­ough and clear, and able to facilitate a trusting relationship. The ill physician should be encouraged to express sui­cidal ideation freely—without judgments, restrictions, or threats—to a trusted psy­chiatrist. Questions should be clear with­out possibility of misinterpretation. Ask:
   • “Do you have thoughts of death, dying, or wanting to be dead?”
   • “Do you think about suicide?”
   • “Do you feel you might act on those thoughts?”
   • “What keeps you safe?”

Physicians and other health profes­sional have a higher relative risk of sui­cide (Table 1).2 Hospitalization should be considered and the decision based on the severity of the illness and the associ­ated risk. Dr. D has several risk factors for suicide, including marital discord, pain, professional demands, and access to lethal means (Table 2).1,3,4

Dr. D’s depressive symptoms became worse when he discovered his wife was hav­ing an affair. The depression became so debili­tating that he requested, and was granted, an 8-week medical leave. Once away from the daily pressures of work, his depression improved somewhat, but conflict with his wife intensified and thoughts of suicide became more frequent. Soon afterward, Dr. D and his wife separated and he moved out. His supervi­sor recommended that Dr. D obtain treatment, but it was only after the separation that Dr. D decided to seek psychiatric care.

What type of psychotherapy is recommended for physicians with suicidal ideation?
   a) psychodynamic psychotherapy
   b) person-centered therapy
   c) cognitive-behavioral therapy (CBT)
   d) dialectical behavior therapy (DBT)

The authors’ observation
Reassure your physician−patients that it is safe and reasonable to take personal time off from work to recover from any ill­ness, whether physical or mental. Consider the best treatment approaches to ensure patient’s safety, comfort, and rapid recov­ery. A critical part of treatment is exploring and identifying changes needed to achieve a life that is compatible with the ideal self, the patient’s view of himself, his beliefs, goals, and life’s meaning.

Physicians are at particular risk of losing the ideal self.⁵ Loss of the ideal self is com­mon, and can be life threatening. Person-centered psychotherapy, CBT, supportive psychotherapy, DBT, and pharmacotherapy are used to lessen emotional distress and promote adaptive coping strategies, but approaches are different. Short-term coun­seling can reduce the effects of job stress,⁶ but a longer-term intervention likely is nec­essary for a mood disorder with thoughts of self-harm.

CBT emphasizes helping physicians rec­ognize cognitive distortions and finding solutions. The behavioral aspects of CBT pro­mote physical and mental relaxation, which is helpful in easing muscle tension, lowering heart rate, and decreasing the tendency to hyperventilate during stress.⁷ Mindfulness-based stress reduction programs can provide physical and mental benefits.⁸ DBT, a type of behavioral therapy, combines mindfulness, acceptance of the current state, skills to regu­late emotion, and positive interpersonal rela­tionship strategies.⁹

Pharmacotherapy should be focused on improving sleep, anxiety, appetite, and mood. Your patient may have other symp­toms that need to be addressed: Ask what symptom bothers your patient the most, then work to provide solutions. Some interventions could promote adaptive cop­ing strategies to identify ways to increase perceived control over the work day.¹⁰

TREATMENT Self-exploration
The treatment team instructs Dr. D to take a personal inventory of the elements of his ideal self, along the lines suggested in person-centered therapy.^11,12 How did Dr. D envision his practice when he was in residency? What other domains of life were important to him? When Dr. D comes back with his list, the need for change is discussed and the process for incorporating these elements into his life begins. He begins to realize that returning to the elements of his ideal self brought oppor­tunities, friendship, love, and faith back into his life.^13,14

Maintaining balance between work respon­sibilities and pleasurable activities is part of achieving the ideal self. Recreation, social sup­port, and exercise decrease the experience of stress and promote wellness.^15,16

An important discussion centers on Dr. D’s risk of losing meaning in life after distancing himself from his original motivation to help people though practicing medicine. Dr. D understands that the distance between his expectations and dreams as a student and his current reality contributed to his depression.¹⁷ These conversations and changes in behavior brings Dr. D’s actual life closer to this ideal self, reducing self-discrepancy and lessening neg­ative mood.¹⁸

The treating psychiatrist is aware of the reporting requirements to the state medi­cal board, which are discussed with Dr. D. No report is deemed necessary.

The authors’ observation
Dr. D’s treatment course was challenging and required a multi-component approach. Establishing trust, while defining the limits of confidentiality, formed the foundation for the therapeutic relationship. The treatment provider asked for names of colleagues or friends to be contacted in case of an emer­gency. Dr. D chose his physician supervisor and agreed that the psychiatrist could con­tact the supervisor and vice versa.

Medication was prescribed at the end of the first session to begin to address anxiety and sleep problems. The initial medication was fluvoxamine, 50 mg/d, for anxiety and depression, clonazepam, 0.5 mg/d for anxiety, and zolpidem, 10 mg/d, for sleep. Adjustments were made in the dosage of antidepressant and responses monitored closely until the therapeutic dosage was reached with minimal side effects. Sleep improved, irritability lessened, and Dr. D’s obsessive, negative thinking and depres­sion improved. Deeper, restorative sleep also began to reduce physical tension and pain. Improved sleep and decreased mea­sures of depression are associated with sig­nificantly reduced risk of suicide.¹⁹

A treating psychiatrist should be aware of the state medical board requirements. In Ohio, where this case unfolded, reporting is required when the physician−patient is deemed unable to practice medicine according to acceptable and prevailing standards of care.²⁰

Relieving tension and somatic complaints
An important part of the treatment plan consisted of managing chronic muscle ten­sion and pain. We decided to front-load treatment, addressing the severe depres­sion, anxiety, and pain simultaneously. Even moderate pain relief would give Dr. D a greater sense of control and improve his mood.

Dr. D understood that a return to nor­mal biorhythms was necessary to form the foundation for the next step of therapy.²¹ The treatment team introduced mindful breathing, but Dr. D questioned how some­thing so simple could lift severe depres­sion. Focused, mindful breathing was not a cure, but a first step in regaining control over the current disarray of physical and emotional variations. We encouraged daily practice and he agreed to 5 practice ses­sions per week.

Next, the treatment team introduced progressive relaxation. Again, the simplic­ity of this process of tensing and relaxing groups of muscles was met with disbe­lief. Our therapist explained that volun­tarily producing muscle tension facilitates the relaxation response of both the mind and the body. The mind first commands the muscles to do what it does easily— “tense”; then is asked to elicit what is more difficult—“relax.” Repetition of the simple commands “tense—relax” in the arms, legs, back, abdomen, shoulders, neck, and face establishes a calming rhythm, again increasing the sense of control.22 We strongly encouraged daily practice of this exercise and Dr. D committed to the mind­ful breathing and relaxation exercise.

OUTCOME Recovery, maintenance
Dr. D and his psychotherapist address his anger, all-or-nothing thinking, and loneliness. Grief over his failed marriage was identified, giving them an opportunity to explore this loss and past, perceived losses of his parents’  affection in the context of the therapeutic relationship. Supportive therapy promoted ways to fulfill his ideal self.

Treatment lasted 2 years. Dr. D’s prior depressive episode indicates a need for maintenance medication. The antidepres­sant is continued and, with help from sup­portive psychotherapy, stress management, 8 weeks away from work, and the life changes mentioned above, our patient has not had a relapse.

Bottom Line
Depression and thoughts of suicide are common among physicians. Grant time off from work and reassure the physician that he (she) is entitled to seek medical treatment without repercussions. Adapt the type of psychotherapy to the physician’s specific concerns. Because physicians are at particular risk for loss of the ideal self, first consider person-centered therapy.

Related Resources
• Vanderbilt Center for Professional Health. www.mc.vanderbilt.edu/cph.
• Federation of State Physician Health Programs, Inc. www.fsphp.org.

Drug Brand Names
Clonazepam • Klonopin       Fluvoxamine • Luvox      Zolpidem • Ambien

AcknowledgementThe authors wish to acknowledge the contribution of Rachel Sieke, BS, Research Assistant, Department of Psychiatry, University of Toledo Medical Center, Toledo, Ohio.

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

The risk of developing venous thromboembolism is generally greater for women using oral contraceptives with newer types of progestogen hormones than for those taking older, second-generation birth control pills, study results showed.

“Women exposed to drospirenone, gestodene, cyproterone, and desogestrel within the last 28 days had around a four times increased risk of venous thromboembolism,” the investigators found. Women exposed to levonorgestrel, norethisterone, and norgestimate had about a 2.5 times greater risk of venous thromboembolism than did women not exposed in the past year, said Yana Vinogradova and her colleagues at the University of Nottingham (England) (BMJ. 2015 May 26 [doi:10.1136/bmj.h2135]).

The researchers conducted two nested case-control studies using data from 618 primary care practices in the Clinical Practice Research Datalink (CPRD) and 722 practices in the QResearch primary care database. A total of 5,062 cases from CPRD and 5,500 cases from QResearch were matched one to five with 19,638 and 22,396 controls, respectively.

areeya_ann/Thinkstock.com

Approximately 29% of CPRD patients and 26% of QResearch patients used oral contraceptives, most commonly levonorgestrel. Overall, any use of combined oral contraceptives resulted in a three times increased risk for venous thromboembolism, compared with no use in the past year.

After accounting for smoking, obesity, a wide range of other health conditions, alcohol consumption, polycystic ovary syndrome and recent infections, surgeries, leg/hip fractures, and hospital admission, the researchers calculated an increased odds ratio for each hormone: desogestrel (4.28), cyproterone (4.27), drospirenone (4.12), gestodene (3.64), levonorgestrel (2.38), norgestimate (2.53), and norethisterone (2.56). The increased VTE risk in patients on these hormones was compared with no exposure to oral contraceptives in the previous year.

In terms of numbers needed to harm, the researchers estimated that use of levonorgestrel and norgestimate resulted in 6 extra cases of VTE each year per 10,000 treated women aged 15-49, and 7 extra cases for women aged 25-49.

Desogestrel and cyproterone each contributed 14 additional cases of VTE each year per 10,000 treated women aged 15-49, and drospirenone, desogestrel, and cyproterone each contributed to an extra 17 cases of VTE each year per 10,000 women aged 25-49.

“We believe this study has the statistical power and sufficient adjustment for relevant confounders to be regarded as an important clarifying study, which has produced the most reliable possible risk estimates using currently available U.K. prescription data,” the researchers wrote.

There was no external funding for the study. Julia Hippisley-Cox is the unpaid director of QResearch, a not-for-profit organization that is a joint partnership between the University of Nottingham and EMIS, a commercial IT supplier. She is also a paid director of ClinRisk, which produces clinical risk algorithm-related software.

The risk of developing venous thromboembolism is generally greater for women using oral contraceptives with newer types of progestogen hormones than for those taking older, second-generation birth control pills, study results showed.

“Women exposed to drospirenone, gestodene, cyproterone, and desogestrel within the last 28 days had around a four times increased risk of venous thromboembolism,” the investigators found. Women exposed to levonorgestrel, norethisterone, and norgestimate had about a 2.5 times greater risk of venous thromboembolism than did women not exposed in the past year, said Yana Vinogradova and her colleagues at the University of Nottingham (England) (BMJ. 2015 May 26 [doi:10.1136/bmj.h2135]).

The researchers conducted two nested case-control studies using data from 618 primary care practices in the Clinical Practice Research Datalink (CPRD) and 722 practices in the QResearch primary care database. A total of 5,062 cases from CPRD and 5,500 cases from QResearch were matched one to five with 19,638 and 22,396 controls, respectively.

areeya_ann/Thinkstock.com

Approximately 29% of CPRD patients and 26% of QResearch patients used oral contraceptives, most commonly levonorgestrel. Overall, any use of combined oral contraceptives resulted in a three times increased risk for venous thromboembolism, compared with no use in the past year.

After accounting for smoking, obesity, a wide range of other health conditions, alcohol consumption, polycystic ovary syndrome and recent infections, surgeries, leg/hip fractures, and hospital admission, the researchers calculated an increased odds ratio for each hormone: desogestrel (4.28), cyproterone (4.27), drospirenone (4.12), gestodene (3.64), levonorgestrel (2.38), norgestimate (2.53), and norethisterone (2.56). The increased VTE risk in patients on these hormones was compared with no exposure to oral contraceptives in the previous year.

In terms of numbers needed to harm, the researchers estimated that use of levonorgestrel and norgestimate resulted in 6 extra cases of VTE each year per 10,000 treated women aged 15-49, and 7 extra cases for women aged 25-49.

Desogestrel and cyproterone each contributed 14 additional cases of VTE each year per 10,000 treated women aged 15-49, and drospirenone, desogestrel, and cyproterone each contributed to an extra 17 cases of VTE each year per 10,000 women aged 25-49.

“We believe this study has the statistical power and sufficient adjustment for relevant confounders to be regarded as an important clarifying study, which has produced the most reliable possible risk estimates using currently available U.K. prescription data,” the researchers wrote.

There was no external funding for the study. Julia Hippisley-Cox is the unpaid director of QResearch, a not-for-profit organization that is a joint partnership between the University of Nottingham and EMIS, a commercial IT supplier. She is also a paid director of ClinRisk, which produces clinical risk algorithm-related software.

The risk of developing venous thromboembolism is generally greater for women using oral contraceptives with newer types of progestogen hormones than for those taking older, second-generation birth control pills, study results showed.

“Women exposed to drospirenone, gestodene, cyproterone, and desogestrel within the last 28 days had around a four times increased risk of venous thromboembolism,” the investigators found. Women exposed to levonorgestrel, norethisterone, and norgestimate had about a 2.5 times greater risk of venous thromboembolism than did women not exposed in the past year, said Yana Vinogradova and her colleagues at the University of Nottingham (England) (BMJ. 2015 May 26 [doi:10.1136/bmj.h2135]).

The researchers conducted two nested case-control studies using data from 618 primary care practices in the Clinical Practice Research Datalink (CPRD) and 722 practices in the QResearch primary care database. A total of 5,062 cases from CPRD and 5,500 cases from QResearch were matched one to five with 19,638 and 22,396 controls, respectively.

areeya_ann/Thinkstock.com

Approximately 29% of CPRD patients and 26% of QResearch patients used oral contraceptives, most commonly levonorgestrel. Overall, any use of combined oral contraceptives resulted in a three times increased risk for venous thromboembolism, compared with no use in the past year.

After accounting for smoking, obesity, a wide range of other health conditions, alcohol consumption, polycystic ovary syndrome and recent infections, surgeries, leg/hip fractures, and hospital admission, the researchers calculated an increased odds ratio for each hormone: desogestrel (4.28), cyproterone (4.27), drospirenone (4.12), gestodene (3.64), levonorgestrel (2.38), norgestimate (2.53), and norethisterone (2.56). The increased VTE risk in patients on these hormones was compared with no exposure to oral contraceptives in the previous year.

In terms of numbers needed to harm, the researchers estimated that use of levonorgestrel and norgestimate resulted in 6 extra cases of VTE each year per 10,000 treated women aged 15-49, and 7 extra cases for women aged 25-49.

Desogestrel and cyproterone each contributed 14 additional cases of VTE each year per 10,000 treated women aged 15-49, and drospirenone, desogestrel, and cyproterone each contributed to an extra 17 cases of VTE each year per 10,000 women aged 25-49.

“We believe this study has the statistical power and sufficient adjustment for relevant confounders to be regarded as an important clarifying study, which has produced the most reliable possible risk estimates using currently available U.K. prescription data,” the researchers wrote.

There was no external funding for the study. Julia Hippisley-Cox is the unpaid director of QResearch, a not-for-profit organization that is a joint partnership between the University of Nottingham and EMIS, a commercial IT supplier. She is also a paid director of ClinRisk, which produces clinical risk algorithm-related software.

Ms. H, age 42, was given a diagnosis of bipolar disorder 10 years ago and has been taking carbamazepine, 1,200 mg/d, and olanzapine, 10 mg/d, for the past 2 years. She has not experienced a mood episode while on this regimen, and her car­bamazepine level was 9.2 μg/mL 6 months ago. The only adverse effect she experienced was weight gain of approximately 10 lb. Ms. H takes a calcium supplement, but no other medications.

Ms. H reports to her psychiatrist that, for the past few days, she has been feeling nau­seated, fatigued, and dizzy, but has contin­ued taking her medications as prescribed. Her carbamazepine level is found to be 13.1 μg/mL. Ms. H states she has not started any new medications or supplements; her serum creatinine and liver function test results are within normal limits.

Upon further questioning, Ms. H says that an upper respiratory infection has been “going around her office,” so she increased her vitamin C intake by drinking 2 glasses of grapefruit juice a day (she doesn’t like orange juice). She has heard grapefruit juice can cause problems with some drugs so she is careful not to drink it at the same time she takes her medications. Her psychiatrist recognizes there may be a drug interaction involved, and recommends Ms. H hold her carbamazepine for 1 day and not consume any more grapefruit juice. A few days later, she reports feeling much better during a fol­low-up call and she makes an appointment to have her carbamazepine level rechecked in a we

Although grapefruit products are high in vitamins and low in calories, they can be associated with potentially serious drug interactions. The interaction between grapefruit juice and the calcium channel blocker felodipine was discovered inad­vertently >20 years ago; since that time, possible interactions with >85 medica­tions have been identified.1 Interactions with grapefruit products are complicated because, although most result in increased drug exposure, reduced exposure of the medication also can occur. Additionally, the degree and clinical significance of the interaction varies among individuals and from one drug to another.

Mechanism of action
Most interactions with grapefruit products are thought to result from the inhibition of intestinal cytochrome P450 3A4 (CYP3A4). CYP3A4 is involved in the metabolism of numerous drugs, and is the most abun­dant cytochrome P450 enzyme in the liver and epithelial cells lining the intestine.² Although hepatic CYP3A4 is thought to be minimally affected by grapefruit, inhi­bition of intestinal CYP3A4 can result in an overall increase in bioavailability of medications that are substrates and raise the risk of potential toxicity.³ Grapefruit contains various chemicals collectively known as furanocoumarins, which are largely responsible for inhibition of intes­tinal CYP3A4.⁴ Additionally, Seville oranges and the pomelo (a large, sweet grapefruit-like citrus fruit) also contain furanocoumarins and could have a simi­lar effect, warranting caution with certain medications.⁵

Inhibition of CYP3A4 by furanocouma­rins cannot be reversed, and new enzymes must be synthesized to return to the pre­vious level of function.⁶ Therefore, drug interactions resulting from CYP3A4 inhi­bition can last for as long as 72 hours after ingesting grapefruit products.⁷ Separating consumption of grapefruit products and medication administration will not help manage this interaction.

Grapefruit products also could affect drug disposition through effects on vari­ous drug transporters. Decreased systemic exposure to certain medications could occur through grapefruit’s inhibition of organic anion-transporting polypeptides (OATPs). OATPs form a family of drug uptake transporters found in the intestine, liver, kidney, and brain.8 For drugs that are substrates of OATPs, grapefruit’s inhibition of this transporter can result in decreased absorption and a resulting decrease in effi­cacy. Flavanoids in grapefruit, such as nar­ingin, inhibit OATPs, which is competitive in nature.9 Unlike the irreversible inhibi­tion of CYP3A4 by furanocoumarins, flava­noids effects on OATPs have been shown to decrease within 4 hours.¹⁰

No psychotropic medications have been identified as being susceptible to this interaction, but for those medications affected—including fexofenadine and levothyroxine—separating consumption of grapefruit and medication administra­tion by 4 hours could avoid this interac­tion.¹¹ Additional data indicate that orange juice and apple juice could have similar effects on OATPs.¹²

Perhaps the most well-known drug transporter, P-glycoprotein is part of the multidrug-resistant subfamily of trans­porters. It is located throughout the body, including in the intestine, kidneys, liver, and blood-brain barrier. P-glycoprotein acts as an export pump to decrease the cellular concentration of many different drug substrates, and many agents can alter P-glycoprotein’s expression or function.

Small changes in P-glycoprotein’s activ­ity can result in substantial changes in the disposition of substrates, which can include certain antineoplastics and antiretrovi­rals. Most reports have found grapefruit juice inhibits P-glycoprotein-mediated efflux; however, there also are reports of transporter activation.⁶ Additionally, P-glycoprotein and CYP3A4 share many substrates, so it can be difficult to iso­late the contribution of P-glycoprotein to grapefruit−drug interactions.¹³ The effect of grapefruit on P-glycoprotein activity has been difficult to fully elucidate; more studies are needed.

Grapefruit consumption and its effect
Drug interactions can occur by consum­ing commercially produced grapefruit juice and juice from concentrate, as well as freshly squeezed juice and grapefruit seg­ments.¹⁴ CYP3A4-inhibiting furanocouma­rins also have been isolated in grapefruit peel; it is not known, however, whether items made from peel (marmalade, can­died peel) contain concentrations high enough to pose a risk of a drug interac­tion.¹⁴ Contributing to the unpredictabil­ity of grapefruit-drug interactions, the amount or concentration of furanocou­marins can vary among grapefruit prod­ucts and brands.¹⁵ This variability can be influenced by the variety or maturity of the fruit and the fruit’s exposure to envi­ronmental stress.⁴

The frequency of consuming a grape­fruit product can influence the degree of a drug interaction. In general, consum­ing one 8-oz glass of grapefruit juice or the segments from a whole grapefruit is enough to alter a susceptible drug’s phar­macokinetics.¹⁴ Regular grapefruit product consumption, however, can result in an overall greater effect.^16,17

Lilja et al¹⁶ conducted a randomized, 4-phase, crossover study to look at the effect of grapefruit juice dose on kinetics of triazolam. Grapefruit juice was found to increase the mean area under the concentration-time curve (AUC) of tri­azolam compared with water, but no dif­ference was found between single glasses of normal-strength and double-strength grapefruit juice. However, repeated consumption of double-strength grape­fruit juice (200 mL, 3 times/d for 3 days) increased triazolam’s mean AUC by 143%, compared with an increase of 49% with just a single 200-mL glass of double-strength juice.¹⁶ Recurrent consumption of grapefruit juice (8 oz, 3 times/d for 6 days) also was found to increase the kinetics of the antihypertensive felodipine more than a single glass of grapefruit juice.¹⁷

Clinical consequences of an interaction between a drug and grapefruit can be difficult to predict. Drug concentration changes caused by a grapefruit interac­tion could vary based on interindividual differences. The amount and activity of intestinal CYP3A4 can vary from per­son to person, and can be influenced by genetic polymorphisms in addition to race, age, and environmental variables.¹⁸ Interindividual sensitivity to a change in a drug’s concentration also will differ, and patient-specific factors, such as concomi­tant drugs or diseases, could influence the likelihood of harm.

Interactions with grapefruit products are not necessarily a “class effect,” and specific drugs within a therapeutic cat­egory can be affected (although others might not). Several drug-specific charac­teristics can help gauge the risk of a clini­cally relevant interaction with grapefruit, including:  
   • metabolism through CYP3A4  
   • low bioavailability  
   • oral administration  
   • a narrow therapeutic index.¹

For drugs with low bioavailability because of first-pass metabolism, grape­fruit’s inhibition of intestinal CYP3A4 can result in a greater relative increase in plasma concentrations compared with a drug with high bioavailability.¹⁹

For example, an increase in bioavailabil­ity from 5% to 10% will result in a much larger increase in AUC and overall clinical exposure compared with an increase from 85% to 90% even though both represent an absolute increase of 5%. Although a drug does not have to have low oral bioavail­ability for an interaction to occur, lower bioavailability means that a drug has a higher likelihood of causing a significant interaction because of altered pharmaco­kinetics. Of note, injectable medications will not interact with grapefruit because metabolism through intestinal CYP3A4 is bypassed and grapefruit does not signifi­cantly inhibit hepatic CYP3A4.

Although grapefruit products could alter the pharmacokinetics of susceptible drugs, those changes might not be associated with adverse effects. Therefore, a factor to con­sider in evaluating a potential interaction with grapefruit is the drug’s therapeutic index and its risk of serious adverse effects. Drugs with a narrow therapeutic index are of particular concern because a significant increase in therapeutic or adverse effects could result from a relatively small increase in the drug’s concentration.⁷

Which medications are affected?
Among medications identified as interact­ing with grapefruit, some cardiovascular agents and several of the HMG-CoA reduc­tase inhibitors (statins) have garnered the most attention. However, grapefruit also can affect the metabolism of several psy­chotropic medications through inhibition of intestinal CYP3A4 (Table).^16,20-35 Prescribing information for some drugs warns against consuming grapefruit while using the medication. Among CNS agents, buspirone, carbamazepine, lurasidone, pimozide, triazolam, and oral midazolam all have such warnings in their product labeling.

Buspirone currently is not recommended with “large quantities of grapefruit juice.”²⁰ A randomized, 2-phase crossover study looking at the effects of grapefruit juice on buspirone’s pharmacokinetics found that double-strength grapefruit juice (200 mL, administered 3 times/d for 3 days) resulted in a 9.2-fold increase in mean AUC and a 4.3-fold increase in mean Cmax after a single 10-mg buspirone dose.22 Highlighting the wide interindivid­ual variability seen with drug-grapefruit interactions, the increase found in buspi­rone’s AUC ranged from 3-fold to 20-fold among study participants.²²

Carbamazepine product labeling lists grapefruit juice as a CYP3A4 inhibi­tor that is expected to or has been found to increase plasma levels of the drug.²⁰ Carbamazepine’s bioavailability is influ­enced by intestinal CYP3A4 activity; in a randomized, 2-phase crossover study of 10 patients with epilepsy, grapefruit juice was found to increase AUC of carbamaze­pine by 41% and Cmax by 40%.^23,36

Lurasidone and pimozide, although not specifically studied, have product labels that recommend avoiding grapefruit juice because it could inhibit metabolism of these agents by CYP3A4.²⁰ Of particular concern is the potential for elevated levels of pimozide to increase the risk of adverse cardiovascular effects including QT inter­val prolongation.¹⁹

Midazolam. Although grapefruit juice does not affect the disposition of IV mid­azolam, pretreatment with grapefruit juice was found to increase the AUC and Cmax of oral midazolam by 52% and 56%, respectively.³⁰
 

Other considerations in drug-grapefruit interactions
Cautionary statements about a possible interaction with grapefruit juice for many other psychotropics can be found in com­monly used drug information references or online sources. If you are concerned about a possible interaction and avoiding grape­fruit products is not feasible, consider a different medication in the same class.

However, you also should consider the level of evidence supporting any pur­ported interaction. Several psychotropic agents do have studies or case reports sup­porting an interaction with grapefruit, but cautionary statements could be based on theoretical concerns because of a medica­tion’s bioavailability, metabolic pathway, and concern for increased adverse events related to higher drug concentrations. Adding to the confusion, cautionary state­ments can be found about medications, such as clozapine, that have not been shown to have an interaction with grape­fruit juice when studied.

With many of the drugs that have a reported or theoretical interaction with grapefruit, data are inconsistent as to whether the resulting interaction will be clinically relevant. A number of variables relating to the individual patient, grape­fruit product, or particular drug can play a role in the significance of an interaction. Additionally, effects on drug disposition can last for a few days after consuming a grapefruit product.

Keep alert to situations of increased risk
Recall that the case patient, Ms. H, pre­sented with an elevated carbamazepine level and suffered resulting adverse effects because of an interaction between the drug and grapefruit juice. Although Ms. H was careful to separate intake of grapefruit juice from carbamazepine administra­tion, grapefruit’s inhibition of intestinal CYP3A4 still was present, leading to the interaction.

It is important for health care profes­sionals to recognize this potential risk and to advise patients regarding possible inter­actions between medications and grape­fruit products.

Related Resources
• U.S. Food and Drug Administration. Grapefruit juice and medicine may not mix. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm.
• Hanley MJ, Cancalon P, Widmer WW, et al. The ef­fect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7(3):267-286.
• Andrade C. Fruit juice, organic anion transporting polypeptides, and drug interactions in psychiatry. J Clin Psychiatry. 2014;75(11):e1323-e1325.
 

Drug Brand Names
Alprazolam • Xanax                                     Lurasidone • Latuda
Buspirone • BuSpar                                     Midazolam • Versed
Carbamazepine • Tegretol                            Methadone • Dolophine
Clomipramine • Anafranil                             Nefazodone • Serzone
Clozapine • Clozaril                                     Olanzapine • Zyprexa
Diazepam • Valium                                     Pimozide • Orap
Felodipine • Plendil                                     Quetiapine • Seroquel
Fexofenadine • Allegra                                Sertraline • Zoloft
Fluoxetine • Prozac                                    Trazodone • Desyrel
Fluvoxamine • Luvox                                  Triazolam • Halcion
Haloperidol • Haldol                                   Ziprasidone • Geodon
Levothyroxine • Levoxyl, Synthroid   

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 42, was given a diagnosis of bipolar disorder 10 years ago and has been taking carbamazepine, 1,200 mg/d, and olanzapine, 10 mg/d, for the past 2 years. She has not experienced a mood episode while on this regimen, and her car­bamazepine level was 9.2 μg/mL 6 months ago. The only adverse effect she experienced was weight gain of approximately 10 lb. Ms. H takes a calcium supplement, but no other medications.

Ms. H reports to her psychiatrist that, for the past few days, she has been feeling nau­seated, fatigued, and dizzy, but has contin­ued taking her medications as prescribed. Her carbamazepine level is found to be 13.1 μg/mL. Ms. H states she has not started any new medications or supplements; her serum creatinine and liver function test results are within normal limits.

Upon further questioning, Ms. H says that an upper respiratory infection has been “going around her office,” so she increased her vitamin C intake by drinking 2 glasses of grapefruit juice a day (she doesn’t like orange juice). She has heard grapefruit juice can cause problems with some drugs so she is careful not to drink it at the same time she takes her medications. Her psychiatrist recognizes there may be a drug interaction involved, and recommends Ms. H hold her carbamazepine for 1 day and not consume any more grapefruit juice. A few days later, she reports feeling much better during a fol­low-up call and she makes an appointment to have her carbamazepine level rechecked in a we

Although grapefruit products are high in vitamins and low in calories, they can be associated with potentially serious drug interactions. The interaction between grapefruit juice and the calcium channel blocker felodipine was discovered inad­vertently >20 years ago; since that time, possible interactions with >85 medica­tions have been identified.1 Interactions with grapefruit products are complicated because, although most result in increased drug exposure, reduced exposure of the medication also can occur. Additionally, the degree and clinical significance of the interaction varies among individuals and from one drug to another.

Mechanism of action
Most interactions with grapefruit products are thought to result from the inhibition of intestinal cytochrome P450 3A4 (CYP3A4). CYP3A4 is involved in the metabolism of numerous drugs, and is the most abun­dant cytochrome P450 enzyme in the liver and epithelial cells lining the intestine.² Although hepatic CYP3A4 is thought to be minimally affected by grapefruit, inhi­bition of intestinal CYP3A4 can result in an overall increase in bioavailability of medications that are substrates and raise the risk of potential toxicity.³ Grapefruit contains various chemicals collectively known as furanocoumarins, which are largely responsible for inhibition of intes­tinal CYP3A4.⁴ Additionally, Seville oranges and the pomelo (a large, sweet grapefruit-like citrus fruit) also contain furanocoumarins and could have a simi­lar effect, warranting caution with certain medications.⁵

Inhibition of CYP3A4 by furanocouma­rins cannot be reversed, and new enzymes must be synthesized to return to the pre­vious level of function.⁶ Therefore, drug interactions resulting from CYP3A4 inhi­bition can last for as long as 72 hours after ingesting grapefruit products.⁷ Separating consumption of grapefruit products and medication administration will not help manage this interaction.

Grapefruit products also could affect drug disposition through effects on vari­ous drug transporters. Decreased systemic exposure to certain medications could occur through grapefruit’s inhibition of organic anion-transporting polypeptides (OATPs). OATPs form a family of drug uptake transporters found in the intestine, liver, kidney, and brain.8 For drugs that are substrates of OATPs, grapefruit’s inhibition of this transporter can result in decreased absorption and a resulting decrease in effi­cacy. Flavanoids in grapefruit, such as nar­ingin, inhibit OATPs, which is competitive in nature.9 Unlike the irreversible inhibi­tion of CYP3A4 by furanocoumarins, flava­noids effects on OATPs have been shown to decrease within 4 hours.¹⁰

No psychotropic medications have been identified as being susceptible to this interaction, but for those medications affected—including fexofenadine and levothyroxine—separating consumption of grapefruit and medication administra­tion by 4 hours could avoid this interac­tion.¹¹ Additional data indicate that orange juice and apple juice could have similar effects on OATPs.¹²

Perhaps the most well-known drug transporter, P-glycoprotein is part of the multidrug-resistant subfamily of trans­porters. It is located throughout the body, including in the intestine, kidneys, liver, and blood-brain barrier. P-glycoprotein acts as an export pump to decrease the cellular concentration of many different drug substrates, and many agents can alter P-glycoprotein’s expression or function.

Small changes in P-glycoprotein’s activ­ity can result in substantial changes in the disposition of substrates, which can include certain antineoplastics and antiretrovi­rals. Most reports have found grapefruit juice inhibits P-glycoprotein-mediated efflux; however, there also are reports of transporter activation.⁶ Additionally, P-glycoprotein and CYP3A4 share many substrates, so it can be difficult to iso­late the contribution of P-glycoprotein to grapefruit−drug interactions.¹³ The effect of grapefruit on P-glycoprotein activity has been difficult to fully elucidate; more studies are needed.

Grapefruit consumption and its effect
Drug interactions can occur by consum­ing commercially produced grapefruit juice and juice from concentrate, as well as freshly squeezed juice and grapefruit seg­ments.¹⁴ CYP3A4-inhibiting furanocouma­rins also have been isolated in grapefruit peel; it is not known, however, whether items made from peel (marmalade, can­died peel) contain concentrations high enough to pose a risk of a drug interac­tion.¹⁴ Contributing to the unpredictabil­ity of grapefruit-drug interactions, the amount or concentration of furanocou­marins can vary among grapefruit prod­ucts and brands.¹⁵ This variability can be influenced by the variety or maturity of the fruit and the fruit’s exposure to envi­ronmental stress.⁴

The frequency of consuming a grape­fruit product can influence the degree of a drug interaction. In general, consum­ing one 8-oz glass of grapefruit juice or the segments from a whole grapefruit is enough to alter a susceptible drug’s phar­macokinetics.¹⁴ Regular grapefruit product consumption, however, can result in an overall greater effect.^16,17

Lilja et al¹⁶ conducted a randomized, 4-phase, crossover study to look at the effect of grapefruit juice dose on kinetics of triazolam. Grapefruit juice was found to increase the mean area under the concentration-time curve (AUC) of tri­azolam compared with water, but no dif­ference was found between single glasses of normal-strength and double-strength grapefruit juice. However, repeated consumption of double-strength grape­fruit juice (200 mL, 3 times/d for 3 days) increased triazolam’s mean AUC by 143%, compared with an increase of 49% with just a single 200-mL glass of double-strength juice.¹⁶ Recurrent consumption of grapefruit juice (8 oz, 3 times/d for 6 days) also was found to increase the kinetics of the antihypertensive felodipine more than a single glass of grapefruit juice.¹⁷

Clinical consequences of an interaction between a drug and grapefruit can be difficult to predict. Drug concentration changes caused by a grapefruit interac­tion could vary based on interindividual differences. The amount and activity of intestinal CYP3A4 can vary from per­son to person, and can be influenced by genetic polymorphisms in addition to race, age, and environmental variables.¹⁸ Interindividual sensitivity to a change in a drug’s concentration also will differ, and patient-specific factors, such as concomi­tant drugs or diseases, could influence the likelihood of harm.

Interactions with grapefruit products are not necessarily a “class effect,” and specific drugs within a therapeutic cat­egory can be affected (although others might not). Several drug-specific charac­teristics can help gauge the risk of a clini­cally relevant interaction with grapefruit, including:  
   • metabolism through CYP3A4  
   • low bioavailability  
   • oral administration  
   • a narrow therapeutic index.¹

For drugs with low bioavailability because of first-pass metabolism, grape­fruit’s inhibition of intestinal CYP3A4 can result in a greater relative increase in plasma concentrations compared with a drug with high bioavailability.¹⁹

For example, an increase in bioavailabil­ity from 5% to 10% will result in a much larger increase in AUC and overall clinical exposure compared with an increase from 85% to 90% even though both represent an absolute increase of 5%. Although a drug does not have to have low oral bioavail­ability for an interaction to occur, lower bioavailability means that a drug has a higher likelihood of causing a significant interaction because of altered pharmaco­kinetics. Of note, injectable medications will not interact with grapefruit because metabolism through intestinal CYP3A4 is bypassed and grapefruit does not signifi­cantly inhibit hepatic CYP3A4.

Although grapefruit products could alter the pharmacokinetics of susceptible drugs, those changes might not be associated with adverse effects. Therefore, a factor to con­sider in evaluating a potential interaction with grapefruit is the drug’s therapeutic index and its risk of serious adverse effects. Drugs with a narrow therapeutic index are of particular concern because a significant increase in therapeutic or adverse effects could result from a relatively small increase in the drug’s concentration.⁷

Which medications are affected?
Among medications identified as interact­ing with grapefruit, some cardiovascular agents and several of the HMG-CoA reduc­tase inhibitors (statins) have garnered the most attention. However, grapefruit also can affect the metabolism of several psy­chotropic medications through inhibition of intestinal CYP3A4 (Table).^16,20-35 Prescribing information for some drugs warns against consuming grapefruit while using the medication. Among CNS agents, buspirone, carbamazepine, lurasidone, pimozide, triazolam, and oral midazolam all have such warnings in their product labeling.

Buspirone currently is not recommended with “large quantities of grapefruit juice.”²⁰ A randomized, 2-phase crossover study looking at the effects of grapefruit juice on buspirone’s pharmacokinetics found that double-strength grapefruit juice (200 mL, administered 3 times/d for 3 days) resulted in a 9.2-fold increase in mean AUC and a 4.3-fold increase in mean Cmax after a single 10-mg buspirone dose.22 Highlighting the wide interindivid­ual variability seen with drug-grapefruit interactions, the increase found in buspi­rone’s AUC ranged from 3-fold to 20-fold among study participants.²²

Carbamazepine product labeling lists grapefruit juice as a CYP3A4 inhibi­tor that is expected to or has been found to increase plasma levels of the drug.²⁰ Carbamazepine’s bioavailability is influ­enced by intestinal CYP3A4 activity; in a randomized, 2-phase crossover study of 10 patients with epilepsy, grapefruit juice was found to increase AUC of carbamaze­pine by 41% and Cmax by 40%.^23,36

Lurasidone and pimozide, although not specifically studied, have product labels that recommend avoiding grapefruit juice because it could inhibit metabolism of these agents by CYP3A4.²⁰ Of particular concern is the potential for elevated levels of pimozide to increase the risk of adverse cardiovascular effects including QT inter­val prolongation.¹⁹

Midazolam. Although grapefruit juice does not affect the disposition of IV mid­azolam, pretreatment with grapefruit juice was found to increase the AUC and Cmax of oral midazolam by 52% and 56%, respectively.³⁰
 

Other considerations in drug-grapefruit interactions
Cautionary statements about a possible interaction with grapefruit juice for many other psychotropics can be found in com­monly used drug information references or online sources. If you are concerned about a possible interaction and avoiding grape­fruit products is not feasible, consider a different medication in the same class.

However, you also should consider the level of evidence supporting any pur­ported interaction. Several psychotropic agents do have studies or case reports sup­porting an interaction with grapefruit, but cautionary statements could be based on theoretical concerns because of a medica­tion’s bioavailability, metabolic pathway, and concern for increased adverse events related to higher drug concentrations. Adding to the confusion, cautionary state­ments can be found about medications, such as clozapine, that have not been shown to have an interaction with grape­fruit juice when studied.

With many of the drugs that have a reported or theoretical interaction with grapefruit, data are inconsistent as to whether the resulting interaction will be clinically relevant. A number of variables relating to the individual patient, grape­fruit product, or particular drug can play a role in the significance of an interaction. Additionally, effects on drug disposition can last for a few days after consuming a grapefruit product.

Keep alert to situations of increased risk
Recall that the case patient, Ms. H, pre­sented with an elevated carbamazepine level and suffered resulting adverse effects because of an interaction between the drug and grapefruit juice. Although Ms. H was careful to separate intake of grapefruit juice from carbamazepine administra­tion, grapefruit’s inhibition of intestinal CYP3A4 still was present, leading to the interaction.

It is important for health care profes­sionals to recognize this potential risk and to advise patients regarding possible inter­actions between medications and grape­fruit products.

Related Resources
• U.S. Food and Drug Administration. Grapefruit juice and medicine may not mix. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm.
• Hanley MJ, Cancalon P, Widmer WW, et al. The ef­fect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7(3):267-286.
• Andrade C. Fruit juice, organic anion transporting polypeptides, and drug interactions in psychiatry. J Clin Psychiatry. 2014;75(11):e1323-e1325.
 

Drug Brand Names
Alprazolam • Xanax                                     Lurasidone • Latuda
Buspirone • BuSpar                                     Midazolam • Versed
Carbamazepine • Tegretol                            Methadone • Dolophine
Clomipramine • Anafranil                             Nefazodone • Serzone
Clozapine • Clozaril                                     Olanzapine • Zyprexa
Diazepam • Valium                                     Pimozide • Orap
Felodipine • Plendil                                     Quetiapine • Seroquel
Fexofenadine • Allegra                                Sertraline • Zoloft
Fluoxetine • Prozac                                    Trazodone • Desyrel
Fluvoxamine • Luvox                                  Triazolam • Halcion
Haloperidol • Haldol                                   Ziprasidone • Geodon
Levothyroxine • Levoxyl, Synthroid   

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 42, was given a diagnosis of bipolar disorder 10 years ago and has been taking carbamazepine, 1,200 mg/d, and olanzapine, 10 mg/d, for the past 2 years. She has not experienced a mood episode while on this regimen, and her car­bamazepine level was 9.2 μg/mL 6 months ago. The only adverse effect she experienced was weight gain of approximately 10 lb. Ms. H takes a calcium supplement, but no other medications.

Ms. H reports to her psychiatrist that, for the past few days, she has been feeling nau­seated, fatigued, and dizzy, but has contin­ued taking her medications as prescribed. Her carbamazepine level is found to be 13.1 μg/mL. Ms. H states she has not started any new medications or supplements; her serum creatinine and liver function test results are within normal limits.

Upon further questioning, Ms. H says that an upper respiratory infection has been “going around her office,” so she increased her vitamin C intake by drinking 2 glasses of grapefruit juice a day (she doesn’t like orange juice). She has heard grapefruit juice can cause problems with some drugs so she is careful not to drink it at the same time she takes her medications. Her psychiatrist recognizes there may be a drug interaction involved, and recommends Ms. H hold her carbamazepine for 1 day and not consume any more grapefruit juice. A few days later, she reports feeling much better during a fol­low-up call and she makes an appointment to have her carbamazepine level rechecked in a we

Although grapefruit products are high in vitamins and low in calories, they can be associated with potentially serious drug interactions. The interaction between grapefruit juice and the calcium channel blocker felodipine was discovered inad­vertently >20 years ago; since that time, possible interactions with >85 medica­tions have been identified.1 Interactions with grapefruit products are complicated because, although most result in increased drug exposure, reduced exposure of the medication also can occur. Additionally, the degree and clinical significance of the interaction varies among individuals and from one drug to another.

Mechanism of action
Most interactions with grapefruit products are thought to result from the inhibition of intestinal cytochrome P450 3A4 (CYP3A4). CYP3A4 is involved in the metabolism of numerous drugs, and is the most abun­dant cytochrome P450 enzyme in the liver and epithelial cells lining the intestine.² Although hepatic CYP3A4 is thought to be minimally affected by grapefruit, inhi­bition of intestinal CYP3A4 can result in an overall increase in bioavailability of medications that are substrates and raise the risk of potential toxicity.³ Grapefruit contains various chemicals collectively known as furanocoumarins, which are largely responsible for inhibition of intes­tinal CYP3A4.⁴ Additionally, Seville oranges and the pomelo (a large, sweet grapefruit-like citrus fruit) also contain furanocoumarins and could have a simi­lar effect, warranting caution with certain medications.⁵

Inhibition of CYP3A4 by furanocouma­rins cannot be reversed, and new enzymes must be synthesized to return to the pre­vious level of function.⁶ Therefore, drug interactions resulting from CYP3A4 inhi­bition can last for as long as 72 hours after ingesting grapefruit products.⁷ Separating consumption of grapefruit products and medication administration will not help manage this interaction.

Grapefruit products also could affect drug disposition through effects on vari­ous drug transporters. Decreased systemic exposure to certain medications could occur through grapefruit’s inhibition of organic anion-transporting polypeptides (OATPs). OATPs form a family of drug uptake transporters found in the intestine, liver, kidney, and brain.8 For drugs that are substrates of OATPs, grapefruit’s inhibition of this transporter can result in decreased absorption and a resulting decrease in effi­cacy. Flavanoids in grapefruit, such as nar­ingin, inhibit OATPs, which is competitive in nature.9 Unlike the irreversible inhibi­tion of CYP3A4 by furanocoumarins, flava­noids effects on OATPs have been shown to decrease within 4 hours.¹⁰

No psychotropic medications have been identified as being susceptible to this interaction, but for those medications affected—including fexofenadine and levothyroxine—separating consumption of grapefruit and medication administra­tion by 4 hours could avoid this interac­tion.¹¹ Additional data indicate that orange juice and apple juice could have similar effects on OATPs.¹²

Perhaps the most well-known drug transporter, P-glycoprotein is part of the multidrug-resistant subfamily of trans­porters. It is located throughout the body, including in the intestine, kidneys, liver, and blood-brain barrier. P-glycoprotein acts as an export pump to decrease the cellular concentration of many different drug substrates, and many agents can alter P-glycoprotein’s expression or function.

Small changes in P-glycoprotein’s activ­ity can result in substantial changes in the disposition of substrates, which can include certain antineoplastics and antiretrovi­rals. Most reports have found grapefruit juice inhibits P-glycoprotein-mediated efflux; however, there also are reports of transporter activation.⁶ Additionally, P-glycoprotein and CYP3A4 share many substrates, so it can be difficult to iso­late the contribution of P-glycoprotein to grapefruit−drug interactions.¹³ The effect of grapefruit on P-glycoprotein activity has been difficult to fully elucidate; more studies are needed.

Grapefruit consumption and its effect
Drug interactions can occur by consum­ing commercially produced grapefruit juice and juice from concentrate, as well as freshly squeezed juice and grapefruit seg­ments.¹⁴ CYP3A4-inhibiting furanocouma­rins also have been isolated in grapefruit peel; it is not known, however, whether items made from peel (marmalade, can­died peel) contain concentrations high enough to pose a risk of a drug interac­tion.¹⁴ Contributing to the unpredictabil­ity of grapefruit-drug interactions, the amount or concentration of furanocou­marins can vary among grapefruit prod­ucts and brands.¹⁵ This variability can be influenced by the variety or maturity of the fruit and the fruit’s exposure to envi­ronmental stress.⁴

The frequency of consuming a grape­fruit product can influence the degree of a drug interaction. In general, consum­ing one 8-oz glass of grapefruit juice or the segments from a whole grapefruit is enough to alter a susceptible drug’s phar­macokinetics.¹⁴ Regular grapefruit product consumption, however, can result in an overall greater effect.^16,17

Lilja et al¹⁶ conducted a randomized, 4-phase, crossover study to look at the effect of grapefruit juice dose on kinetics of triazolam. Grapefruit juice was found to increase the mean area under the concentration-time curve (AUC) of tri­azolam compared with water, but no dif­ference was found between single glasses of normal-strength and double-strength grapefruit juice. However, repeated consumption of double-strength grape­fruit juice (200 mL, 3 times/d for 3 days) increased triazolam’s mean AUC by 143%, compared with an increase of 49% with just a single 200-mL glass of double-strength juice.¹⁶ Recurrent consumption of grapefruit juice (8 oz, 3 times/d for 6 days) also was found to increase the kinetics of the antihypertensive felodipine more than a single glass of grapefruit juice.¹⁷

Clinical consequences of an interaction between a drug and grapefruit can be difficult to predict. Drug concentration changes caused by a grapefruit interac­tion could vary based on interindividual differences. The amount and activity of intestinal CYP3A4 can vary from per­son to person, and can be influenced by genetic polymorphisms in addition to race, age, and environmental variables.¹⁸ Interindividual sensitivity to a change in a drug’s concentration also will differ, and patient-specific factors, such as concomi­tant drugs or diseases, could influence the likelihood of harm.

Interactions with grapefruit products are not necessarily a “class effect,” and specific drugs within a therapeutic cat­egory can be affected (although others might not). Several drug-specific charac­teristics can help gauge the risk of a clini­cally relevant interaction with grapefruit, including:  
   • metabolism through CYP3A4  
   • low bioavailability  
   • oral administration  
   • a narrow therapeutic index.¹

For drugs with low bioavailability because of first-pass metabolism, grape­fruit’s inhibition of intestinal CYP3A4 can result in a greater relative increase in plasma concentrations compared with a drug with high bioavailability.¹⁹

For example, an increase in bioavailabil­ity from 5% to 10% will result in a much larger increase in AUC and overall clinical exposure compared with an increase from 85% to 90% even though both represent an absolute increase of 5%. Although a drug does not have to have low oral bioavail­ability for an interaction to occur, lower bioavailability means that a drug has a higher likelihood of causing a significant interaction because of altered pharmaco­kinetics. Of note, injectable medications will not interact with grapefruit because metabolism through intestinal CYP3A4 is bypassed and grapefruit does not signifi­cantly inhibit hepatic CYP3A4.

Although grapefruit products could alter the pharmacokinetics of susceptible drugs, those changes might not be associated with adverse effects. Therefore, a factor to con­sider in evaluating a potential interaction with grapefruit is the drug’s therapeutic index and its risk of serious adverse effects. Drugs with a narrow therapeutic index are of particular concern because a significant increase in therapeutic or adverse effects could result from a relatively small increase in the drug’s concentration.⁷

Which medications are affected?
Among medications identified as interact­ing with grapefruit, some cardiovascular agents and several of the HMG-CoA reduc­tase inhibitors (statins) have garnered the most attention. However, grapefruit also can affect the metabolism of several psy­chotropic medications through inhibition of intestinal CYP3A4 (Table).^16,20-35 Prescribing information for some drugs warns against consuming grapefruit while using the medication. Among CNS agents, buspirone, carbamazepine, lurasidone, pimozide, triazolam, and oral midazolam all have such warnings in their product labeling.

Buspirone currently is not recommended with “large quantities of grapefruit juice.”²⁰ A randomized, 2-phase crossover study looking at the effects of grapefruit juice on buspirone’s pharmacokinetics found that double-strength grapefruit juice (200 mL, administered 3 times/d for 3 days) resulted in a 9.2-fold increase in mean AUC and a 4.3-fold increase in mean Cmax after a single 10-mg buspirone dose.22 Highlighting the wide interindivid­ual variability seen with drug-grapefruit interactions, the increase found in buspi­rone’s AUC ranged from 3-fold to 20-fold among study participants.²²

Carbamazepine product labeling lists grapefruit juice as a CYP3A4 inhibi­tor that is expected to or has been found to increase plasma levels of the drug.²⁰ Carbamazepine’s bioavailability is influ­enced by intestinal CYP3A4 activity; in a randomized, 2-phase crossover study of 10 patients with epilepsy, grapefruit juice was found to increase AUC of carbamaze­pine by 41% and Cmax by 40%.^23,36

Lurasidone and pimozide, although not specifically studied, have product labels that recommend avoiding grapefruit juice because it could inhibit metabolism of these agents by CYP3A4.²⁰ Of particular concern is the potential for elevated levels of pimozide to increase the risk of adverse cardiovascular effects including QT inter­val prolongation.¹⁹

Midazolam. Although grapefruit juice does not affect the disposition of IV mid­azolam, pretreatment with grapefruit juice was found to increase the AUC and Cmax of oral midazolam by 52% and 56%, respectively.³⁰
 

Other considerations in drug-grapefruit interactions
Cautionary statements about a possible interaction with grapefruit juice for many other psychotropics can be found in com­monly used drug information references or online sources. If you are concerned about a possible interaction and avoiding grape­fruit products is not feasible, consider a different medication in the same class.

However, you also should consider the level of evidence supporting any pur­ported interaction. Several psychotropic agents do have studies or case reports sup­porting an interaction with grapefruit, but cautionary statements could be based on theoretical concerns because of a medica­tion’s bioavailability, metabolic pathway, and concern for increased adverse events related to higher drug concentrations. Adding to the confusion, cautionary state­ments can be found about medications, such as clozapine, that have not been shown to have an interaction with grape­fruit juice when studied.

With many of the drugs that have a reported or theoretical interaction with grapefruit, data are inconsistent as to whether the resulting interaction will be clinically relevant. A number of variables relating to the individual patient, grape­fruit product, or particular drug can play a role in the significance of an interaction. Additionally, effects on drug disposition can last for a few days after consuming a grapefruit product.

Keep alert to situations of increased risk
Recall that the case patient, Ms. H, pre­sented with an elevated carbamazepine level and suffered resulting adverse effects because of an interaction between the drug and grapefruit juice. Although Ms. H was careful to separate intake of grapefruit juice from carbamazepine administra­tion, grapefruit’s inhibition of intestinal CYP3A4 still was present, leading to the interaction.

It is important for health care profes­sionals to recognize this potential risk and to advise patients regarding possible inter­actions between medications and grape­fruit products.

Related Resources
• U.S. Food and Drug Administration. Grapefruit juice and medicine may not mix. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm.
• Hanley MJ, Cancalon P, Widmer WW, et al. The ef­fect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7(3):267-286.
• Andrade C. Fruit juice, organic anion transporting polypeptides, and drug interactions in psychiatry. J Clin Psychiatry. 2014;75(11):e1323-e1325.
 

Drug Brand Names
Alprazolam • Xanax                                     Lurasidone • Latuda
Buspirone • BuSpar                                     Midazolam • Versed
Carbamazepine • Tegretol                            Methadone • Dolophine
Clomipramine • Anafranil                             Nefazodone • Serzone
Clozapine • Clozaril                                     Olanzapine • Zyprexa
Diazepam • Valium                                     Pimozide • Orap
Felodipine • Plendil                                     Quetiapine • Seroquel
Fexofenadine • Allegra                                Sertraline • Zoloft
Fluoxetine • Prozac                                    Trazodone • Desyrel
Fluvoxamine • Luvox                                  Triazolam • Halcion
Haloperidol • Haldol                                   Ziprasidone • Geodon
Levothyroxine • Levoxyl, Synthroid   

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Current Psychiatry welcomed more than 650 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Co-chairs Richard Balon, MD, and Donald W. Black, MD, April 16-18, 2015, at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 18 AMA PRA Category 1 Credits™. We welcome you to join us next year in Chicago, March 10-12, 2016.

THURSDAY, APRIL 16, 2015

MORNING SESSION

Attention-deficit/hyperactivity disorder (ADHD) is a lifespan disorder that is “everywhere,” Anthony L. Rostain, MD, MA, University of Pennsylvania Perelman School of Medicine, began—including in adults and even “seniors.” This means that the disorder “is not a diagnosis of exclusion,” and that “comorbidity is the rule,” including learning difficulties. Among adults, the focus of symptoms and management is on executive dysfunction and its characteristics: difficulty multitasking, problems keeping commitments, and excessive reliance on help from others. Inattention and disorganization are hallmarks of adult ADHD, and become worse as environmental demands (work, home) increase; hyperactivity decreases with age. Dr. Rostain recommends ruling out other causes of a patient’s symptoms when an adult self-reports ADHD, including transient stressors, medical conditions, psychiatric disorders, and malingering.
 

Donald W. Black, MD

Donald W. Black, MD, University of Iowa, reviewed DSM-5 criteria for borderline personality disorder (BPD) and offered tips for avoiding misdiagnosis, including obtaining collateral information and using rating scales. Co-occuring disorders, such as depression and substance abuse, are common. Treatment for BPD patients includes psychotherapy (individual or group), medication, and lifestyle changes. Psychotropics treat symptoms of depression, anxiety, hostility, and impulsivity of BPD but not the fundamental nature of the disorder. When establishing a patient’s treatment plan, consider the stage of illness, evaluate for any co-occurring disorders, and ask the patient what he (she) wants from treatment.

Dr. Rostain began by discussing the neurobiological basis of ADHD, which guides pharmacotherapy. He reviewed the response rate of FDA-approved agents for adults with ADHD, including stimulants, atomoxetine, and alpha-adrenergic agonists. Best response is seen with stimulants, but some patients improve with bupropion and tricyclic antidepressants (TCAs). Employ a multimodal treatment approach, Dr. Rostain recommended, which should include psychoeducation and environmental restructuring, because, as he says, “Pills don’t teach skills.” He also reviewed strategies for treating ADHD in patients who have a comorbid disorder, such as bipolar disorder, major depressive disorder, or substance abuse.

Patients with psychotic depression meet criteria for major depressive disorder but also have delusions or hallucinations. Diagnostic issues include increased guilt, cognitive impairment, paranoia, and increased hopelessness. Anthony J. Rothschild, MD, University of Massachusetts Medical School, reviewed methods for differentiating psychotic depression from schizophrenia, posttraumatic stress disorder, obsessive-compulsive disorder, and body dysmorphic disorder. There are no FDA-approved medications for psychotic depression, Dr. Rothschild explained; however, evidence shows that the combination of an antidepressant and an antipsychotic is superior to monotherapy with an agent from either class. In addition, he noted, studies show a high response rate with electroconvulsive therapy (ECT).

AFTERNOON SESSION

Return of symptoms after initial remission— while the patient is still taking an antidepressant—is considered tachyphylaxis, or “poop out.” Residual depressive symptoms, when a patient meets criteria for remission but still has troubling symptoms, is a different phenomenon, although symptoms can overlap. First, Dr. Rothschild advised, ensure that patients are given an adequate trial of an antidepressant. Options are similar when tachyphylaxis or residual symptoms are present: switch drugs or add augmentation therapy, such as lithium, thyroid hormone, or an atypical antipsychotic. Data on the efficacy for bupropion and buspirone are not strong. For treatment-resistant depression when a patient does not respond to 3 adequate antidepressant trials—consider ECT or rTMS, if available, or a monoamine oxidase inhibitor or a TCA.

Dr. Black defines antisocial personality disorder (ASPD) as a disorder of lifelong serial misbehavior, one characterized by impaired relationships, aggressive behavior, non-aggressive delinquent behavior, manipulation, and a disturbing lack of conscience. There is no standard treatment for ASPD, and no FDA-approved medications; however, potential treatments have not been adequately studied, he pointed out. Cognitive-behavioral therapy might be appropriate in mild cases; some patients benefit from specific programs— for example, ones that address drug or alcohol addiction or anger, although evidence is limited. When treating ASPD patients, Dr. Black concluded, be mindful of high attrition, possible misuse of prescribed medications, and drug-drug or drug-alcohol interactions.

Bipolar disorder is associated with the highest risk of suicide and increased lethality among all psychiatric disorders. Lithium has evidence of an anti-suicidality effect and may reduce suicide by decreasing relapse, aggression, and impulsivity. An FDA advisory on increased risk of suicidality with anticonvulsants was based on data about patients with epilepsy, not bipolar disorder. Second-generation antipsychotics, including olanzapine, quetiapine, and lurasidone, have been shown to be effective for bipolar depression. Avoid antidepressants if possible, Philip G. Janicak, MD, Northwestern University Feinberg School of Medicine, advised; if you must prescribe one, reassess the need for the drug often. Several psychotherapy modalities have evidence supporting their use in bipolar disorder.

FRIDAY, APRIL 17, 2015

MORNING SESSION

Henry A. Nasrallah, MD

Henry A. Nasrallah, MD, Saint Louis University School of Medicine, offered enlightening historical touch-points on how psychiatry’s understanding of, and its approach to, schizophrenia have changed in the past 50 years. His goal? To challenge practitioners to rethink ideas about the disorder and how they care for affected patients. From a laundry list of comparative shifts, here are a few of Dr. Nasrallah’s “then” and “now” observations:

• The old paradigm was: Clinical and functional deterioration are inevitable in schizophrenia. The new paradigm is: Complete remission and restoration of function are feasible in many patients when they are fully adherent to the treatment plan.

• The old: Long-acting injectable (LAI) antipsychotics are a last-resort treatment, to be prescribed after a patient is stabilized. The new: Use LAI antipsychotics early in the course.

• Old: Begin treatment when psychosis appears. New: Work to prevent conversion to psychosis.

• Old: The disorder is considered a con­sequence of neurochemical dysregulation. New: Impaired neuroplasticity is to blame.

• Old: Treatment is a matter of trial and error. New: We can apply pharmaco-genomics to predict a patient’s response to various drugs and thus increase the likelihood of therapeutic success.

In his second presentation, Dr. Nasrallah described the many pathways to psychosis and several psychotic disorders other than schizophrenia, including schizoaffective, delusional disorder, and psychotic disorder caused by a general medical condition. He listed symptom clusters in psychosis beyond positive and negative symptoms, including neuromotor symptoms, mood symptoms, and neurocognitive deficits. Development of schizophrenia is multifactorial and involves risk genes and environmental factors seen before conception, during birth, and in early childhood; good prenatal care is the best way to prevent schizophrenia, Dr. Nasrallah noted. Several general medical conditions can produce schizophrenia-like psychosis, including some CNS disorders, toxins, autoimmune diseases, infectious diseases, and chromosomal abnormalities. The session concluded with a live interview with one of Dr. Nasrallah’s patients, whose schizophrenia is in remission with clozapine.

Drug abuse can mask signs and symptoms of bipolar disorder, which can delay diagnosis. Commonly abused substances are nicotine, alcohol, Cannabis, and cocaine; polysubstance abuse is the rule. Bipolar disorder and substance abuse share common mechanisms: impulsivity, poor modulation of motivation and response to reward, and behavioral sensitization. Treatment approaches should be flexible. Dr. Janicak reviewed the evidence for using anticonvulsants, antipsychotics, and bupropion for alcohol, Cannabis, and cocaine abuse; there are no data on treating opioid abuse. He also discussed the evidence for using naltrexone, acamprosate, disulfiram, and varenicline, as well as psychotherapeutic options, to treat substance abuse. Dr. Janicak encouraged clinicians in the audience to treat substance abuse in bipolar disorder patients themselves, instead of referring them to a subspecialist.

Untreated psychiatric disorders increase obstetrical complications, possibly through decreased self-care or increased stress. For mild or moderate depression, psychotherapy might be sufficient treatment; but for severe cases, medication is the first-line approach. In her presentation on mood disorders during pregnancy, Marlene P. Freeman, MD, Massachusetts General Hospital, advises that clinicians select medications based on known safety information, patient preference, and the previous course of illness. Results of studies that lasted 4 to 5 years do not show major long-term adverse effects of antidepressant exposure on neurodevelopment or neurobehavior. When treating patients for bipolar disorder, valproate is associated with an increased risk of adverse cognitive and neurodevelopmental effects in infants compared with other anticonvulsants; evidence suggests that lamotrigine is a safer option. The research does not show an increased risk of major malformations with second-generation antipsychotics.

Alina Suris, PhD, receives the 2015 George Winokur Research Award from Carol S. North, MD, for her article on sirolimus as a novel treatment for veterans with posttraumaic stress disorder.

AFTERNOON SESSION

Most women have premenstrual symptoms; a minority have a full-blown syndrome, now known as premenstrual dysphoric disorder (PMDD). This is not an existing mood disorder that becomes worse premenstrually. Clinician and patients should track the temporal relationship of symptoms on a calendar for a few months. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been well studied and are effective compared with placebo, but don’t help all patients with PMDD. Consider flexible dosing strategies with SSRIs—perhaps daily use, a higher dosage premenstrually, and as-needed administration. Start with an oral contraceptive or SSRI; if symptoms don’t respond, add the other. Serotonergic antidepressants have been shown helpful for hot flashes and depressive symptoms in perimenopause. Dr. Freeman reviewed the evidence for using complementary and alternative therapies for menopausal symptoms and hot flushes.

Smoking contributes to excess mortality in seriously mentally ill patients as a result of such tobacco-related illnesses as heart disease, lung disease, and cancer. Overall improvement in mental health as well as physical health is seen when a patient stops smoking. All nicotine replacement products are effective, but patients often don’t use them long enough or correctly. Robert M. Anthenelli, MD, University of California, San Diego, said to begin sustained-release bupropion 1 or 2 weeks before quit date; maintain the dosage for 1 to 12 weeks after quit date and consider maintenance therapy for as long as 6 months. Varenicline is superior to placebo and bupropion, but is known to have gastrointestinal (GI) and sleep disturbance adverse effects. Quitting smoking can increase the blood level of some psychotropics, meaning that you might need to reduce their dosage. It is best to begin smoking cessation when patients are mentally stable, when motivated, and stable on their medications.

In discussing trends in substance abuse, Dr. Anthenelli

faddish. Fentanyl and fentanyl analogues are 100 times more powerful than morphine; ingestion of even a minuscule dose can be fatal. Synthetic cannabinoids primarily are a problem among adolescents; they are more dangerous than marijuana and are associated with aggressive and suicidal behaviors. A standard toxicology screen will not detect synthetic cannabinoids.

E-cigarettes are considered by users to be safer than tobacco cigarettes—and probably are—but they still put patients at risk of nicotine addiction. There are no safety data on e-cigarettes; the devices might contain potentially harmful chemicals and potentially toxic nicotine levels. Dr. Anthenelli reported that topiramate is “the best medication I’ve used” for alcohol abuse disorder. The drug is not FDA-approved for this use, but has been used in a number of studies with positive outcomes.

SATURDAY, APRIL 18, 2015

MORNING SESSION

Psychiatrists are well positioned to help patients with mental illness lose weight because of their psychotherapeutic background. Best treatment strategy is diet plus exercise plus behavioral modification. Robert M. McCarron, DO, University of California, Davis, recommends keeping it simple and telling patients to only consider calories of foods, and not to worry about sodium or fat content. Ask patients “How many minutes a day of exercise can you do?” but recommend that patients walk for 30 minutes a day at 4 mph, 5 days per week, which will help patients lose 1% to 3% of body weight. For treatment-refractory obese patients, consider medications such as bupropion, orlistat, lorcaserin, topiramate, or metformin; for those with a BMI ≥40, recommend bariatric surgery.

George T. Grossberg, MD, Saint Louis University School of Medicine, reviewed the evidence for anxiety disorders in older adults, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder. Older patients with cardiovascular disease, cancer, Parkinson’s disease, diabetes, GI disorders, or chronic obstructive pulmonary disease are at high risk of anxiety symptoms. In a study of centenarians, predictors of anxiety are worse health perception, financial concerns related to medical expenses, higher number of medical conditions, and loneliness. Secondary anxiety is prevalent in Alzheimer’s disease; the condition can present as fidgeting, pacing, anger, or agitation, and can be prompted by a change in routine. Acute, new-onset anxiety symptoms should trigger a complete medical evaluation, including a review of medications, supplements, and substance use. In geriatric patients, minimize use of benzodiazepines and avoid anticholinergics.

Overall, psychiatry patients do not receive optimal preventive and primary medical care, leading to decreased life expectancy, often as a result of cardiovascular disease. Psychiatric patients have a high rate of dyslipidemia, hypertension, smoking, and obesity. Psychiatrists often don’t treat these conditions, but they need to be aware of changing standard practices in preventive medicine; be able to recognize a potential problem; and make referrals when appropriate. Dr. McCarron reviewed age-based screening recommendations for hypertension, dyslipidemia, and diabetes from the book Preventive Medical Care in Psychiatry, which he co-edited. He recommends using online cardiovascular risk calculators to determine which patients need to be screened.

AFTERNOON SESSION

Some older patients who abuse substances took drugs as young adults and never gave them up; others have rediscovered drugs in later life. Potential indicators of alcohol abuse in older patients are changes in cognition, mood, memory, hygiene, or sleep. Substance abuse in older adults frequently is comorbid with depression or bereavement, anxiety, and adjustment disorders. Dr. Grossberg recommends addressing the topic directly with patients. Although there are few data to guide treatment, prompt detection and appropriate treatment can improve the quality of life of older adults and their family.

SPONSORS AND SUPPORTERS
• American Professional Agency
• American Psychiatric Publishing
• Arbor Pharmaceuticals
• AstraZeneca
• Banner Health
• Bassett Healthcare Network
• Ministry Health Care
• Pine Rest Christian Mental Health Services
• PRMS
• Sinai Health System
• Sunovion
• Takeda Pharmaceuticals
• U.S. Army Healthcare
• Wexford Health Sources
• Wolters Kluwer Health

The meeting organizers acknowledge the support provided by the sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-directors. Sponsors and supporters did not have input in these areas.

Current Psychiatry welcomed more than 650 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Co-chairs Richard Balon, MD, and Donald W. Black, MD, April 16-18, 2015, at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 18 AMA PRA Category 1 Credits™. We welcome you to join us next year in Chicago, March 10-12, 2016.

THURSDAY, APRIL 16, 2015

MORNING SESSION

Attention-deficit/hyperactivity disorder (ADHD) is a lifespan disorder that is “everywhere,” Anthony L. Rostain, MD, MA, University of Pennsylvania Perelman School of Medicine, began—including in adults and even “seniors.” This means that the disorder “is not a diagnosis of exclusion,” and that “comorbidity is the rule,” including learning difficulties. Among adults, the focus of symptoms and management is on executive dysfunction and its characteristics: difficulty multitasking, problems keeping commitments, and excessive reliance on help from others. Inattention and disorganization are hallmarks of adult ADHD, and become worse as environmental demands (work, home) increase; hyperactivity decreases with age. Dr. Rostain recommends ruling out other causes of a patient’s symptoms when an adult self-reports ADHD, including transient stressors, medical conditions, psychiatric disorders, and malingering.
 

Donald W. Black, MD

Donald W. Black, MD, University of Iowa, reviewed DSM-5 criteria for borderline personality disorder (BPD) and offered tips for avoiding misdiagnosis, including obtaining collateral information and using rating scales. Co-occuring disorders, such as depression and substance abuse, are common. Treatment for BPD patients includes psychotherapy (individual or group), medication, and lifestyle changes. Psychotropics treat symptoms of depression, anxiety, hostility, and impulsivity of BPD but not the fundamental nature of the disorder. When establishing a patient’s treatment plan, consider the stage of illness, evaluate for any co-occurring disorders, and ask the patient what he (she) wants from treatment.

Dr. Rostain began by discussing the neurobiological basis of ADHD, which guides pharmacotherapy. He reviewed the response rate of FDA-approved agents for adults with ADHD, including stimulants, atomoxetine, and alpha-adrenergic agonists. Best response is seen with stimulants, but some patients improve with bupropion and tricyclic antidepressants (TCAs). Employ a multimodal treatment approach, Dr. Rostain recommended, which should include psychoeducation and environmental restructuring, because, as he says, “Pills don’t teach skills.” He also reviewed strategies for treating ADHD in patients who have a comorbid disorder, such as bipolar disorder, major depressive disorder, or substance abuse.

Patients with psychotic depression meet criteria for major depressive disorder but also have delusions or hallucinations. Diagnostic issues include increased guilt, cognitive impairment, paranoia, and increased hopelessness. Anthony J. Rothschild, MD, University of Massachusetts Medical School, reviewed methods for differentiating psychotic depression from schizophrenia, posttraumatic stress disorder, obsessive-compulsive disorder, and body dysmorphic disorder. There are no FDA-approved medications for psychotic depression, Dr. Rothschild explained; however, evidence shows that the combination of an antidepressant and an antipsychotic is superior to monotherapy with an agent from either class. In addition, he noted, studies show a high response rate with electroconvulsive therapy (ECT).

AFTERNOON SESSION

Return of symptoms after initial remission— while the patient is still taking an antidepressant—is considered tachyphylaxis, or “poop out.” Residual depressive symptoms, when a patient meets criteria for remission but still has troubling symptoms, is a different phenomenon, although symptoms can overlap. First, Dr. Rothschild advised, ensure that patients are given an adequate trial of an antidepressant. Options are similar when tachyphylaxis or residual symptoms are present: switch drugs or add augmentation therapy, such as lithium, thyroid hormone, or an atypical antipsychotic. Data on the efficacy for bupropion and buspirone are not strong. For treatment-resistant depression when a patient does not respond to 3 adequate antidepressant trials—consider ECT or rTMS, if available, or a monoamine oxidase inhibitor or a TCA.

Dr. Black defines antisocial personality disorder (ASPD) as a disorder of lifelong serial misbehavior, one characterized by impaired relationships, aggressive behavior, non-aggressive delinquent behavior, manipulation, and a disturbing lack of conscience. There is no standard treatment for ASPD, and no FDA-approved medications; however, potential treatments have not been adequately studied, he pointed out. Cognitive-behavioral therapy might be appropriate in mild cases; some patients benefit from specific programs— for example, ones that address drug or alcohol addiction or anger, although evidence is limited. When treating ASPD patients, Dr. Black concluded, be mindful of high attrition, possible misuse of prescribed medications, and drug-drug or drug-alcohol interactions.

Bipolar disorder is associated with the highest risk of suicide and increased lethality among all psychiatric disorders. Lithium has evidence of an anti-suicidality effect and may reduce suicide by decreasing relapse, aggression, and impulsivity. An FDA advisory on increased risk of suicidality with anticonvulsants was based on data about patients with epilepsy, not bipolar disorder. Second-generation antipsychotics, including olanzapine, quetiapine, and lurasidone, have been shown to be effective for bipolar depression. Avoid antidepressants if possible, Philip G. Janicak, MD, Northwestern University Feinberg School of Medicine, advised; if you must prescribe one, reassess the need for the drug often. Several psychotherapy modalities have evidence supporting their use in bipolar disorder.

FRIDAY, APRIL 17, 2015

MORNING SESSION

Henry A. Nasrallah, MD

Henry A. Nasrallah, MD, Saint Louis University School of Medicine, offered enlightening historical touch-points on how psychiatry’s understanding of, and its approach to, schizophrenia have changed in the past 50 years. His goal? To challenge practitioners to rethink ideas about the disorder and how they care for affected patients. From a laundry list of comparative shifts, here are a few of Dr. Nasrallah’s “then” and “now” observations:

• The old paradigm was: Clinical and functional deterioration are inevitable in schizophrenia. The new paradigm is: Complete remission and restoration of function are feasible in many patients when they are fully adherent to the treatment plan.

• The old: Long-acting injectable (LAI) antipsychotics are a last-resort treatment, to be prescribed after a patient is stabilized. The new: Use LAI antipsychotics early in the course.

• Old: Begin treatment when psychosis appears. New: Work to prevent conversion to psychosis.

• Old: The disorder is considered a con­sequence of neurochemical dysregulation. New: Impaired neuroplasticity is to blame.

• Old: Treatment is a matter of trial and error. New: We can apply pharmaco-genomics to predict a patient’s response to various drugs and thus increase the likelihood of therapeutic success.

In his second presentation, Dr. Nasrallah described the many pathways to psychosis and several psychotic disorders other than schizophrenia, including schizoaffective, delusional disorder, and psychotic disorder caused by a general medical condition. He listed symptom clusters in psychosis beyond positive and negative symptoms, including neuromotor symptoms, mood symptoms, and neurocognitive deficits. Development of schizophrenia is multifactorial and involves risk genes and environmental factors seen before conception, during birth, and in early childhood; good prenatal care is the best way to prevent schizophrenia, Dr. Nasrallah noted. Several general medical conditions can produce schizophrenia-like psychosis, including some CNS disorders, toxins, autoimmune diseases, infectious diseases, and chromosomal abnormalities. The session concluded with a live interview with one of Dr. Nasrallah’s patients, whose schizophrenia is in remission with clozapine.

Drug abuse can mask signs and symptoms of bipolar disorder, which can delay diagnosis. Commonly abused substances are nicotine, alcohol, Cannabis, and cocaine; polysubstance abuse is the rule. Bipolar disorder and substance abuse share common mechanisms: impulsivity, poor modulation of motivation and response to reward, and behavioral sensitization. Treatment approaches should be flexible. Dr. Janicak reviewed the evidence for using anticonvulsants, antipsychotics, and bupropion for alcohol, Cannabis, and cocaine abuse; there are no data on treating opioid abuse. He also discussed the evidence for using naltrexone, acamprosate, disulfiram, and varenicline, as well as psychotherapeutic options, to treat substance abuse. Dr. Janicak encouraged clinicians in the audience to treat substance abuse in bipolar disorder patients themselves, instead of referring them to a subspecialist.

Untreated psychiatric disorders increase obstetrical complications, possibly through decreased self-care or increased stress. For mild or moderate depression, psychotherapy might be sufficient treatment; but for severe cases, medication is the first-line approach. In her presentation on mood disorders during pregnancy, Marlene P. Freeman, MD, Massachusetts General Hospital, advises that clinicians select medications based on known safety information, patient preference, and the previous course of illness. Results of studies that lasted 4 to 5 years do not show major long-term adverse effects of antidepressant exposure on neurodevelopment or neurobehavior. When treating patients for bipolar disorder, valproate is associated with an increased risk of adverse cognitive and neurodevelopmental effects in infants compared with other anticonvulsants; evidence suggests that lamotrigine is a safer option. The research does not show an increased risk of major malformations with second-generation antipsychotics.

Alina Suris, PhD, receives the 2015 George Winokur Research Award from Carol S. North, MD, for her article on sirolimus as a novel treatment for veterans with posttraumaic stress disorder.

AFTERNOON SESSION

Most women have premenstrual symptoms; a minority have a full-blown syndrome, now known as premenstrual dysphoric disorder (PMDD). This is not an existing mood disorder that becomes worse premenstrually. Clinician and patients should track the temporal relationship of symptoms on a calendar for a few months. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been well studied and are effective compared with placebo, but don’t help all patients with PMDD. Consider flexible dosing strategies with SSRIs—perhaps daily use, a higher dosage premenstrually, and as-needed administration. Start with an oral contraceptive or SSRI; if symptoms don’t respond, add the other. Serotonergic antidepressants have been shown helpful for hot flashes and depressive symptoms in perimenopause. Dr. Freeman reviewed the evidence for using complementary and alternative therapies for menopausal symptoms and hot flushes.

Smoking contributes to excess mortality in seriously mentally ill patients as a result of such tobacco-related illnesses as heart disease, lung disease, and cancer. Overall improvement in mental health as well as physical health is seen when a patient stops smoking. All nicotine replacement products are effective, but patients often don’t use them long enough or correctly. Robert M. Anthenelli, MD, University of California, San Diego, said to begin sustained-release bupropion 1 or 2 weeks before quit date; maintain the dosage for 1 to 12 weeks after quit date and consider maintenance therapy for as long as 6 months. Varenicline is superior to placebo and bupropion, but is known to have gastrointestinal (GI) and sleep disturbance adverse effects. Quitting smoking can increase the blood level of some psychotropics, meaning that you might need to reduce their dosage. It is best to begin smoking cessation when patients are mentally stable, when motivated, and stable on their medications.

In discussing trends in substance abuse, Dr. Anthenelli

faddish. Fentanyl and fentanyl analogues are 100 times more powerful than morphine; ingestion of even a minuscule dose can be fatal. Synthetic cannabinoids primarily are a problem among adolescents; they are more dangerous than marijuana and are associated with aggressive and suicidal behaviors. A standard toxicology screen will not detect synthetic cannabinoids.

E-cigarettes are considered by users to be safer than tobacco cigarettes—and probably are—but they still put patients at risk of nicotine addiction. There are no safety data on e-cigarettes; the devices might contain potentially harmful chemicals and potentially toxic nicotine levels. Dr. Anthenelli reported that topiramate is “the best medication I’ve used” for alcohol abuse disorder. The drug is not FDA-approved for this use, but has been used in a number of studies with positive outcomes.

SATURDAY, APRIL 18, 2015

MORNING SESSION

Psychiatrists are well positioned to help patients with mental illness lose weight because of their psychotherapeutic background. Best treatment strategy is diet plus exercise plus behavioral modification. Robert M. McCarron, DO, University of California, Davis, recommends keeping it simple and telling patients to only consider calories of foods, and not to worry about sodium or fat content. Ask patients “How many minutes a day of exercise can you do?” but recommend that patients walk for 30 minutes a day at 4 mph, 5 days per week, which will help patients lose 1% to 3% of body weight. For treatment-refractory obese patients, consider medications such as bupropion, orlistat, lorcaserin, topiramate, or metformin; for those with a BMI ≥40, recommend bariatric surgery.

George T. Grossberg, MD, Saint Louis University School of Medicine, reviewed the evidence for anxiety disorders in older adults, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder. Older patients with cardiovascular disease, cancer, Parkinson’s disease, diabetes, GI disorders, or chronic obstructive pulmonary disease are at high risk of anxiety symptoms. In a study of centenarians, predictors of anxiety are worse health perception, financial concerns related to medical expenses, higher number of medical conditions, and loneliness. Secondary anxiety is prevalent in Alzheimer’s disease; the condition can present as fidgeting, pacing, anger, or agitation, and can be prompted by a change in routine. Acute, new-onset anxiety symptoms should trigger a complete medical evaluation, including a review of medications, supplements, and substance use. In geriatric patients, minimize use of benzodiazepines and avoid anticholinergics.

Overall, psychiatry patients do not receive optimal preventive and primary medical care, leading to decreased life expectancy, often as a result of cardiovascular disease. Psychiatric patients have a high rate of dyslipidemia, hypertension, smoking, and obesity. Psychiatrists often don’t treat these conditions, but they need to be aware of changing standard practices in preventive medicine; be able to recognize a potential problem; and make referrals when appropriate. Dr. McCarron reviewed age-based screening recommendations for hypertension, dyslipidemia, and diabetes from the book Preventive Medical Care in Psychiatry, which he co-edited. He recommends using online cardiovascular risk calculators to determine which patients need to be screened.

AFTERNOON SESSION

Some older patients who abuse substances took drugs as young adults and never gave them up; others have rediscovered drugs in later life. Potential indicators of alcohol abuse in older patients are changes in cognition, mood, memory, hygiene, or sleep. Substance abuse in older adults frequently is comorbid with depression or bereavement, anxiety, and adjustment disorders. Dr. Grossberg recommends addressing the topic directly with patients. Although there are few data to guide treatment, prompt detection and appropriate treatment can improve the quality of life of older adults and their family.

SPONSORS AND SUPPORTERS
• American Professional Agency
• American Psychiatric Publishing
• Arbor Pharmaceuticals
• AstraZeneca
• Banner Health
• Bassett Healthcare Network
• Ministry Health Care
• Pine Rest Christian Mental Health Services
• PRMS
• Sinai Health System
• Sunovion
• Takeda Pharmaceuticals
• U.S. Army Healthcare
• Wexford Health Sources
• Wolters Kluwer Health

The meeting organizers acknowledge the support provided by the sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-directors. Sponsors and supporters did not have input in these areas.

Current Psychiatry welcomed more than 650 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Co-chairs Richard Balon, MD, and Donald W. Black, MD, April 16-18, 2015, at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 18 AMA PRA Category 1 Credits™. We welcome you to join us next year in Chicago, March 10-12, 2016.

THURSDAY, APRIL 16, 2015

MORNING SESSION

Attention-deficit/hyperactivity disorder (ADHD) is a lifespan disorder that is “everywhere,” Anthony L. Rostain, MD, MA, University of Pennsylvania Perelman School of Medicine, began—including in adults and even “seniors.” This means that the disorder “is not a diagnosis of exclusion,” and that “comorbidity is the rule,” including learning difficulties. Among adults, the focus of symptoms and management is on executive dysfunction and its characteristics: difficulty multitasking, problems keeping commitments, and excessive reliance on help from others. Inattention and disorganization are hallmarks of adult ADHD, and become worse as environmental demands (work, home) increase; hyperactivity decreases with age. Dr. Rostain recommends ruling out other causes of a patient’s symptoms when an adult self-reports ADHD, including transient stressors, medical conditions, psychiatric disorders, and malingering.
 

Donald W. Black, MD

Donald W. Black, MD, University of Iowa, reviewed DSM-5 criteria for borderline personality disorder (BPD) and offered tips for avoiding misdiagnosis, including obtaining collateral information and using rating scales. Co-occuring disorders, such as depression and substance abuse, are common. Treatment for BPD patients includes psychotherapy (individual or group), medication, and lifestyle changes. Psychotropics treat symptoms of depression, anxiety, hostility, and impulsivity of BPD but not the fundamental nature of the disorder. When establishing a patient’s treatment plan, consider the stage of illness, evaluate for any co-occurring disorders, and ask the patient what he (she) wants from treatment.

Dr. Rostain began by discussing the neurobiological basis of ADHD, which guides pharmacotherapy. He reviewed the response rate of FDA-approved agents for adults with ADHD, including stimulants, atomoxetine, and alpha-adrenergic agonists. Best response is seen with stimulants, but some patients improve with bupropion and tricyclic antidepressants (TCAs). Employ a multimodal treatment approach, Dr. Rostain recommended, which should include psychoeducation and environmental restructuring, because, as he says, “Pills don’t teach skills.” He also reviewed strategies for treating ADHD in patients who have a comorbid disorder, such as bipolar disorder, major depressive disorder, or substance abuse.

Patients with psychotic depression meet criteria for major depressive disorder but also have delusions or hallucinations. Diagnostic issues include increased guilt, cognitive impairment, paranoia, and increased hopelessness. Anthony J. Rothschild, MD, University of Massachusetts Medical School, reviewed methods for differentiating psychotic depression from schizophrenia, posttraumatic stress disorder, obsessive-compulsive disorder, and body dysmorphic disorder. There are no FDA-approved medications for psychotic depression, Dr. Rothschild explained; however, evidence shows that the combination of an antidepressant and an antipsychotic is superior to monotherapy with an agent from either class. In addition, he noted, studies show a high response rate with electroconvulsive therapy (ECT).

AFTERNOON SESSION

Return of symptoms after initial remission— while the patient is still taking an antidepressant—is considered tachyphylaxis, or “poop out.” Residual depressive symptoms, when a patient meets criteria for remission but still has troubling symptoms, is a different phenomenon, although symptoms can overlap. First, Dr. Rothschild advised, ensure that patients are given an adequate trial of an antidepressant. Options are similar when tachyphylaxis or residual symptoms are present: switch drugs or add augmentation therapy, such as lithium, thyroid hormone, or an atypical antipsychotic. Data on the efficacy for bupropion and buspirone are not strong. For treatment-resistant depression when a patient does not respond to 3 adequate antidepressant trials—consider ECT or rTMS, if available, or a monoamine oxidase inhibitor or a TCA.

Dr. Black defines antisocial personality disorder (ASPD) as a disorder of lifelong serial misbehavior, one characterized by impaired relationships, aggressive behavior, non-aggressive delinquent behavior, manipulation, and a disturbing lack of conscience. There is no standard treatment for ASPD, and no FDA-approved medications; however, potential treatments have not been adequately studied, he pointed out. Cognitive-behavioral therapy might be appropriate in mild cases; some patients benefit from specific programs— for example, ones that address drug or alcohol addiction or anger, although evidence is limited. When treating ASPD patients, Dr. Black concluded, be mindful of high attrition, possible misuse of prescribed medications, and drug-drug or drug-alcohol interactions.

Bipolar disorder is associated with the highest risk of suicide and increased lethality among all psychiatric disorders. Lithium has evidence of an anti-suicidality effect and may reduce suicide by decreasing relapse, aggression, and impulsivity. An FDA advisory on increased risk of suicidality with anticonvulsants was based on data about patients with epilepsy, not bipolar disorder. Second-generation antipsychotics, including olanzapine, quetiapine, and lurasidone, have been shown to be effective for bipolar depression. Avoid antidepressants if possible, Philip G. Janicak, MD, Northwestern University Feinberg School of Medicine, advised; if you must prescribe one, reassess the need for the drug often. Several psychotherapy modalities have evidence supporting their use in bipolar disorder.

FRIDAY, APRIL 17, 2015

MORNING SESSION

Henry A. Nasrallah, MD

Henry A. Nasrallah, MD, Saint Louis University School of Medicine, offered enlightening historical touch-points on how psychiatry’s understanding of, and its approach to, schizophrenia have changed in the past 50 years. His goal? To challenge practitioners to rethink ideas about the disorder and how they care for affected patients. From a laundry list of comparative shifts, here are a few of Dr. Nasrallah’s “then” and “now” observations:

• The old paradigm was: Clinical and functional deterioration are inevitable in schizophrenia. The new paradigm is: Complete remission and restoration of function are feasible in many patients when they are fully adherent to the treatment plan.

• The old: Long-acting injectable (LAI) antipsychotics are a last-resort treatment, to be prescribed after a patient is stabilized. The new: Use LAI antipsychotics early in the course.

• Old: Begin treatment when psychosis appears. New: Work to prevent conversion to psychosis.

• Old: The disorder is considered a con­sequence of neurochemical dysregulation. New: Impaired neuroplasticity is to blame.

• Old: Treatment is a matter of trial and error. New: We can apply pharmaco-genomics to predict a patient’s response to various drugs and thus increase the likelihood of therapeutic success.

In his second presentation, Dr. Nasrallah described the many pathways to psychosis and several psychotic disorders other than schizophrenia, including schizoaffective, delusional disorder, and psychotic disorder caused by a general medical condition. He listed symptom clusters in psychosis beyond positive and negative symptoms, including neuromotor symptoms, mood symptoms, and neurocognitive deficits. Development of schizophrenia is multifactorial and involves risk genes and environmental factors seen before conception, during birth, and in early childhood; good prenatal care is the best way to prevent schizophrenia, Dr. Nasrallah noted. Several general medical conditions can produce schizophrenia-like psychosis, including some CNS disorders, toxins, autoimmune diseases, infectious diseases, and chromosomal abnormalities. The session concluded with a live interview with one of Dr. Nasrallah’s patients, whose schizophrenia is in remission with clozapine.

Drug abuse can mask signs and symptoms of bipolar disorder, which can delay diagnosis. Commonly abused substances are nicotine, alcohol, Cannabis, and cocaine; polysubstance abuse is the rule. Bipolar disorder and substance abuse share common mechanisms: impulsivity, poor modulation of motivation and response to reward, and behavioral sensitization. Treatment approaches should be flexible. Dr. Janicak reviewed the evidence for using anticonvulsants, antipsychotics, and bupropion for alcohol, Cannabis, and cocaine abuse; there are no data on treating opioid abuse. He also discussed the evidence for using naltrexone, acamprosate, disulfiram, and varenicline, as well as psychotherapeutic options, to treat substance abuse. Dr. Janicak encouraged clinicians in the audience to treat substance abuse in bipolar disorder patients themselves, instead of referring them to a subspecialist.

Untreated psychiatric disorders increase obstetrical complications, possibly through decreased self-care or increased stress. For mild or moderate depression, psychotherapy might be sufficient treatment; but for severe cases, medication is the first-line approach. In her presentation on mood disorders during pregnancy, Marlene P. Freeman, MD, Massachusetts General Hospital, advises that clinicians select medications based on known safety information, patient preference, and the previous course of illness. Results of studies that lasted 4 to 5 years do not show major long-term adverse effects of antidepressant exposure on neurodevelopment or neurobehavior. When treating patients for bipolar disorder, valproate is associated with an increased risk of adverse cognitive and neurodevelopmental effects in infants compared with other anticonvulsants; evidence suggests that lamotrigine is a safer option. The research does not show an increased risk of major malformations with second-generation antipsychotics.

Alina Suris, PhD, receives the 2015 George Winokur Research Award from Carol S. North, MD, for her article on sirolimus as a novel treatment for veterans with posttraumaic stress disorder.

AFTERNOON SESSION

Most women have premenstrual symptoms; a minority have a full-blown syndrome, now known as premenstrual dysphoric disorder (PMDD). This is not an existing mood disorder that becomes worse premenstrually. Clinician and patients should track the temporal relationship of symptoms on a calendar for a few months. Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been well studied and are effective compared with placebo, but don’t help all patients with PMDD. Consider flexible dosing strategies with SSRIs—perhaps daily use, a higher dosage premenstrually, and as-needed administration. Start with an oral contraceptive or SSRI; if symptoms don’t respond, add the other. Serotonergic antidepressants have been shown helpful for hot flashes and depressive symptoms in perimenopause. Dr. Freeman reviewed the evidence for using complementary and alternative therapies for menopausal symptoms and hot flushes.

Smoking contributes to excess mortality in seriously mentally ill patients as a result of such tobacco-related illnesses as heart disease, lung disease, and cancer. Overall improvement in mental health as well as physical health is seen when a patient stops smoking. All nicotine replacement products are effective, but patients often don’t use them long enough or correctly. Robert M. Anthenelli, MD, University of California, San Diego, said to begin sustained-release bupropion 1 or 2 weeks before quit date; maintain the dosage for 1 to 12 weeks after quit date and consider maintenance therapy for as long as 6 months. Varenicline is superior to placebo and bupropion, but is known to have gastrointestinal (GI) and sleep disturbance adverse effects. Quitting smoking can increase the blood level of some psychotropics, meaning that you might need to reduce their dosage. It is best to begin smoking cessation when patients are mentally stable, when motivated, and stable on their medications.

In discussing trends in substance abuse, Dr. Anthenelli

faddish. Fentanyl and fentanyl analogues are 100 times more powerful than morphine; ingestion of even a minuscule dose can be fatal. Synthetic cannabinoids primarily are a problem among adolescents; they are more dangerous than marijuana and are associated with aggressive and suicidal behaviors. A standard toxicology screen will not detect synthetic cannabinoids.

E-cigarettes are considered by users to be safer than tobacco cigarettes—and probably are—but they still put patients at risk of nicotine addiction. There are no safety data on e-cigarettes; the devices might contain potentially harmful chemicals and potentially toxic nicotine levels. Dr. Anthenelli reported that topiramate is “the best medication I’ve used” for alcohol abuse disorder. The drug is not FDA-approved for this use, but has been used in a number of studies with positive outcomes.

SATURDAY, APRIL 18, 2015

MORNING SESSION

Psychiatrists are well positioned to help patients with mental illness lose weight because of their psychotherapeutic background. Best treatment strategy is diet plus exercise plus behavioral modification. Robert M. McCarron, DO, University of California, Davis, recommends keeping it simple and telling patients to only consider calories of foods, and not to worry about sodium or fat content. Ask patients “How many minutes a day of exercise can you do?” but recommend that patients walk for 30 minutes a day at 4 mph, 5 days per week, which will help patients lose 1% to 3% of body weight. For treatment-refractory obese patients, consider medications such as bupropion, orlistat, lorcaserin, topiramate, or metformin; for those with a BMI ≥40, recommend bariatric surgery.

George T. Grossberg, MD, Saint Louis University School of Medicine, reviewed the evidence for anxiety disorders in older adults, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, and posttraumatic stress disorder. Older patients with cardiovascular disease, cancer, Parkinson’s disease, diabetes, GI disorders, or chronic obstructive pulmonary disease are at high risk of anxiety symptoms. In a study of centenarians, predictors of anxiety are worse health perception, financial concerns related to medical expenses, higher number of medical conditions, and loneliness. Secondary anxiety is prevalent in Alzheimer’s disease; the condition can present as fidgeting, pacing, anger, or agitation, and can be prompted by a change in routine. Acute, new-onset anxiety symptoms should trigger a complete medical evaluation, including a review of medications, supplements, and substance use. In geriatric patients, minimize use of benzodiazepines and avoid anticholinergics.

Overall, psychiatry patients do not receive optimal preventive and primary medical care, leading to decreased life expectancy, often as a result of cardiovascular disease. Psychiatric patients have a high rate of dyslipidemia, hypertension, smoking, and obesity. Psychiatrists often don’t treat these conditions, but they need to be aware of changing standard practices in preventive medicine; be able to recognize a potential problem; and make referrals when appropriate. Dr. McCarron reviewed age-based screening recommendations for hypertension, dyslipidemia, and diabetes from the book Preventive Medical Care in Psychiatry, which he co-edited. He recommends using online cardiovascular risk calculators to determine which patients need to be screened.

AFTERNOON SESSION

Some older patients who abuse substances took drugs as young adults and never gave them up; others have rediscovered drugs in later life. Potential indicators of alcohol abuse in older patients are changes in cognition, mood, memory, hygiene, or sleep. Substance abuse in older adults frequently is comorbid with depression or bereavement, anxiety, and adjustment disorders. Dr. Grossberg recommends addressing the topic directly with patients. Although there are few data to guide treatment, prompt detection and appropriate treatment can improve the quality of life of older adults and their family.

SPONSORS AND SUPPORTERS
• American Professional Agency
• American Psychiatric Publishing
• Arbor Pharmaceuticals
• AstraZeneca
• Banner Health
• Bassett Healthcare Network
• Ministry Health Care
• Pine Rest Christian Mental Health Services
• PRMS
• Sinai Health System
• Sunovion
• Takeda Pharmaceuticals
• U.S. Army Healthcare
• Wexford Health Sources
• Wolters Kluwer Health

The meeting organizers acknowledge the support provided by the sponsors. Determination of educational content for this program and the selection of speakers are responsibilities of the program director and co-directors. Sponsors and supporters did not have input in these areas.

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

The obsessive pursuit of another has long been described in fiction and the scientific literature, but was conceptualized as “stalking” only rela­tively recently—first, under the guise of celebrity stalking and, later, as a public health issue recognized as affecting the general population. A useful working definition of stalking is “… the willful, malicious, and repeated fol­lowing of and harassing of another person that threatens his/her safety.”¹

Stalking victims report numerous, severe, life-changing effects from being stalked, including physical, social, and psychological harm. They typically experience mood, anxi­ety, and posttraumatic stress symptoms that require prompt evaluation and treatment.

Prevalence and other characteristics
Stalking and its subsequent victimization are common. Here are statistics:
   • in the United States, approximately 1 million women and 370,000 men are stalked annually
   • women are 3 times more likely to be stalked than raped²
   • lifetime prevalence of stalking victimization is 20% (women, 23.5%; men, 10.5%)
   • 75% of stalking victims are women
   • 77% of stalking emerges from a prior acquaintance, including 49% that originated in a romantic relationship
   • 33% of stalking encounters eventually lead to physical violence; slightly >10% of encounters lead to sexual violence
   • stalking persists for an extended period; on average, almost 2 years.³

Penalties. Stalking can result in interven­tion by the criminal justice system. Legal sanctions levied on the perpetrator vary, depending on (among other variables) the severity of stalking; type of stalking; motive of the stalker; and the strength of incriminating evidence. Surprisingly, the outcome of the perpetrator’s prosecution (arrest, conviction, length of sentence) is unrelated to whether the victim reported continued stalking at follow-up.^4,5

What are the symptoms and the dam­age? Given the intrusive nature of stalking behaviors and the extended period during which stalking persists, victims typically experience harmful psychological effects that range from subclinical symptoms to overt psychiatric disorders.

Stalking can have a profound impact on the victim and result in numerous psycho­logical symptoms that become the focus of clinical attention. The typically chronic nature of stalking probably plays a signifi­cant role in its contributions to its victims’ psychological distress.⁶ Melton⁷ found that the most common adverse effect of stalk­ing was related to the emotional impact of being stalked—with victims feeling scared, depressed, humiliated, embarrassed, dis­trustful of others, and angry or hateful.

Stalking victims report traumatic stress, hypervigilance, excessive fear, and anxiety coupled with disruptions in employment and social interactions.⁸ Many report hav­ing become highly distrustful or suspicious (44%); fearful (42%); nervous (31%); angry (27%); paranoid (36%); and depressed (21%). In general, victims have elevated scores on the Trauma Symptom Checklist.⁹

Stalking in the setting of intimate part­ner abuse is associated with harmful out­comes for the victim. These include repeat physical violence, psychological distress, and impaired physical or mental health, or both.^3,7,10

Stalking victims who are female; had a prior relationship with the stalker; have experienced a greater variety of stalking behaviors; are divorced or separated; and have received government assistance were found to be more likely to experience mul­tiple negative outcomes from stalking.¹¹

Effects on mental health. Stalking victims have a higher incidence of mental disorders and comorbid illnesses compared with the general population,¹² with the most robust associations identified between stalking victimization, major depressive disorder, and panic disorder. Stalking contributes to symptoms of posttraumatic stress disor­der,¹³ and there is an association between posttraumatic stress and poor general health.¹⁴ Stalking victims report higher cur­rent use of psychotropic medications.¹²

Victims who blame themselves for being stalked report a significantly higher severity of depression, anxiety, and post­traumatic stress symptoms. Those who ruminate more about the stalking expe­rience, or who explicitly emphasize the terror of stalking to a greater extent, also report a significantly higher severity of symptoms.¹⁵

Spitzberg³ reported that stalking victim­ization has several possible effects on vic­tims (Table 1).

The degree of a victim’s symptoms corre­lates partially with the severity of stalking. However, other variables play a crucial role in explaining the level of distress among stalking victims¹⁵; these include the types of coping strategies adopted by victims. Self-blame, catastrophizing, and rumination are significantly associated with malad­justment; on the other hand, positive reap­praisal—thoughts of attaching a positive meaning to the event, in terms of personal growth—is associated with greater psycho­logical adjustment.

The more stalking a victim experiences (and, presumably, experiences greater dis­tress), the greater the variety of coping strat­egies she (he) employs.¹⁶

How should stalking victims be treated?
Stalking victims are an underserved popu­lation. Practitioners often are unsure how to address stalking; furthermore, available treatments can be ineffective.

There is a great deal of variability in what professionals who work with stalk­ing victims believe is appropriate practice. Services provided to victims vary widely,¹⁷ and the field has not yet come to a consen­sus on best practices.¹⁶

Proceed case by case. Practitioners must understand the nuances of each case to con­sider what might work at a particular point in time, and information from victims can help guide decision-making.16 Evidence suggests that stalking victims can feel frus­trated in their attempt to seek help, particu­larly from the criminal justice system; it is possible that such bad experiences may dis­suade them from seeking help later.^5,8,18 It is worth noting that, as the frequency of stalk­ing decreases for any given victim, her (his) perception of safety increases and distress diminishes.¹⁶

Few communities have attempted to address systemically the problem of stalk­ing. Existing anti-stalking programs have focused on the criminal justice aspects of intervention,⁸ with less emphasis on treat­ing victims.

Some stalking victims rely on friends and family for support and assistance, but research shows that most reach out to agen­cies for assistance and, generally, seek help from multiple sources.¹⁸ Typically, stalking victims are served by 2 types of victim ser­vice organizations:
   • specialized, small, private and non­profit agencies (eg, domestic violence shelters, rape crisis centers, victims’ rights advocacy organizations)
   • small units housed in police depart­ments and prosecutors’ offices.¹⁷

Note: When victims seek services at criminal justice agencies, they may be feel­ing particularly unsafe and distressed. This underscores the importance of co-locating victim service providers and criminal jus­tice agencies.¹⁶

Stalking victims might benefit from multi-disciplinary team consultation, including input from psychiatric, psy­chotherapeutic, and law enforcement or security professionals. Key priorities for practitioners to address with stalking vic­tims are given in Table 2.¹⁹

Stalking behavior does not significantly decrease when victims are in contact with victim services.16 Practitioners can integrate this prospect into their understanding of stalking when they work with victims: That is, it is likely that the problem will not go away quickly, even with intervention.

Victims’ needs remain great and broad-based. Spence-Diehl et al¹⁷ conducted a survey of service providers for stalking victims, evaluating the needs of those vic­tims and the response of their communities. Some of their recommendations for better meeting victims’ needs are in Table 3.¹⁶

At the heart of a client-centered model of victim assistance is the provider’s abil­ity to listen to a victim’s story and respond in a nonjudgmental manner. This approach honors the victim’s circumstances and her personal understanding of risk.²¹
 

Bottom Line
Stalking victims are a distinctive population, experiencing numerous emotional, physical, and social effects of their stalking over an extended period. Services to treat this underserved population need to be further developed. A multifaceted approach to treating victims incorporates psychological, somatic, and practical interventions, and a victim-centered approach is associated with better outcomes.
 

Related Resources
• Harmon RB, O’Connor M. Forcier A, et al. The impact of anti-stalking training on front line service providers: using the anti-stalking training evaluation protocol (ASTEP). J Forensic Science. 2004;49(5):1050-1055.
• Spitzberg BH, Cupach WR. The state of the art of stalking: tak­ing stock of the emerging literature. Aggression and Violence Behavior. 2007;12(1):64-86.
 

Disclosure
The author reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

Some of my patients e-mail me questions about their prescriptions, test results, treat­ment, appointments, etc. I’m often unsure about the best way to respond. If I use e-mail to communicate with patients, what step(s) should I take to minimize medicolegal risks?

Submitted by “Dr. V”

Medicine adopts new communi­cation technologies cautiously. Calling patients seems unremark­able to us now, but it took decades after the invention of the telephone for doctors to feel comfortable talking to patients other than in face-to-face meetings.^1,2

Patients want to communicate with their physicians via electronic mail,³ but concerns about security, confidentiality, and liability stop many physicians from using e-mail in their practice. Yet many medical organiza­tions, including the Institute of Medicine,⁴ the American Medical Association,⁵ and the American Psychiatric Association,⁶ recog­nize that e-mail can facilitate care, if used properly.

Although e-mailing patients may feel awkward, a growing minority of clinicians regularly use e-mail for patient communi­cation.^2,7 In this article, we discuss ways to help safeguard your patients and their com­munications and to protect yourself from legal headaches.⁸

As you’re reading, please remember that we’re discussing communications to patients through standard e-mail, not secure portals (such as MyChart) that allow patients to contact physicians confi­dentially through their electronic medical records.

Privacy and security
Doctor-patient e-mails implicate the same professional, ethical, and legal responsibili­ties that govern any communication with patients.^2,9,10 If handled improperly, out­side-the-office doctor-patient communica­tion can breach traditional duties to protect confidentiality, or they can violate provi­sions of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).¹¹ Confidentiality breaches can lead to mal­practice litigation, and HIPAA infractions can result in civil and criminal penal­ties levied by federal agencies.¹² Further, e-mails that breach ethical standards (Table 1⁵) can generate complaints to your state’s medical licensure board.

E-mail appeals to many patients, if for no other reason than to save time or avoid the inconvenience of playing “phone tag” with the doctor’s office. But e-mail has drawbacks. Patients may think or behave as though online communications are inti­mate and confidential, but they usually aren’t. If e-mail programs are left open or aren’t password protected, friends and fam­ily members might look at messages and even act upon them. For this reason, doc­tors often cannot be sure whether they are communicating with the patient or with someone else who has gained access to the patient’s e-mail account.

Parties outside the treatment relation­ship could have access to e-mail data stored on servers.⁶ Also, it’s easy to misread or mistype an e-mail address and send confi­dential information to the wrong person. A truly “secure” e-mail exchange uses encryp­tion software that protects messages dur­ing transmission and storage and requires users to authenticate who they are through actions that link their identity to the e-mail address.¹³ But some patients and physicians do not know about the availability of such security measures, and implementing them can feel cumbersome to those who are not computer savvy. Not surprisingly, then, recent studies have shown that such mea­sures are used infrequently by physicians and patients.¹⁴

Topics for e-mail communication
One way to minimize potential privacy problems is to limit the topics and types of communication dealt with by e-mail. Several experts and organizations have published suggestions, recommendations, and resources for doing this with common practices (Table 2).^6,7,15

Receiving e-mail permission
Many patients e-mail their physicians with­out the physicians’ prior agreement. But physicians who plan to use e-mail in their practice should get patients’ explicit consent. This can be done verbally, with the content of the discussion documented in the medi­cal record. But it’s better to have patients authorize e-mail communications in writing by means of a permission form that also sets out your office’s e-mail policies, expected response times, and privacy limitations.

Commonly recommended contents of such forms^5-7,9,15,16 include:
   • discussing security mechanisms and limits of security
   • e-mail encryption requirements (or waiving them, if the patient prefers)
   • providing an expected response time
   • indemnifying you or your institution for information loss caused by techni­cal failure
   • identifying who reads e-mails (eg, office staff members, a nurse, physician [only])
   • asking patients to put their name and other identifying information in the body of the message, not the subject line
   • asking patients to put the type of ques­tion in the subject line (eg, “prescrip­tion,” “appointment,” “billing”)
   • asking patients to use the “auto reply” feature to acknowledge receipt of your messages.

In addition to using patient consent forms, other suggestions and recommendations for physicians include:
   • Do not use e-mail to establish patient-physician relationships, only to supplement personal encounters.
   • If you work for an agency or institution, know and follow its guidelines and policies.
   • If a rule or “boundary” is breached (eg, a patient sends you a detailed e-mail on a topic beyond the scope of your previous agreement), address this directly in a treat­ment session.
   • File e-mail correspondence, including your reply, in the patient’s medical record.
   • Use encryption technology if it is avail­able, practical, and user-friendly.
   • Use a practice-dedicated e-mail address with an automatic response that explains when e-mail will be answered and reminds patients to seek immediate help for urgent matters.

Real legal risk
Earlier, we described conceivable legal risks that e-mail might create. But has e-mail caused legal problems for physicians? At least 3 recent published decisions answer: “Yes.” And, remember, only a fraction of legal cases lead to published decisions.
   • Huffine v Department of Health¹⁷ con­cerns a psychiatrist who was censured by the Washington state medical quality assur­ance commission for several boundary crossings, including sending his adolescent patient overly intimate e-mails.
   • Wheeler v Kron¹⁸ lists a variety of legal claims—intentional infliction of emotional distress, negligent infliction of emotional distress, general negligence, and medical malpractice—that arose from a psychia­trist’s e-mailed concerns about visitation arrangements in a divorcing couple’s cus­tody dispute. Although the court dismissed the last 3 claims, it allowed the intentional infliction of emotional distress claim to proceed.
   • Ortegoza v Kho¹⁹ includes excerpts of e-mails between a primary care physician and his married patient, with whom the physician had affair that led to a medical malpractice lawsuit.
 

Bottom Line
Most patients want to e-mail their physicians, and many psychiatrists find e-mail helpful in caring for patients. If you are using e-mail in your practice or are contemplating doing so, get the patient’s permission (preferably in writing), and follow the recommendations and guidelines cited in this article’s references.
 

Related Resources
• Kane B, Sands DZ. Guidelines for the clinical use of elec­tronic mail with patients. http://jamia.oxfordjournals.org/content/5/1/104.long.
• Professional Risk Management Services, Inc. Sample email consent and guide to email use. www.psychprogram.com/currentpsychiatry.html.

Dear Dr. Mossman,

Some of my patients e-mail me questions about their prescriptions, test results, treat­ment, appointments, etc. I’m often unsure about the best way to respond. If I use e-mail to communicate with patients, what step(s) should I take to minimize medicolegal risks?

Submitted by “Dr. V”

Medicine adopts new communi­cation technologies cautiously. Calling patients seems unremark­able to us now, but it took decades after the invention of the telephone for doctors to feel comfortable talking to patients other than in face-to-face meetings.^1,2

Patients want to communicate with their physicians via electronic mail,³ but concerns about security, confidentiality, and liability stop many physicians from using e-mail in their practice. Yet many medical organiza­tions, including the Institute of Medicine,⁴ the American Medical Association,⁵ and the American Psychiatric Association,⁶ recog­nize that e-mail can facilitate care, if used properly.

Although e-mailing patients may feel awkward, a growing minority of clinicians regularly use e-mail for patient communi­cation.^2,7 In this article, we discuss ways to help safeguard your patients and their com­munications and to protect yourself from legal headaches.⁸

As you’re reading, please remember that we’re discussing communications to patients through standard e-mail, not secure portals (such as MyChart) that allow patients to contact physicians confi­dentially through their electronic medical records.

Privacy and security
Doctor-patient e-mails implicate the same professional, ethical, and legal responsibili­ties that govern any communication with patients.^2,9,10 If handled improperly, out­side-the-office doctor-patient communica­tion can breach traditional duties to protect confidentiality, or they can violate provi­sions of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).¹¹ Confidentiality breaches can lead to mal­practice litigation, and HIPAA infractions can result in civil and criminal penal­ties levied by federal agencies.¹² Further, e-mails that breach ethical standards (Table 1⁵) can generate complaints to your state’s medical licensure board.

E-mail appeals to many patients, if for no other reason than to save time or avoid the inconvenience of playing “phone tag” with the doctor’s office. But e-mail has drawbacks. Patients may think or behave as though online communications are inti­mate and confidential, but they usually aren’t. If e-mail programs are left open or aren’t password protected, friends and fam­ily members might look at messages and even act upon them. For this reason, doc­tors often cannot be sure whether they are communicating with the patient or with someone else who has gained access to the patient’s e-mail account.

Parties outside the treatment relation­ship could have access to e-mail data stored on servers.⁶ Also, it’s easy to misread or mistype an e-mail address and send confi­dential information to the wrong person. A truly “secure” e-mail exchange uses encryp­tion software that protects messages dur­ing transmission and storage and requires users to authenticate who they are through actions that link their identity to the e-mail address.¹³ But some patients and physicians do not know about the availability of such security measures, and implementing them can feel cumbersome to those who are not computer savvy. Not surprisingly, then, recent studies have shown that such mea­sures are used infrequently by physicians and patients.¹⁴

Topics for e-mail communication
One way to minimize potential privacy problems is to limit the topics and types of communication dealt with by e-mail. Several experts and organizations have published suggestions, recommendations, and resources for doing this with common practices (Table 2).^6,7,15

Receiving e-mail permission
Many patients e-mail their physicians with­out the physicians’ prior agreement. But physicians who plan to use e-mail in their practice should get patients’ explicit consent. This can be done verbally, with the content of the discussion documented in the medi­cal record. But it’s better to have patients authorize e-mail communications in writing by means of a permission form that also sets out your office’s e-mail policies, expected response times, and privacy limitations.

Commonly recommended contents of such forms^5-7,9,15,16 include:
   • discussing security mechanisms and limits of security
   • e-mail encryption requirements (or waiving them, if the patient prefers)
   • providing an expected response time
   • indemnifying you or your institution for information loss caused by techni­cal failure
   • identifying who reads e-mails (eg, office staff members, a nurse, physician [only])
   • asking patients to put their name and other identifying information in the body of the message, not the subject line
   • asking patients to put the type of ques­tion in the subject line (eg, “prescrip­tion,” “appointment,” “billing”)
   • asking patients to use the “auto reply” feature to acknowledge receipt of your messages.

In addition to using patient consent forms, other suggestions and recommendations for physicians include:
   • Do not use e-mail to establish patient-physician relationships, only to supplement personal encounters.
   • If you work for an agency or institution, know and follow its guidelines and policies.
   • If a rule or “boundary” is breached (eg, a patient sends you a detailed e-mail on a topic beyond the scope of your previous agreement), address this directly in a treat­ment session.
   • File e-mail correspondence, including your reply, in the patient’s medical record.
   • Use encryption technology if it is avail­able, practical, and user-friendly.
   • Use a practice-dedicated e-mail address with an automatic response that explains when e-mail will be answered and reminds patients to seek immediate help for urgent matters.

Real legal risk
Earlier, we described conceivable legal risks that e-mail might create. But has e-mail caused legal problems for physicians? At least 3 recent published decisions answer: “Yes.” And, remember, only a fraction of legal cases lead to published decisions.
   • Huffine v Department of Health¹⁷ con­cerns a psychiatrist who was censured by the Washington state medical quality assur­ance commission for several boundary crossings, including sending his adolescent patient overly intimate e-mails.
   • Wheeler v Kron¹⁸ lists a variety of legal claims—intentional infliction of emotional distress, negligent infliction of emotional distress, general negligence, and medical malpractice—that arose from a psychia­trist’s e-mailed concerns about visitation arrangements in a divorcing couple’s cus­tody dispute. Although the court dismissed the last 3 claims, it allowed the intentional infliction of emotional distress claim to proceed.
   • Ortegoza v Kho¹⁹ includes excerpts of e-mails between a primary care physician and his married patient, with whom the physician had affair that led to a medical malpractice lawsuit.
 

Bottom Line
Most patients want to e-mail their physicians, and many psychiatrists find e-mail helpful in caring for patients. If you are using e-mail in your practice or are contemplating doing so, get the patient’s permission (preferably in writing), and follow the recommendations and guidelines cited in this article’s references.
 

Related Resources
• Kane B, Sands DZ. Guidelines for the clinical use of elec­tronic mail with patients. http://jamia.oxfordjournals.org/content/5/1/104.long.
• Professional Risk Management Services, Inc. Sample email consent and guide to email use. www.psychprogram.com/currentpsychiatry.html.

Dear Dr. Mossman,

Some of my patients e-mail me questions about their prescriptions, test results, treat­ment, appointments, etc. I’m often unsure about the best way to respond. If I use e-mail to communicate with patients, what step(s) should I take to minimize medicolegal risks?

Submitted by “Dr. V”

Medicine adopts new communi­cation technologies cautiously. Calling patients seems unremark­able to us now, but it took decades after the invention of the telephone for doctors to feel comfortable talking to patients other than in face-to-face meetings.^1,2

Patients want to communicate with their physicians via electronic mail,³ but concerns about security, confidentiality, and liability stop many physicians from using e-mail in their practice. Yet many medical organiza­tions, including the Institute of Medicine,⁴ the American Medical Association,⁵ and the American Psychiatric Association,⁶ recog­nize that e-mail can facilitate care, if used properly.

Although e-mailing patients may feel awkward, a growing minority of clinicians regularly use e-mail for patient communi­cation.^2,7 In this article, we discuss ways to help safeguard your patients and their com­munications and to protect yourself from legal headaches.⁸

As you’re reading, please remember that we’re discussing communications to patients through standard e-mail, not secure portals (such as MyChart) that allow patients to contact physicians confi­dentially through their electronic medical records.

Privacy and security
Doctor-patient e-mails implicate the same professional, ethical, and legal responsibili­ties that govern any communication with patients.^2,9,10 If handled improperly, out­side-the-office doctor-patient communica­tion can breach traditional duties to protect confidentiality, or they can violate provi­sions of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).¹¹ Confidentiality breaches can lead to mal­practice litigation, and HIPAA infractions can result in civil and criminal penal­ties levied by federal agencies.¹² Further, e-mails that breach ethical standards (Table 1⁵) can generate complaints to your state’s medical licensure board.

E-mail appeals to many patients, if for no other reason than to save time or avoid the inconvenience of playing “phone tag” with the doctor’s office. But e-mail has drawbacks. Patients may think or behave as though online communications are inti­mate and confidential, but they usually aren’t. If e-mail programs are left open or aren’t password protected, friends and fam­ily members might look at messages and even act upon them. For this reason, doc­tors often cannot be sure whether they are communicating with the patient or with someone else who has gained access to the patient’s e-mail account.

Parties outside the treatment relation­ship could have access to e-mail data stored on servers.⁶ Also, it’s easy to misread or mistype an e-mail address and send confi­dential information to the wrong person. A truly “secure” e-mail exchange uses encryp­tion software that protects messages dur­ing transmission and storage and requires users to authenticate who they are through actions that link their identity to the e-mail address.¹³ But some patients and physicians do not know about the availability of such security measures, and implementing them can feel cumbersome to those who are not computer savvy. Not surprisingly, then, recent studies have shown that such mea­sures are used infrequently by physicians and patients.¹⁴

Topics for e-mail communication
One way to minimize potential privacy problems is to limit the topics and types of communication dealt with by e-mail. Several experts and organizations have published suggestions, recommendations, and resources for doing this with common practices (Table 2).^6,7,15

Receiving e-mail permission
Many patients e-mail their physicians with­out the physicians’ prior agreement. But physicians who plan to use e-mail in their practice should get patients’ explicit consent. This can be done verbally, with the content of the discussion documented in the medi­cal record. But it’s better to have patients authorize e-mail communications in writing by means of a permission form that also sets out your office’s e-mail policies, expected response times, and privacy limitations.

Commonly recommended contents of such forms^5-7,9,15,16 include:
   • discussing security mechanisms and limits of security
   • e-mail encryption requirements (or waiving them, if the patient prefers)
   • providing an expected response time
   • indemnifying you or your institution for information loss caused by techni­cal failure
   • identifying who reads e-mails (eg, office staff members, a nurse, physician [only])
   • asking patients to put their name and other identifying information in the body of the message, not the subject line
   • asking patients to put the type of ques­tion in the subject line (eg, “prescrip­tion,” “appointment,” “billing”)
   • asking patients to use the “auto reply” feature to acknowledge receipt of your messages.

In addition to using patient consent forms, other suggestions and recommendations for physicians include:
   • Do not use e-mail to establish patient-physician relationships, only to supplement personal encounters.
   • If you work for an agency or institution, know and follow its guidelines and policies.
   • If a rule or “boundary” is breached (eg, a patient sends you a detailed e-mail on a topic beyond the scope of your previous agreement), address this directly in a treat­ment session.
   • File e-mail correspondence, including your reply, in the patient’s medical record.
   • Use encryption technology if it is avail­able, practical, and user-friendly.
   • Use a practice-dedicated e-mail address with an automatic response that explains when e-mail will be answered and reminds patients to seek immediate help for urgent matters.

Real legal risk
Earlier, we described conceivable legal risks that e-mail might create. But has e-mail caused legal problems for physicians? At least 3 recent published decisions answer: “Yes.” And, remember, only a fraction of legal cases lead to published decisions.
   • Huffine v Department of Health¹⁷ con­cerns a psychiatrist who was censured by the Washington state medical quality assur­ance commission for several boundary crossings, including sending his adolescent patient overly intimate e-mails.
   • Wheeler v Kron¹⁸ lists a variety of legal claims—intentional infliction of emotional distress, negligent infliction of emotional distress, general negligence, and medical malpractice—that arose from a psychia­trist’s e-mailed concerns about visitation arrangements in a divorcing couple’s cus­tody dispute. Although the court dismissed the last 3 claims, it allowed the intentional infliction of emotional distress claim to proceed.
   • Ortegoza v Kho¹⁹ includes excerpts of e-mails between a primary care physician and his married patient, with whom the physician had affair that led to a medical malpractice lawsuit.
 

Bottom Line
Most patients want to e-mail their physicians, and many psychiatrists find e-mail helpful in caring for patients. If you are using e-mail in your practice or are contemplating doing so, get the patient’s permission (preferably in writing), and follow the recommendations and guidelines cited in this article’s references.
 

Related Resources
• Kane B, Sands DZ. Guidelines for the clinical use of elec­tronic mail with patients. http://jamia.oxfordjournals.org/content/5/1/104.long.
• Professional Risk Management Services, Inc. Sample email consent and guide to email use. www.psychprogram.com/currentpsychiatry.html.

Persistently high depressive symptoms are associated with increased stroke risk, according to a study published May 13 in Journal of the American Heart Association. This research included health information from 16,178 men and women age 50 or older who participated in the Health and Retirement Study between 1998 and 2010. Participants were interviewed every two years about depressive symptoms, history of stroke, and stroke risk factors, among other health measures. Stroke risk was elevated among participants with stable high (hazard ratio [HR], 2.14) or remitted (HR, 1.66) depressive symptoms, compared with participants with stable low or no depressive symptoms. Stable high depressive symptoms predicted stroke among all subgroups. Remitted depressive symptoms predicted increased stroke risk among women (HR, 1.86) and non-Hispanic white participants (HR, 1.66).

Chronic traumatic encephalopathy (CTE) is associated with altered and accelerated deposition of amyloid β, according to a study published online ahead of print May 6 in Acta Neuropathologica. Researchers studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE. The investigators found that amyloid β deposition was present in 52% of subjects with CTE. Moreover, amyloid β deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE, compared with a normal aging population. In addition, amyloid β deposition was significantly associated with the presence of the APOE e4 allele, older age at symptom onset, and older age at death. Neuritic plaques were significantly associated with increased CTE tauopathy stage, comorbid Lewy body disease, and dementia.

Low-dose tetrahydrocannabinol (THC) does not significantly reduce dementia-related neuropsychiatric symptoms at 21 days, though it is well tolerated, according to a study published online ahead of print May 13 in Neurology. In a double-blind, placebo-controlled study, investigators randomly assigned patients with dementia and clinically relevant neuropsychiatric symptoms to receive 1.5 mg of THC or matched placebo three times daily for three weeks. Neuropsychiatric symptoms were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant. Changes in scores for agitation, quality of life, or activities of daily living also were not significantly different between treatment arms. The number of patients experiencing mild or moderate adverse events was similar in both groups. No effects on vital signs, weight, or episodic memory were observed.

Exposure to elevated levels of fine particulate matter is associated with smaller total cerebral brain volume, according to a study published in the May issue of Stroke. Researchers analyzed 943 adults in the Framingham Offspring Study who were relatively healthy and free of dementia and stroke. Investigators evaluated associations between exposure to fine particulate matter and total cerebral brain volume, hippocampal volume, white matter hyperintensity volume, and covert brain infarcts. A 2-μg/m³ increase in fine particulate matter was associated with –0.32% smaller total cerebral brain volume and 1.46 higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter.

Higher occupational attainment is associated with longer survival in autopsy-confirmed frontotemporal lobar degeneration, according to a study published online ahead of print April 22 in Neurology. Researchers performed a retrospective chart review of 83 demographically matched patients with autopsy-confirmed frontotemporal lobar degeneration or Alzheimer’s disease. They used linear regression to test for associations among occupational attainment, education, and patient survival. Median survival was 81 months among patients with frontotemporal lobar degeneration and 95 months among patients with Alzheimer’s disease. Years of education and occupational attainment were similar for both groups. Higher occupational attainment was associated with longer survival in frontotemporal lobar degeneration, but not in Alzheimer’s disease. The findings support the theory that education, occupation, and mental activity create cognitive reserve and protect against disease.

Obesity is a major risk factor for the incidence and chronicity of excessive daytime sleepiness (EDS), and weight loss is associated with its remission, according to a study published March 1 in Sleep. Investigators followed up 1,395 people from a random, general population sample of 1,741 participants in the Penn State Adult Cohort after 7.5 years. The incidence of EDS was 8.2%. Of people with EDS, 62% had remission. Significant interactions between depression and polysomnographic parameters on incident EDS showed that in depressed individuals, incident EDS was associated with sleep disturbances. In individuals without depression, incident EDS was associated with increased physiologic sleep propensity. Diabetes, allergy or asthma, anemia, and sleep complaints also predicted EDS. “EDS has huge implications for public health and policy,” stated the researchers.

Patients with celiac disease have an increased risk of neuropathy, according to a study published online ahead of print May 11 in JAMA Neurology. Between October 27, 2006, and February 12, 2008, researchers collected data on small-intestinal biopsies performed in pathology departments between June 16, 1969, and February 4, 2008. Investigators compared the risk of neuropathy in 28,232 patients with celiac disease with that of 139,473 age- and sex-matched controls. Celiac disease was associated with a 2.5-fold increased risk of subsequent neuropathy. In addition, the investigators found an increased risk of chronic inflammatory demyelinating neuropathy, autonomic neuropathy, and mononeuritis multiplex in patients with celiac disease. They found no association, however, between celiac disease and acute inflammatory demyelinating polyneuropathy. Physicians should screen patients with neuropathy for celiac disease, said the researchers.

A professional life that stimulates verbal intelligence and executive function may help to sustain good cognitive function in people age 75 and older, according to a study published online ahead of print April 29 in Neurology. For the study, 1,054 people age 75 or older underwent the Mini-Mental State Examination every one-and-a-half years for eight years. In multivariate mixed-model analyses, a high level of mentally demanding work tasks stimulating verbal intelligence was significantly associated with better cognitive functioning at baseline and a lower rate of cognitive decline during the eight-year follow-up period, compared with a low level of these tasks. The rate of cognitive decline in old age was also significantly lower in individuals who had a high level of mentally demanding work tasks stimulating executive function.

In Get With the Guidelines-Stroke hospitals, electronic health records are not associated with higher-quality care or better clinical outcomes for stroke care, according to a study published May 12 in Journal of the American College of Cardiology. Researchers studied 626,473 patients from 1,236 US hospitals in Get With the Guidelines-Stroke from 2007 through 2010. They used the American Hospital Association annual survey to determine the presence of electronic health records. Hospitals with electronic health records were larger and were more often teaching hospitals and stroke centers. After controlling for patient and hospital characteristics, patients admitted to hospitals with electronic health records had similar odds of receiving “all-or-none care.” The odds of having a length of stay greater than four days was slightly lower at hospitals with electronic health records.

Off-label use of the Lariat device for left atrial appendage exclusion to prevent stroke in patients with atrial fibrillation entails significant risks of adverse events, according to a study published online ahead of print May 4 in JAMA Internal Medicine. Investigators searched PubMed, EMBASE, CINAHL, and the Cochrane Library from January 2007 through August 2014 to identify all studies reporting use of the Lariat device in three or more patients. They queried the FDA MAUDE database for adverse events reports related to Lariat use. Five reports of Lariat device use in 309 participants were identified. The FDA MAUDE database contained 35 unique reports of adverse events with use of the Lariat device. Among these reports were five adverse event reports that noted pericardial effusion and death and an additional 23 that reported urgent cardiac surgery, but not death.

Insomnia is linked to functional and cognitive impairment among patients with shift work disorder, according to a study published April 15 in Journal of Clinical Sleep Medicine. The analysis included 34 night workers, 26 of whom were diagnosed with shift work disorder. Participants underwent an overnight laboratory protocol including a multiple sleep latency test (MSLT), an event-related brain potential (ERP) task, and various questionnaires. Participants reporting insomnia without sleepiness were the most impaired on the Endicott Work Productivity Scale (EWPS) and significantly more impaired than controls. Participants reporting insomnia and sleepiness were not statistically different from controls. Neither MSLT nor the Epworth Sleepiness Scale correlated with EWPS scores or ERP amplitudes. The mean of the Insomnia Severity Indices measurements, however, correlated with the EWPS.

The measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease, according to a study published online ahead of print May 13 in Lancet. In the Prospective Urban-Rural Epidemiology study, researchers enrolled households that each included at least one member between ages 35 and 70. The investigators measured participants’ grip strength with a Jamar dynamometer. Median follow-up was four years. Grip strength was inversely associated with all-cause mortality, cardiovascular mortality, noncardiovascular mortality, myocardial infarction, and stroke. Grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure was. The researchers found no significant association between grip strength and incident diabetes, risk of hospital admission for pneumonia or chronic obstructive pulmonary disease, injury from fall, or fracture.

Sleep deprivation is particularly problematic for decision-making involving uncertainty and unexpected change, according to a study published in the May issue of Sleep. Twenty-six subjects were randomized to 62 hours of total sleep deprivation or to a control condition. Researchers conducted performance testing at baseline, after two nights of total sleep deprivation or rested control, and following two nights of recovery sleep. Participants performed a decision task that involved initial learning of response sets and subsequent reversal of contingencies. Working memory and psychomotor vigilance tests also were administered. Sleep-deprived subjects had difficulty with initial learning of stimuli sets and profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Sleep deprivation did not significantly affect working memory scanning performance.

—Kimberly Williams

Persistently high depressive symptoms are associated with increased stroke risk, according to a study published May 13 in Journal of the American Heart Association. This research included health information from 16,178 men and women age 50 or older who participated in the Health and Retirement Study between 1998 and 2010. Participants were interviewed every two years about depressive symptoms, history of stroke, and stroke risk factors, among other health measures. Stroke risk was elevated among participants with stable high (hazard ratio [HR], 2.14) or remitted (HR, 1.66) depressive symptoms, compared with participants with stable low or no depressive symptoms. Stable high depressive symptoms predicted stroke among all subgroups. Remitted depressive symptoms predicted increased stroke risk among women (HR, 1.86) and non-Hispanic white participants (HR, 1.66).

Chronic traumatic encephalopathy (CTE) is associated with altered and accelerated deposition of amyloid β, according to a study published online ahead of print May 6 in Acta Neuropathologica. Researchers studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE. The investigators found that amyloid β deposition was present in 52% of subjects with CTE. Moreover, amyloid β deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE, compared with a normal aging population. In addition, amyloid β deposition was significantly associated with the presence of the APOE e4 allele, older age at symptom onset, and older age at death. Neuritic plaques were significantly associated with increased CTE tauopathy stage, comorbid Lewy body disease, and dementia.

Low-dose tetrahydrocannabinol (THC) does not significantly reduce dementia-related neuropsychiatric symptoms at 21 days, though it is well tolerated, according to a study published online ahead of print May 13 in Neurology. In a double-blind, placebo-controlled study, investigators randomly assigned patients with dementia and clinically relevant neuropsychiatric symptoms to receive 1.5 mg of THC or matched placebo three times daily for three weeks. Neuropsychiatric symptoms were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant. Changes in scores for agitation, quality of life, or activities of daily living also were not significantly different between treatment arms. The number of patients experiencing mild or moderate adverse events was similar in both groups. No effects on vital signs, weight, or episodic memory were observed.

Exposure to elevated levels of fine particulate matter is associated with smaller total cerebral brain volume, according to a study published in the May issue of Stroke. Researchers analyzed 943 adults in the Framingham Offspring Study who were relatively healthy and free of dementia and stroke. Investigators evaluated associations between exposure to fine particulate matter and total cerebral brain volume, hippocampal volume, white matter hyperintensity volume, and covert brain infarcts. A 2-μg/m³ increase in fine particulate matter was associated with –0.32% smaller total cerebral brain volume and 1.46 higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter.

Higher occupational attainment is associated with longer survival in autopsy-confirmed frontotemporal lobar degeneration, according to a study published online ahead of print April 22 in Neurology. Researchers performed a retrospective chart review of 83 demographically matched patients with autopsy-confirmed frontotemporal lobar degeneration or Alzheimer’s disease. They used linear regression to test for associations among occupational attainment, education, and patient survival. Median survival was 81 months among patients with frontotemporal lobar degeneration and 95 months among patients with Alzheimer’s disease. Years of education and occupational attainment were similar for both groups. Higher occupational attainment was associated with longer survival in frontotemporal lobar degeneration, but not in Alzheimer’s disease. The findings support the theory that education, occupation, and mental activity create cognitive reserve and protect against disease.

Obesity is a major risk factor for the incidence and chronicity of excessive daytime sleepiness (EDS), and weight loss is associated with its remission, according to a study published March 1 in Sleep. Investigators followed up 1,395 people from a random, general population sample of 1,741 participants in the Penn State Adult Cohort after 7.5 years. The incidence of EDS was 8.2%. Of people with EDS, 62% had remission. Significant interactions between depression and polysomnographic parameters on incident EDS showed that in depressed individuals, incident EDS was associated with sleep disturbances. In individuals without depression, incident EDS was associated with increased physiologic sleep propensity. Diabetes, allergy or asthma, anemia, and sleep complaints also predicted EDS. “EDS has huge implications for public health and policy,” stated the researchers.

Patients with celiac disease have an increased risk of neuropathy, according to a study published online ahead of print May 11 in JAMA Neurology. Between October 27, 2006, and February 12, 2008, researchers collected data on small-intestinal biopsies performed in pathology departments between June 16, 1969, and February 4, 2008. Investigators compared the risk of neuropathy in 28,232 patients with celiac disease with that of 139,473 age- and sex-matched controls. Celiac disease was associated with a 2.5-fold increased risk of subsequent neuropathy. In addition, the investigators found an increased risk of chronic inflammatory demyelinating neuropathy, autonomic neuropathy, and mononeuritis multiplex in patients with celiac disease. They found no association, however, between celiac disease and acute inflammatory demyelinating polyneuropathy. Physicians should screen patients with neuropathy for celiac disease, said the researchers.

A professional life that stimulates verbal intelligence and executive function may help to sustain good cognitive function in people age 75 and older, according to a study published online ahead of print April 29 in Neurology. For the study, 1,054 people age 75 or older underwent the Mini-Mental State Examination every one-and-a-half years for eight years. In multivariate mixed-model analyses, a high level of mentally demanding work tasks stimulating verbal intelligence was significantly associated with better cognitive functioning at baseline and a lower rate of cognitive decline during the eight-year follow-up period, compared with a low level of these tasks. The rate of cognitive decline in old age was also significantly lower in individuals who had a high level of mentally demanding work tasks stimulating executive function.

In Get With the Guidelines-Stroke hospitals, electronic health records are not associated with higher-quality care or better clinical outcomes for stroke care, according to a study published May 12 in Journal of the American College of Cardiology. Researchers studied 626,473 patients from 1,236 US hospitals in Get With the Guidelines-Stroke from 2007 through 2010. They used the American Hospital Association annual survey to determine the presence of electronic health records. Hospitals with electronic health records were larger and were more often teaching hospitals and stroke centers. After controlling for patient and hospital characteristics, patients admitted to hospitals with electronic health records had similar odds of receiving “all-or-none care.” The odds of having a length of stay greater than four days was slightly lower at hospitals with electronic health records.

Off-label use of the Lariat device for left atrial appendage exclusion to prevent stroke in patients with atrial fibrillation entails significant risks of adverse events, according to a study published online ahead of print May 4 in JAMA Internal Medicine. Investigators searched PubMed, EMBASE, CINAHL, and the Cochrane Library from January 2007 through August 2014 to identify all studies reporting use of the Lariat device in three or more patients. They queried the FDA MAUDE database for adverse events reports related to Lariat use. Five reports of Lariat device use in 309 participants were identified. The FDA MAUDE database contained 35 unique reports of adverse events with use of the Lariat device. Among these reports were five adverse event reports that noted pericardial effusion and death and an additional 23 that reported urgent cardiac surgery, but not death.

Insomnia is linked to functional and cognitive impairment among patients with shift work disorder, according to a study published April 15 in Journal of Clinical Sleep Medicine. The analysis included 34 night workers, 26 of whom were diagnosed with shift work disorder. Participants underwent an overnight laboratory protocol including a multiple sleep latency test (MSLT), an event-related brain potential (ERP) task, and various questionnaires. Participants reporting insomnia without sleepiness were the most impaired on the Endicott Work Productivity Scale (EWPS) and significantly more impaired than controls. Participants reporting insomnia and sleepiness were not statistically different from controls. Neither MSLT nor the Epworth Sleepiness Scale correlated with EWPS scores or ERP amplitudes. The mean of the Insomnia Severity Indices measurements, however, correlated with the EWPS.

The measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease, according to a study published online ahead of print May 13 in Lancet. In the Prospective Urban-Rural Epidemiology study, researchers enrolled households that each included at least one member between ages 35 and 70. The investigators measured participants’ grip strength with a Jamar dynamometer. Median follow-up was four years. Grip strength was inversely associated with all-cause mortality, cardiovascular mortality, noncardiovascular mortality, myocardial infarction, and stroke. Grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure was. The researchers found no significant association between grip strength and incident diabetes, risk of hospital admission for pneumonia or chronic obstructive pulmonary disease, injury from fall, or fracture.

Sleep deprivation is particularly problematic for decision-making involving uncertainty and unexpected change, according to a study published in the May issue of Sleep. Twenty-six subjects were randomized to 62 hours of total sleep deprivation or to a control condition. Researchers conducted performance testing at baseline, after two nights of total sleep deprivation or rested control, and following two nights of recovery sleep. Participants performed a decision task that involved initial learning of response sets and subsequent reversal of contingencies. Working memory and psychomotor vigilance tests also were administered. Sleep-deprived subjects had difficulty with initial learning of stimuli sets and profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Sleep deprivation did not significantly affect working memory scanning performance.

—Kimberly Williams

Persistently high depressive symptoms are associated with increased stroke risk, according to a study published May 13 in Journal of the American Heart Association. This research included health information from 16,178 men and women age 50 or older who participated in the Health and Retirement Study between 1998 and 2010. Participants were interviewed every two years about depressive symptoms, history of stroke, and stroke risk factors, among other health measures. Stroke risk was elevated among participants with stable high (hazard ratio [HR], 2.14) or remitted (HR, 1.66) depressive symptoms, compared with participants with stable low or no depressive symptoms. Stable high depressive symptoms predicted stroke among all subgroups. Remitted depressive symptoms predicted increased stroke risk among women (HR, 1.86) and non-Hispanic white participants (HR, 1.66).

Chronic traumatic encephalopathy (CTE) is associated with altered and accelerated deposition of amyloid β, according to a study published online ahead of print May 6 in Acta Neuropathologica. Researchers studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE. The investigators found that amyloid β deposition was present in 52% of subjects with CTE. Moreover, amyloid β deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE, compared with a normal aging population. In addition, amyloid β deposition was significantly associated with the presence of the APOE e4 allele, older age at symptom onset, and older age at death. Neuritic plaques were significantly associated with increased CTE tauopathy stage, comorbid Lewy body disease, and dementia.

Low-dose tetrahydrocannabinol (THC) does not significantly reduce dementia-related neuropsychiatric symptoms at 21 days, though it is well tolerated, according to a study published online ahead of print May 13 in Neurology. In a double-blind, placebo-controlled study, investigators randomly assigned patients with dementia and clinically relevant neuropsychiatric symptoms to receive 1.5 mg of THC or matched placebo three times daily for three weeks. Neuropsychiatric symptoms were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant. Changes in scores for agitation, quality of life, or activities of daily living also were not significantly different between treatment arms. The number of patients experiencing mild or moderate adverse events was similar in both groups. No effects on vital signs, weight, or episodic memory were observed.

Exposure to elevated levels of fine particulate matter is associated with smaller total cerebral brain volume, according to a study published in the May issue of Stroke. Researchers analyzed 943 adults in the Framingham Offspring Study who were relatively healthy and free of dementia and stroke. Investigators evaluated associations between exposure to fine particulate matter and total cerebral brain volume, hippocampal volume, white matter hyperintensity volume, and covert brain infarcts. A 2-μg/m³ increase in fine particulate matter was associated with –0.32% smaller total cerebral brain volume and 1.46 higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter.

Higher occupational attainment is associated with longer survival in autopsy-confirmed frontotemporal lobar degeneration, according to a study published online ahead of print April 22 in Neurology. Researchers performed a retrospective chart review of 83 demographically matched patients with autopsy-confirmed frontotemporal lobar degeneration or Alzheimer’s disease. They used linear regression to test for associations among occupational attainment, education, and patient survival. Median survival was 81 months among patients with frontotemporal lobar degeneration and 95 months among patients with Alzheimer’s disease. Years of education and occupational attainment were similar for both groups. Higher occupational attainment was associated with longer survival in frontotemporal lobar degeneration, but not in Alzheimer’s disease. The findings support the theory that education, occupation, and mental activity create cognitive reserve and protect against disease.

Obesity is a major risk factor for the incidence and chronicity of excessive daytime sleepiness (EDS), and weight loss is associated with its remission, according to a study published March 1 in Sleep. Investigators followed up 1,395 people from a random, general population sample of 1,741 participants in the Penn State Adult Cohort after 7.5 years. The incidence of EDS was 8.2%. Of people with EDS, 62% had remission. Significant interactions between depression and polysomnographic parameters on incident EDS showed that in depressed individuals, incident EDS was associated with sleep disturbances. In individuals without depression, incident EDS was associated with increased physiologic sleep propensity. Diabetes, allergy or asthma, anemia, and sleep complaints also predicted EDS. “EDS has huge implications for public health and policy,” stated the researchers.

Patients with celiac disease have an increased risk of neuropathy, according to a study published online ahead of print May 11 in JAMA Neurology. Between October 27, 2006, and February 12, 2008, researchers collected data on small-intestinal biopsies performed in pathology departments between June 16, 1969, and February 4, 2008. Investigators compared the risk of neuropathy in 28,232 patients with celiac disease with that of 139,473 age- and sex-matched controls. Celiac disease was associated with a 2.5-fold increased risk of subsequent neuropathy. In addition, the investigators found an increased risk of chronic inflammatory demyelinating neuropathy, autonomic neuropathy, and mononeuritis multiplex in patients with celiac disease. They found no association, however, between celiac disease and acute inflammatory demyelinating polyneuropathy. Physicians should screen patients with neuropathy for celiac disease, said the researchers.

A professional life that stimulates verbal intelligence and executive function may help to sustain good cognitive function in people age 75 and older, according to a study published online ahead of print April 29 in Neurology. For the study, 1,054 people age 75 or older underwent the Mini-Mental State Examination every one-and-a-half years for eight years. In multivariate mixed-model analyses, a high level of mentally demanding work tasks stimulating verbal intelligence was significantly associated with better cognitive functioning at baseline and a lower rate of cognitive decline during the eight-year follow-up period, compared with a low level of these tasks. The rate of cognitive decline in old age was also significantly lower in individuals who had a high level of mentally demanding work tasks stimulating executive function.

In Get With the Guidelines-Stroke hospitals, electronic health records are not associated with higher-quality care or better clinical outcomes for stroke care, according to a study published May 12 in Journal of the American College of Cardiology. Researchers studied 626,473 patients from 1,236 US hospitals in Get With the Guidelines-Stroke from 2007 through 2010. They used the American Hospital Association annual survey to determine the presence of electronic health records. Hospitals with electronic health records were larger and were more often teaching hospitals and stroke centers. After controlling for patient and hospital characteristics, patients admitted to hospitals with electronic health records had similar odds of receiving “all-or-none care.” The odds of having a length of stay greater than four days was slightly lower at hospitals with electronic health records.

Off-label use of the Lariat device for left atrial appendage exclusion to prevent stroke in patients with atrial fibrillation entails significant risks of adverse events, according to a study published online ahead of print May 4 in JAMA Internal Medicine. Investigators searched PubMed, EMBASE, CINAHL, and the Cochrane Library from January 2007 through August 2014 to identify all studies reporting use of the Lariat device in three or more patients. They queried the FDA MAUDE database for adverse events reports related to Lariat use. Five reports of Lariat device use in 309 participants were identified. The FDA MAUDE database contained 35 unique reports of adverse events with use of the Lariat device. Among these reports were five adverse event reports that noted pericardial effusion and death and an additional 23 that reported urgent cardiac surgery, but not death.

Insomnia is linked to functional and cognitive impairment among patients with shift work disorder, according to a study published April 15 in Journal of Clinical Sleep Medicine. The analysis included 34 night workers, 26 of whom were diagnosed with shift work disorder. Participants underwent an overnight laboratory protocol including a multiple sleep latency test (MSLT), an event-related brain potential (ERP) task, and various questionnaires. Participants reporting insomnia without sleepiness were the most impaired on the Endicott Work Productivity Scale (EWPS) and significantly more impaired than controls. Participants reporting insomnia and sleepiness were not statistically different from controls. Neither MSLT nor the Epworth Sleepiness Scale correlated with EWPS scores or ERP amplitudes. The mean of the Insomnia Severity Indices measurements, however, correlated with the EWPS.

The measurement of grip strength is a simple, inexpensive risk-stratifying method for all-cause death, cardiovascular death, and cardiovascular disease, according to a study published online ahead of print May 13 in Lancet. In the Prospective Urban-Rural Epidemiology study, researchers enrolled households that each included at least one member between ages 35 and 70. The investigators measured participants’ grip strength with a Jamar dynamometer. Median follow-up was four years. Grip strength was inversely associated with all-cause mortality, cardiovascular mortality, noncardiovascular mortality, myocardial infarction, and stroke. Grip strength was a stronger predictor of all-cause and cardiovascular mortality than systolic blood pressure was. The researchers found no significant association between grip strength and incident diabetes, risk of hospital admission for pneumonia or chronic obstructive pulmonary disease, injury from fall, or fracture.

Sleep deprivation is particularly problematic for decision-making involving uncertainty and unexpected change, according to a study published in the May issue of Sleep. Twenty-six subjects were randomized to 62 hours of total sleep deprivation or to a control condition. Researchers conducted performance testing at baseline, after two nights of total sleep deprivation or rested control, and following two nights of recovery sleep. Participants performed a decision task that involved initial learning of response sets and subsequent reversal of contingencies. Working memory and psychomotor vigilance tests also were administered. Sleep-deprived subjects had difficulty with initial learning of stimuli sets and profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Sleep deprivation did not significantly affect working memory scanning performance.

—Kimberly Williams

Anaphylaxis is a relatively common occurrence for many adolescents. As primary care doctors, we normally see the patient after the acute phase, and then are required to do the detective work to figure out the causes of the episode. The cause may be obvious, but many times we have to hope for another occurrence with similar circumstances to identify it. Surprisingly, the cause may not be what you think. Factors that contribute to an anaphylaxis response may be related to activity, timing of food ingestion, an environmental factor, or medication.

Let’s look at just one type, exercise-induced anaphylaxis. It’s divided into two categories: food dependent and nonfood dependent. Both are described as an induction of itching, urticaria, and fatigue, with progression to angioedema and hypotension, associated with exercise (J. Allergy Clin. Immunol. 1980;66:106-11).

Food-dependent exercise-induced anaphylaxis occurs when exercise is started 30 minutes after ingesting food. This may be difficult to identify because patients react to the food only if they exercise, so food is usually eliminated as a cause. Wheat and wheat flour are common culprits for this type of reaction because of the omega-5 gliadin, which is the protein in gluten (J. Allergy Clin. Immunol. 1991;87:34-40). In one study, larger amounts of the suspected agent were given; hives and angioedema did start to occur in 20% of patients challenged, which suggested that there was likely a baseline allergy to the food, and exercise itself might be a cofactor in augmentation of the allergic reaction.

In nonfood-dependent exercise-induced anaphylaxis, symptoms of itching, urticaria, and fatigue can occur 5-30 minutes after the start of exercise. Although bronchospasm is rare, it can occur along with angioedema, nausea, vomiting, and hypotension, and can even be fatal if exercise continues. If exercise is stopped, it usually resolves. However, many people try to push through it, which only worsens the symptoms.

Cofactors associated with nonfood-dependent exercise-induced anaphylaxis are ingestion of alcohol and an NSAID several hours beforehand. These agents also might be overlooked if well tolerated independently (Br. J. Dermatol. 2001;145:336-9).

Timing of the episode also plays a role. Premenstrual syndrome can be a factor in augmentation of anaphylaxis, so it also should be considered. Knowing the date of the last menstrual cycle and identifying if the anaphylaxis is episodic will identify premenstrual syndrome as a cause.

The work-up should include standard allergy testing and determination of tryptase levels. Skin testing is essential to identify offending agents, and is rarely negative. If a food is suspected and skin testing is negative, repeat the skin testing in 6 months. In one study, wheat extract was found to be positive in only 29% of persons suspected of having a wheat allergy, but when the paste of wheat flour was tested, 80% were identified. The ImmunoCAP Test also was found to have a sensitivity of 80%, so it is a valuable test to try along with the skin prick.

Tryptase levels should be evaluated because in nonfood-dependent exercise-induced anaphylaxis, these levels are slightly elevated at the time of the anaphylaxis, but return to normal. A patient with mastocytosis, a group of disorders characterized by pathologic mast cells infiltrating the skin, will consistently have elevated tryptase levels. Seasonal allergies associated with pollen, and asthma bronchospasm also should be considered as causes.

Although these exercise-induced anaphylaxis episodes can occur at any age, they are most frequent in the adolescent age group, probably because that’s the time most of this population are involved in organized sports. Upon presentation, a careful detailed history will help to identify the cause of anaphylaxis and result in quicker resolution.

Treatment includes avoidance of the offending agent if identified and an antihistamine, and if symptoms do occur, ceasing exercise immediately to avoid a full-blown anaphylactic reaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].

Anaphylaxis is a relatively common occurrence for many adolescents. As primary care doctors, we normally see the patient after the acute phase, and then are required to do the detective work to figure out the causes of the episode. The cause may be obvious, but many times we have to hope for another occurrence with similar circumstances to identify it. Surprisingly, the cause may not be what you think. Factors that contribute to an anaphylaxis response may be related to activity, timing of food ingestion, an environmental factor, or medication.

Let’s look at just one type, exercise-induced anaphylaxis. It’s divided into two categories: food dependent and nonfood dependent. Both are described as an induction of itching, urticaria, and fatigue, with progression to angioedema and hypotension, associated with exercise (J. Allergy Clin. Immunol. 1980;66:106-11).

Food-dependent exercise-induced anaphylaxis occurs when exercise is started 30 minutes after ingesting food. This may be difficult to identify because patients react to the food only if they exercise, so food is usually eliminated as a cause. Wheat and wheat flour are common culprits for this type of reaction because of the omega-5 gliadin, which is the protein in gluten (J. Allergy Clin. Immunol. 1991;87:34-40). In one study, larger amounts of the suspected agent were given; hives and angioedema did start to occur in 20% of patients challenged, which suggested that there was likely a baseline allergy to the food, and exercise itself might be a cofactor in augmentation of the allergic reaction.

In nonfood-dependent exercise-induced anaphylaxis, symptoms of itching, urticaria, and fatigue can occur 5-30 minutes after the start of exercise. Although bronchospasm is rare, it can occur along with angioedema, nausea, vomiting, and hypotension, and can even be fatal if exercise continues. If exercise is stopped, it usually resolves. However, many people try to push through it, which only worsens the symptoms.

Cofactors associated with nonfood-dependent exercise-induced anaphylaxis are ingestion of alcohol and an NSAID several hours beforehand. These agents also might be overlooked if well tolerated independently (Br. J. Dermatol. 2001;145:336-9).

Timing of the episode also plays a role. Premenstrual syndrome can be a factor in augmentation of anaphylaxis, so it also should be considered. Knowing the date of the last menstrual cycle and identifying if the anaphylaxis is episodic will identify premenstrual syndrome as a cause.

The work-up should include standard allergy testing and determination of tryptase levels. Skin testing is essential to identify offending agents, and is rarely negative. If a food is suspected and skin testing is negative, repeat the skin testing in 6 months. In one study, wheat extract was found to be positive in only 29% of persons suspected of having a wheat allergy, but when the paste of wheat flour was tested, 80% were identified. The ImmunoCAP Test also was found to have a sensitivity of 80%, so it is a valuable test to try along with the skin prick.

Tryptase levels should be evaluated because in nonfood-dependent exercise-induced anaphylaxis, these levels are slightly elevated at the time of the anaphylaxis, but return to normal. A patient with mastocytosis, a group of disorders characterized by pathologic mast cells infiltrating the skin, will consistently have elevated tryptase levels. Seasonal allergies associated with pollen, and asthma bronchospasm also should be considered as causes.

Although these exercise-induced anaphylaxis episodes can occur at any age, they are most frequent in the adolescent age group, probably because that’s the time most of this population are involved in organized sports. Upon presentation, a careful detailed history will help to identify the cause of anaphylaxis and result in quicker resolution.

Treatment includes avoidance of the offending agent if identified and an antihistamine, and if symptoms do occur, ceasing exercise immediately to avoid a full-blown anaphylactic reaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].

Anaphylaxis is a relatively common occurrence for many adolescents. As primary care doctors, we normally see the patient after the acute phase, and then are required to do the detective work to figure out the causes of the episode. The cause may be obvious, but many times we have to hope for another occurrence with similar circumstances to identify it. Surprisingly, the cause may not be what you think. Factors that contribute to an anaphylaxis response may be related to activity, timing of food ingestion, an environmental factor, or medication.

Let’s look at just one type, exercise-induced anaphylaxis. It’s divided into two categories: food dependent and nonfood dependent. Both are described as an induction of itching, urticaria, and fatigue, with progression to angioedema and hypotension, associated with exercise (J. Allergy Clin. Immunol. 1980;66:106-11).

Food-dependent exercise-induced anaphylaxis occurs when exercise is started 30 minutes after ingesting food. This may be difficult to identify because patients react to the food only if they exercise, so food is usually eliminated as a cause. Wheat and wheat flour are common culprits for this type of reaction because of the omega-5 gliadin, which is the protein in gluten (J. Allergy Clin. Immunol. 1991;87:34-40). In one study, larger amounts of the suspected agent were given; hives and angioedema did start to occur in 20% of patients challenged, which suggested that there was likely a baseline allergy to the food, and exercise itself might be a cofactor in augmentation of the allergic reaction.

In nonfood-dependent exercise-induced anaphylaxis, symptoms of itching, urticaria, and fatigue can occur 5-30 minutes after the start of exercise. Although bronchospasm is rare, it can occur along with angioedema, nausea, vomiting, and hypotension, and can even be fatal if exercise continues. If exercise is stopped, it usually resolves. However, many people try to push through it, which only worsens the symptoms.

Cofactors associated with nonfood-dependent exercise-induced anaphylaxis are ingestion of alcohol and an NSAID several hours beforehand. These agents also might be overlooked if well tolerated independently (Br. J. Dermatol. 2001;145:336-9).

Timing of the episode also plays a role. Premenstrual syndrome can be a factor in augmentation of anaphylaxis, so it also should be considered. Knowing the date of the last menstrual cycle and identifying if the anaphylaxis is episodic will identify premenstrual syndrome as a cause.

The work-up should include standard allergy testing and determination of tryptase levels. Skin testing is essential to identify offending agents, and is rarely negative. If a food is suspected and skin testing is negative, repeat the skin testing in 6 months. In one study, wheat extract was found to be positive in only 29% of persons suspected of having a wheat allergy, but when the paste of wheat flour was tested, 80% were identified. The ImmunoCAP Test also was found to have a sensitivity of 80%, so it is a valuable test to try along with the skin prick.

Tryptase levels should be evaluated because in nonfood-dependent exercise-induced anaphylaxis, these levels are slightly elevated at the time of the anaphylaxis, but return to normal. A patient with mastocytosis, a group of disorders characterized by pathologic mast cells infiltrating the skin, will consistently have elevated tryptase levels. Seasonal allergies associated with pollen, and asthma bronchospasm also should be considered as causes.

Although these exercise-induced anaphylaxis episodes can occur at any age, they are most frequent in the adolescent age group, probably because that’s the time most of this population are involved in organized sports. Upon presentation, a careful detailed history will help to identify the cause of anaphylaxis and result in quicker resolution.

Treatment includes avoidance of the offending agent if identified and an antihistamine, and if symptoms do occur, ceasing exercise immediately to avoid a full-blown anaphylactic reaction.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected].