Current Psychiatry

Anorexia nervosa can affect a number of systems of the body, including the otolaryngologic presentation of autophonia^1,2—a rare hyperperception of an abnormally intense hearing of one’s own voice and respiratory sounds.² The most common cause of autophonia in patients with anorexia is a patulous (patent) eusta­chian tube, which can be caused by extreme weight loss.^2,3

Significant reduction in the quantity of fat tissue at the location of the eustachian tube can cause patency.³ This creates an abnor­mal connection between the nasopharynx and tympanic membrane, in which sounds are transmitted directly from the oral cavity to the middle ear, causing autophonia, tin­nitus, or sound distortion.⁴
What are the symptoms?Patients often report hearing their own voice more loudly in the affected ear. This can be distressing, and they might become preoccupied with the sound of their voice—thus affecting quality of life.^2,4

The intensity of symptoms varies: from a mild sensation of a clogged ear to extremely bothersome discomfort much like a middle-ear infection.^2,4 Autophonia, however, cannot be relieved by conven­tional therapies for those conditions.^2,3

A patulous eustachian tube is difficult to detect and can be misdiagnosed as another condition. Pregnancy, stress, fatigue, radia­tion therapy, hormonal therapy, and dra­matic weight loss also can cause a patulous eustachian tube.²
How is the diagnosis made?The diagnosis of autophonia is clinical and begins with a detailed history. Symptoms often appear within the time frame of rapid weight loss and without evidence of infection or other illness.^2,3 The clinical examination is otherwise unremarkable.^2,4
Is there treatment?To improve the patient’s comfort and qual­ity of life, intervention is required, best provided by an integrated team of medi­cal specialists. Weight gain, of course, is the treatment goal in anorexia, but this is a complex process often marked by relapse; a detailed discussion of treatment strate­gies is beyond the scope of this “Pearl.” Symptoms usually diminish as fatty tissue is restored upon successful treatment of anorexia, which closes the abnormal eusta­chian tube opening.^2,3
 

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

Anorexia nervosa can affect a number of systems of the body, including the otolaryngologic presentation of autophonia^1,2—a rare hyperperception of an abnormally intense hearing of one’s own voice and respiratory sounds.² The most common cause of autophonia in patients with anorexia is a patulous (patent) eusta­chian tube, which can be caused by extreme weight loss.^2,3

Significant reduction in the quantity of fat tissue at the location of the eustachian tube can cause patency.³ This creates an abnor­mal connection between the nasopharynx and tympanic membrane, in which sounds are transmitted directly from the oral cavity to the middle ear, causing autophonia, tin­nitus, or sound distortion.⁴
What are the symptoms?Patients often report hearing their own voice more loudly in the affected ear. This can be distressing, and they might become preoccupied with the sound of their voice—thus affecting quality of life.^2,4

The intensity of symptoms varies: from a mild sensation of a clogged ear to extremely bothersome discomfort much like a middle-ear infection.^2,4 Autophonia, however, cannot be relieved by conven­tional therapies for those conditions.^2,3

A patulous eustachian tube is difficult to detect and can be misdiagnosed as another condition. Pregnancy, stress, fatigue, radia­tion therapy, hormonal therapy, and dra­matic weight loss also can cause a patulous eustachian tube.²
How is the diagnosis made?The diagnosis of autophonia is clinical and begins with a detailed history. Symptoms often appear within the time frame of rapid weight loss and without evidence of infection or other illness.^2,3 The clinical examination is otherwise unremarkable.^2,4
Is there treatment?To improve the patient’s comfort and qual­ity of life, intervention is required, best provided by an integrated team of medi­cal specialists. Weight gain, of course, is the treatment goal in anorexia, but this is a complex process often marked by relapse; a detailed discussion of treatment strate­gies is beyond the scope of this “Pearl.” Symptoms usually diminish as fatty tissue is restored upon successful treatment of anorexia, which closes the abnormal eusta­chian tube opening.^2,3
 

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

Anorexia nervosa can affect a number of systems of the body, including the otolaryngologic presentation of autophonia^1,2—a rare hyperperception of an abnormally intense hearing of one’s own voice and respiratory sounds.² The most common cause of autophonia in patients with anorexia is a patulous (patent) eusta­chian tube, which can be caused by extreme weight loss.^2,3

Significant reduction in the quantity of fat tissue at the location of the eustachian tube can cause patency.³ This creates an abnor­mal connection between the nasopharynx and tympanic membrane, in which sounds are transmitted directly from the oral cavity to the middle ear, causing autophonia, tin­nitus, or sound distortion.⁴
What are the symptoms?Patients often report hearing their own voice more loudly in the affected ear. This can be distressing, and they might become preoccupied with the sound of their voice—thus affecting quality of life.^2,4

The intensity of symptoms varies: from a mild sensation of a clogged ear to extremely bothersome discomfort much like a middle-ear infection.^2,4 Autophonia, however, cannot be relieved by conven­tional therapies for those conditions.^2,3

A patulous eustachian tube is difficult to detect and can be misdiagnosed as another condition. Pregnancy, stress, fatigue, radia­tion therapy, hormonal therapy, and dra­matic weight loss also can cause a patulous eustachian tube.²
How is the diagnosis made?The diagnosis of autophonia is clinical and begins with a detailed history. Symptoms often appear within the time frame of rapid weight loss and without evidence of infection or other illness.^2,3 The clinical examination is otherwise unremarkable.^2,4
Is there treatment?To improve the patient’s comfort and qual­ity of life, intervention is required, best provided by an integrated team of medi­cal specialists. Weight gain, of course, is the treatment goal in anorexia, but this is a complex process often marked by relapse; a detailed discussion of treatment strate­gies is beyond the scope of this “Pearl.” Symptoms usually diminish as fatty tissue is restored upon successful treatment of anorexia, which closes the abnormal eusta­chian tube opening.^2,3
 

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

Psychiatrists often serve as risk-management consultants for our medical colleagues. As part of this role, psychiatrists working with trainees— including resident physicians, medical students, and physician assistant students— have an opportunity to emphasize the impor­tance of professional boundaries.¹ Discussing appropriate professional boundaries and describing what might represent a violation of these boundaries is meaningful because a good understanding of these concepts pro­motes high-quality treatment and minimizes professional liability.²

Physical boundaries
Psychiatric patients might be agitated or display potentially dangerous behaviors; discussing the importance of body language and contact between physicians and their patients is, therefore, first and foremost, a matter of safety. Students who can recognize the signs and symptoms of agitation and maintain a safe distance between themselves and their patients are less likely to be injured.

Addressing romantic and sexual rela­tionships between patients and their health care providers also is necessary. One study reported that 21% of medical students sur­veyed might not regard sexual contact with a patient as inappropriate.³ An adequate discus­sion of this topic is necessary to protect train­ees and patients from a catastrophic misstep.

Emotional boundaries
Maintaining appropriate emotional bound­aries is necessary in psychiatry. Given the prevalence of mental illness and substance abuse, many trainees have personal experi­ence with psychiatric illness outside of their training. Discussing issues of transference and countertransference with students will prepare them for intense emotional reac­tions they will experience while working in psychiatry. Students who feel comfortable recognizing their own countertransference feelings and discussing them in supervision with their attending psychiatrist will be more successful in addressing the complex inter­personal challenges that their patients face.

Personal and informational boundaries
Discussing personal and informational boundaries can protect trainees from uncom­fortable experiences in their non-clinical lives. Although, in previous decades, we needed to discourage students only from sharing their home address and telephone number with patients, the Internet and social media have made it easier for patients to discover personal information about their treatment team. Addressing issues related to social networks and instructing students on how to appropriately address and decline requests for personal information can pre­vent unwanted boundary crossings.

Psychiatrists are well suited to discuss these issues with trainees. In doing so, we can help them become knowledgeable health care providers—no matter which medical discipline they specialize in.

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

Psychiatrists often serve as risk-management consultants for our medical colleagues. As part of this role, psychiatrists working with trainees— including resident physicians, medical students, and physician assistant students— have an opportunity to emphasize the impor­tance of professional boundaries.¹ Discussing appropriate professional boundaries and describing what might represent a violation of these boundaries is meaningful because a good understanding of these concepts pro­motes high-quality treatment and minimizes professional liability.²

Physical boundaries
Psychiatric patients might be agitated or display potentially dangerous behaviors; discussing the importance of body language and contact between physicians and their patients is, therefore, first and foremost, a matter of safety. Students who can recognize the signs and symptoms of agitation and maintain a safe distance between themselves and their patients are less likely to be injured.

Addressing romantic and sexual rela­tionships between patients and their health care providers also is necessary. One study reported that 21% of medical students sur­veyed might not regard sexual contact with a patient as inappropriate.³ An adequate discus­sion of this topic is necessary to protect train­ees and patients from a catastrophic misstep.

Emotional boundaries
Maintaining appropriate emotional bound­aries is necessary in psychiatry. Given the prevalence of mental illness and substance abuse, many trainees have personal experi­ence with psychiatric illness outside of their training. Discussing issues of transference and countertransference with students will prepare them for intense emotional reac­tions they will experience while working in psychiatry. Students who feel comfortable recognizing their own countertransference feelings and discussing them in supervision with their attending psychiatrist will be more successful in addressing the complex inter­personal challenges that their patients face.

Personal and informational boundaries
Discussing personal and informational boundaries can protect trainees from uncom­fortable experiences in their non-clinical lives. Although, in previous decades, we needed to discourage students only from sharing their home address and telephone number with patients, the Internet and social media have made it easier for patients to discover personal information about their treatment team. Addressing issues related to social networks and instructing students on how to appropriately address and decline requests for personal information can pre­vent unwanted boundary crossings.

Psychiatrists are well suited to discuss these issues with trainees. In doing so, we can help them become knowledgeable health care providers—no matter which medical discipline they specialize in.

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

Psychiatrists often serve as risk-management consultants for our medical colleagues. As part of this role, psychiatrists working with trainees— including resident physicians, medical students, and physician assistant students— have an opportunity to emphasize the impor­tance of professional boundaries.¹ Discussing appropriate professional boundaries and describing what might represent a violation of these boundaries is meaningful because a good understanding of these concepts pro­motes high-quality treatment and minimizes professional liability.²

Physical boundaries
Psychiatric patients might be agitated or display potentially dangerous behaviors; discussing the importance of body language and contact between physicians and their patients is, therefore, first and foremost, a matter of safety. Students who can recognize the signs and symptoms of agitation and maintain a safe distance between themselves and their patients are less likely to be injured.

Addressing romantic and sexual rela­tionships between patients and their health care providers also is necessary. One study reported that 21% of medical students sur­veyed might not regard sexual contact with a patient as inappropriate.³ An adequate discus­sion of this topic is necessary to protect train­ees and patients from a catastrophic misstep.

Emotional boundaries
Maintaining appropriate emotional bound­aries is necessary in psychiatry. Given the prevalence of mental illness and substance abuse, many trainees have personal experi­ence with psychiatric illness outside of their training. Discussing issues of transference and countertransference with students will prepare them for intense emotional reac­tions they will experience while working in psychiatry. Students who feel comfortable recognizing their own countertransference feelings and discussing them in supervision with their attending psychiatrist will be more successful in addressing the complex inter­personal challenges that their patients face.

Personal and informational boundaries
Discussing personal and informational boundaries can protect trainees from uncom­fortable experiences in their non-clinical lives. Although, in previous decades, we needed to discourage students only from sharing their home address and telephone number with patients, the Internet and social media have made it easier for patients to discover personal information about their treatment team. Addressing issues related to social networks and instructing students on how to appropriately address and decline requests for personal information can pre­vent unwanted boundary crossings.

Psychiatrists are well suited to discuss these issues with trainees. In doing so, we can help them become knowledgeable health care providers—no matter which medical discipline they specialize in.

Disclosure
The author reports 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.

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.

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.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.

Fatigue and depression can be viewed as a “vicious cycle”: Fatigue can be a symptom of major depression, and fatigue can be a risk factor for depression.¹ For example, fatigue associated with a general medical condition or traumatic brain injury can be a risk factor for developing major depressive disorder (MDD).^1-3 It isn’t surprising that fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD.

Despite the observed association between fatigue and depression, their underlying relationship often is unclear. The literature does not differentiate among fatigue associated with depression, fatigue as a treatment-emergent adverse effect, and fatigue as a residual symptom of depression that is partially responsive to treatment.^4,5 To complicate the situation, many medications used to treat MDD can cause fatigue.

Patients often describe fatigue as (1) feeling tired, exhausted, or drained and (2) lacking energy and motivation. Fatigue can be related to impaired wakefulness but is believed to be a different entity than sleepiness.⁶ Residual fatigue can affect social, cognitive, emotional, and physical health.

We reviewed the literature about fatigue as a symptom of MDD by conducting a search of Medline, PubMed, and Google Scholar, using keywords depression, fatigue, residual symptoms, and treatment. We chose the papers cited in this article based on our consensus and because these publications represent expert opinion or the highest quality evi­dence available.

Residual fatigue has an effect on prognosis
Fatigue is a common symptom of MDD that persists in 20% to 30% of patients whose symptoms of depression otherwise remit.^4,7-9 Several studies have linked residual fatigue with the overall prognosis of MDD.⁵ Data from a prospective study demonstrate that depressed patients have a higher risk of relapse when they continue to report symp­toms of fatigue after their symptoms of depression have otherwise entered partial remission.¹⁰ Another study demonstrated that the severity of residual symptoms of depression is a strong predictor of another major depressive episode.¹¹

In a large-scale study, the prevalence of residual fatigue after adequate treat­ment of MDD in both partial responders and remitters was 84.6%.¹² The same study showed that one-third of patients who had been treated for MDD had persistent and clinically significant fatigue, which could suggest a relationship between fatigue and selective serotonin reuptake inhibitors (SSRIs) and other antidepressants.

Another study demonstrated that 64.6% of patients who responded to antidepressant treatment and who had baseline fatigue con­tinued to exhibit symptoms of fatigue after an adequate trial of an antidepressant.¹³

Neurobiological considerations
Studies have shown that the neuronal circuits that malfunction in fatigue are different from those that malfunction in depression.¹⁴ Although the neurobiol­ogy of fatigue has not been determined, decreased neuronal activity in the prefron­tal circuits has been associated with symp­toms of fatigue.¹⁵

In addition, evidence from the litera­ture shows a decrease in hormone secre­tion¹⁶ and cognitive abilities in patients exhibiting symptoms of fatigue.¹⁷ These findings have led some experts to hypoth­esize that symptoms of fatigue associated with depression could be the result of (1) immune dysregulation¹⁸ and (2) an inability of available antidepressants to tar­get the underlying biology of the disorder.²

Despite the hypothesis that fatigue asso­ciated with depression might be biologically related to immune dysregulation, some authors continue to point to an imbalance in neurotransmitters—norepinephrine, his­tamine, dopamine, acetylcholine—as being  associated with fatigue.¹⁴ For example, a study demonstrated that drugs targeting noradrenergic reuptake inhibition were more effective at preventing a relapse of fatigue compared with serotonergic drugs.¹⁹ Another study showed improvement in energy with an increase in the plasma level of desipramine, which affects noradrener­gic neurotransmission.²⁰

Inflammatory cytokines also have been explored in the search for an understand­ing of the etiology of fatigue and depres­sion.²¹ Physical and mental stress promote the release of cytokines, which activate the immune system by inducing an inflam­matory response; this response has been etiologically linked to depressive disor­ders.²² Furthermore, studies have demon­strated an elevated level of inflammatory cytokines in patients who have MDD— suggesting that MDD is associated with a chronic low level of inflammation that crosses the blood−brain barrier.²³

Clinical considerations: A role for rating scales?
Despite the significance of residual fatigue on the quality of life of patients who have MDD, most common rating scales, such as the Hamilton Depression Rating Scale²⁴ and the Montgomery-Åsberg Depression Rating Scale,²⁵ have limited sensitivity for measuring fatigue.²⁶ The Fatigue Associated with Depression (FAsD)²⁷ questionnaire, designed according to FDA guidelines,²⁸ is used to assess fatigue associated with depression. The final version of the FAsD includes 13 items: a 6-item experience sub­scale and a 7-item impact subscale.

Is the FAsD helpful? The experience sub­scale of the FAsD assesses how often the patient experiences different aspects of fatigue (tiredness, exhaustion, lack of energy, physical weakness, and a feeling that everything requires too much effort). The impact subscale of the FAsD assesses the effect of fatigue on daily life.

The overall FAsD score is calculated by taking the mean of each subscale; a change of 0.67 on the experience subscale and 0.57 on the impact subscale are considered clini­cally meaningful.²⁷ The measurement prop­erties of the questionnaire showed internal consistency, reliability, and validity in test­ing. Researchers note, however, that FAsD does not include items to assess the impact of fatigue on cognition. This means that the FAsD might not distinguish between physi­cal and mental aspects of fatigue.

Treatment
It isn’t surprising that residual depres­sion can increase health care utilization and economic burden, including such indirect costs as lost productivity and wages.²⁹ Despite these impacts, there is a paucity of studies evaluating the relation­ship between residual symptoms, such as fatigue, and work productivity. It has been established that improving a depressed patient’s level of energy correlates with improved performance at work.

Treating fatigue as a residual symp­tom of MDD can be complicated because symptoms of fatigue might be:
   • a discrete symptom of MDD
   • a prodromal symptom of another disorder
   • an adverse effect of an antidepressant.^2,30

It is a major clinical problem, there­fore, that antidepressants can alleviate and cause symptoms of fatigue.³¹ Treatment strategy should focus on identifying anti­depressants that are less likely to cause fatigue (ie, noradrenergic or dopaminergic drugs, or both). Adjunctive treatments to target residual fatigue also can be used.³²

There are limited published data on the effective treatment of residual fatigue in patients with MDD. Given the absence of sufficient evidence, agents that promote noradrenergic and dopaminergic neuro­transmission have been the treatment of choice when targeting fatigue in depressed patients.^2,14,21,33

The Table^34-37 lists poten­tial treatment options often used to treat fatigue associated with depression.

SSRIs. Treatment with SSRIs has been asso­ciated with a low probability of achiev­ing remission when targeting fatigue as a symptom of MDD.²¹

One study reported that, after 8 weeks of treatment with an SSRI, treatment-emergent adverse events, such as worsening fatigue and weakness, were observed—along with an overall lack of efficacy in targeting all symptoms of depression.³⁸

Another study demonstrated positive effects when a noradrenergic agent was added to an SSRI in partial responders who continued to complain of residual fatigue.³³

However, studies that compared the effects of SSRIs with those of antidepres­sants that have pronoradrenergic effects showed that the 2 mechanisms of action were not significantly different from each other in their ability to resolve residual symptoms of fatigue.²¹ A limiting factor might be that these studies were retrospec­tive and did not analyze the efficacy of a noradrenergic agent as an adjunct for alle­viating symptoms of fatigue.³⁹

Bupropion. This commonly used medica­tion for fatigue is believed to cause a sig­nificantly lower level of fatigue compared with SSRIs.⁴⁰ The potential utility of bupro­pion in this area could be a reflection of its mechanism of action—ie, the drug targets both noradrenergic and dopaminergic neurotransmission.⁴¹

A study comparing bupropion with SSRIs in targeting somatic symptoms of depression reported a small but statisti­cally significant difference in favor of the bupropion-treated group. However, this finding was confounded by the small effect size and difficulty quantifying somatic symptoms.⁴⁰

Stimulants and modafinil. Psycho-stimulants have been shown to be effica­cious for depression and fatigue, both as monotherapy and adjunctively.^39,42

Modafinil has demonstrated efficacy in open-label trials for improving residual fatigue, but failed to separate from pla­cebo in controlled trials.⁴³ At least 1 other failed study has been published examining modafinil as a treatment for fatigue associ­ated with depression.⁴³

Adjunctive therapy with CNS stimu­lants, such as amphetamine/dextroam­phetamine and methylphenidate, has been used to treat fatigue, with positive results.¹⁶ Modafinil and stimulants also could be tried as an augmentation strategy to other antidepressants; such use is off-label and should be attempted only after careful consideration.¹⁶

Exercise might be a nonpharmacothera­peutic modality that targets the underly­ing physiology associated with fatigue. Exercise releases endorphins, which can affect overall brain chemistry and which have been theorized to diminish symp­toms of fatigue and depression.⁴⁴ Consider exercise in addition to treatment with an antidepressant in selected patients.⁴⁵

To sum up
In general, the literature does not recom­mend one medication as superior to any other for treating fatigue that is a residual symptom of depression. Such hesitation suggests that more empirical studies are needed to determine what is the best and proper management of treating fatigue associated with depression.

Bottom LinE
Fatigue can be a symptom of major depressive disorder (MDD) or a risk factor for depression. Fatigue has been studied as a predictor of relapse after previous response to treatment in patients with MDD. Residual fatigue can affect social, cognitive, emotional, and physical health and can result in increased utilization of health care services. A number of treatment options are available; none has been shown to be superior to the others.

Related Resources
• Leone SS. A disabling combination: fatigue and depression. Br J Psychiatry. 2010;197(2):86-87.
• Targum SD, Fava M. Fatigue as a residual symptom of de­pression. Innov Clin Neurosci. 2011;8(10):40-43.
• Illiades C. How to fight depression fatigue. Everyday Health. http://www.everydayhealth.com/health-report/major-depression-living-well/fight-depression-fatigue.aspx.
• Kerr M. Depression and fatigue: a vicious cycle. Healthline. http://www.healthline.com/health/depression/fatigue.

Drug Brand Names
Amphetamine/dextroamphetamine • Adderall              
Bupropion • Wellbutrin                                                
Desipramine • Norpramin                                           
Methylphenidate • Ritalin
Modafinil • Provigil
Sertraline • Zoloft
Venlafaxine • Effexor

Disclosures
Dr. Sohail reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Macaluso has conducted clinical trials research as principal investigator for the following pharmaceutical manufacturers in the past 12 months: AbbVie, Inc.; Alkermes; AssureRx Health, Inc.; Eisai Co., Ltd.; FORUM Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; and Naurex Inc. All clinical trial and study contracts were with, and payments were made to, University of Kansas Medical Center Research Institute, Kansas City, Kansas, a research institute affiliated with University of Kansas School of Medicine−Wichita.