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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dear Dr. Mossman,

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

Submitted by “Dr. V”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dear Dr. Mossman,

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

Submitted by “Dr. V”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dear Dr. Mossman,

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

Submitted by “Dr. V”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

—Kimberly Williams

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

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

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

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

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

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

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

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

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

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

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

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

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

—Kimberly Williams

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

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

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

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

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

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

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

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

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

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

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

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

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

—Kimberly Williams

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

WASHINGTON – Obese patients implanted with an intragastric balloon lost significantly more weight than those following a behavioral modification program in a randomized, nonblinded trial.

Moreover, weight loss was preserved even after device removal, study author Dr. Barham Abu Dayyeh said at the annual Digestive Disease Week.

The Orbera intragastric balloon (Apollo Endosurgery) could fill a gap in the United States between obesity lifestyle interventions that are minimally effective and a range of bariatric surgical interventions that are effective, but come at a cost of increased complications and health care costs, he said. Moreover, only 1% of qualified patients actually end up having bariatric surgery.

The silicone, saline-filled intragastric balloon (IGB) has been widely used outside the U.S. for more than 17 years in more than 200,000 patients, added Dr. Abu Dayyeh* of Mayo Clinic in Rochester, Minn.

The multicenter trial was designed for premarketing approval in the U.S. of the Orbera IGB and randomly assigned 273 adults with a body mass index (BMI) of 30-40 kg/m² for more than 2 years to a 12-month behavioral modification program with or without endoscopic placement of the IGB filled to 500-600 cc. The balloon was removed at month 6, with regular office visits through 1 year.

Eighteen patients withdrew before treatment; 215 patients were evaluable at 6 months, 206 at 9 months, and 191 at 12 months. The mean baseline BMI was 35 kg/m² and 90% of patients were female.

At 6 months, the mean percent total body weight loss was greater in the IGB group than the control group (about 10% vs. 4%; P < .001), Dr. Abu Dayyeh said, noting that total body weight loss was significantly higher in the balloon group at each time point: 3, 6, 9, and 12 months.

Similarly, the mean percent of excess weight loss at 6 months was better in the balloon group than in the control group (about 40% vs. 13%; P < .001). The majority of excess weight loss achieved at 6 months was also maintained at 12 months, he said.

At 9 months (3 months after device removal), 45.6% of patients in the IGB group had an excess weight loss at least 15% higher than patients in the control group, which exceeded the 30% threshold set as a primary study outcome, he said.

The mean percent excess weight loss was 26.5% at 9 months in the balloon group, which also exceeded the 25% threshold set as a second primary outcome.

This IGB system “appears to meet the thresholds set forth by the ASGE/ASMBS PIVI for endoscopic bariatric therapies intended as a primary obesity intervention,” Dr. Abu Dayyeh said.

The American Society for Gastrointestinal Endoscopy/American Society for Metabolic and Bariatric Surgery PIVI (Preservation and Incorporation of Valuable endoscopic Innovations) recommends that endoscopic bariatric therapies intended as a primary obesity intervention achieve a mean minimum threshold of 25% excess weight loss at 12 months.

At 52 weeks, both groups had an improvement from baseline in diabetes, hypertension, and lipids, but the improvement was greater with the IGB, he said.

Beck Depression Scores and quality of life also improved in both groups, with the improvement again greater with the IGB.

Serious adverse events were reported by 7% of controls and 9.6% of the balloon group including 8 early removals for intolerance, 1 gastric outlet obstruction, 1 laryngospasm during placement, 1 case of severe abdominal cramping, and 1 case of severe dehydration.

Early device removals occurred in 22% of patients, 15 for symptoms and 13 at subject request, Dr. Abu Dayyeh said. No deaths occurred in the trial.

*Changed on July 8, 2015.

[email protected]

On Twitter @pwendl

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Adolescents with slower processing speeds and longer reaction times were at a greater risk of anxiety and depression later in life, according to Catharine R. Gale, Ph.D., of the University of Southampton (England) and her associates.

In this 20-year study of 705 males and females, longer reaction time at 16 years indicated a small but significant association with poorer mental health at age 36.

Adjusting for sex, parental social class, General Health Questionnaire (GHQ) score at age 16 years, health behaviors at age 36 years, and allostatic load had little effect on the association between reaction time and the GHQ score, but the association was weakened with Hospital Anxiety and Depression Scale (HADS) scores for both anxiety and depression. Smoking had a mediating effect on the HADS anxiety score, but not on the depression subscale.

“Further prospective studies of the relation between reaction time and mental health outcomes in other samples are needed to gauge whether reaction time is a true risk factor for mental disorders and to confirm the mediating roles played by smoking and allostatic load,” the investigators noted.

Find the full study in Psychosomatic Medicine (doi:10.1097/PSY.0000000000000189).

[email protected]

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Contraceptive pills

Results of a large, retrospective study support the association between newer contraceptive pills and a higher risk of venous thromboembolism (VTE).

The research showed that pills containing one of the newer types of progestogen—drospirenone, desogestrel, gestodene, and cyproterone—are associated with a nearly 2-fold higher risk of VTE than pills containing older progestogens—levonorgestrel, norethisterone, and norgestimate.

The researchers said this study has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives. However, because it is an observational study, no definitive conclusions can be drawn about cause and effect.

The team described this research in BMJ alongside a related editorial.

Although the increased risk of VTE associated with combined oral contraceptives has been suggested previously, prior studies have used different methods to examine this link. So the relative risks associated with different combinations remain inconclusive.

Yana Vinogradova, of the University of Nottingham in the UK, and her colleagues tried to address these differences to help explain the range of results.

The team used prescription data from 2 large UK general practice databases to measure the associations between the use of combined oral contraceptives and the risk of VTE in women aged 15 to 49, adjusting for other known VTE risk factors.

The researchers matched 10,562 women with VTE to 42,034 control subjects and found that women who used any combined oral contraceptive within the past year had an increased risk of VTE compared with non-users of similar age and health status. The adjusted odds ratio was 2.97.

The risk of VTE was significantly higher for women who used the newer oral contraceptives than the older pills (P<0.001). The adjusted odds ratios were 4.28 for desogestrel, 4.27 for cyproterone, 4.12 for drospirenone, and 3.64 for gestodene, compared to 2.38 for levonorgestrel, 2.53 for norgestimate, and 2.56 for norethisterone.

The number of extra VTE cases per year per 10,000 treated women was lowest for levonorgestrel and norgestimate (6 cases for both) and highest for desogestrel and cyproterone (14 cases for both).

The researchers said that, although this is an observational study, it has produced the most reliable possible VTE risk estimates using currently available UK prescription data.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Platelets for transfusion

The US Food and Drug Administration (FDA) has expanded the authorized use of Verax Biomedical’s Platelet PGD Test, which detects bacteria in platelets intended for transfusion.

The FDA previously approved the test for leukocyte-reduced apheresis platelets (in 2007) and platelets derived from whole blood (in 2009).

Now, the test has been approved for pre-storage pooled platelets and apheresis platelets in platelet additive solution C (PAS-C) and plasma.

This makes the Platelet PGD Test the only rapid test on the market that can check every commonly distributed platelet type in the US, according to Verax Biomedical.

About the test

The Platelet PGD Test is an immunoassay used on the day of transfusion at the point of care—a hospital or transfusion service—to detect bacterial contamination in platelets to be transfused.

The test consists of a disposable plastic cartridge and 3 pretreatment reagents. To use, the tester pretreats a freshly collected platelet sample (500µL) and applies it to the sample well on the test cartridge.

Lights on the cartridge change from yellow to blue-violet when the test is ready to be interpreted, which is typically about 20 minutes after the sample is applied to the cartridge. The lights confirm that the appropriate volume of a sample was added and the testing is complete.

If the test is positive, a pink line will appear in 1 of the 2 windows on the cartridge. One window represents Gram-positive bacteria and the other Gram-negative. Non-reactive samples will have no line in either window.

Now that the FDA has expanded the indications for the Platelet PGD Test, it can be used as a quality control test for pools of up to 6 units of leukocyte-reduced and non-leukocyte-reduced whole-blood-derived platelets suspended in plasma that are pooled within 4 hours of transfusion.

The test can also be used within 24 hours of transfusion as a safety measure following testing with a growth-based, quality control test cleared by the FDA. For this indication, the Platelet PGD Test can be used with:

• Leukocyte-reduced apheresis platelets suspended in plasma
• Leukocyte-reduced apheresis platelets suspended in PAS-C and plasma
• Pre-storage pools of up to 6 leukocyte-reduced whole-blood-derived platelets suspended in plasma.

In studies conducted by Verax Biomedical (described in the summary document here), the Platelet PGD Test successfully detected bacteria in pre-storage pools of whole-blood derived platelets suspended in plasma and leukocyte-reduced apheresis platelets suspended in plasma or PAS-C and plasma.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.

Umbilical cord clamping

Photo by Meutia Chaerani

and Indradi Soemardjan

New research suggests that delayed umbilical cord clamping in full-term infants may confer some minor long-term benefits and, at the very least, does not pose any harm.

Delayed clamping did not appear to have a significant effect on most of the mental and physical measures assessed in the study.

It was associated with improved scores in fine-motor skills and social skills at age 4, but these effects only occurred in boys.

Researchers reported these results in JAMA Pediatrics alongside a related editorial.

Previous research has shown that delaying umbilical cord clamping by 2 to 3 minutes after delivery allows fetal blood remaining in the placental circulation to be transfused back to the newborn, and this is associated with improved iron status at 4 to 6 months of age.

However, there is a lack of knowledge regarding the long-term effects of delayed clamping. So policymakers have been hesitant about making clear recommendations regarding cord clamping in full-term infants.

To gain more insight, Ola Andersson, MD, PhD, of Uppsala University in Sweden, and his colleagues performed follow-up assessments of 263 children who were previously enrolled in a randomized trial of cord clamping in full-term infants born in a Swedish hospital.

The team assessed the effects of delayed cord clamping on childhood development at age 4. Delayed clamping (n=141) was defined as occurring 3 or more minutes after delivery, and early clamping (n=122) was defined as occurring 10 seconds or fewer after delivery.

The researchers evaluated child behavior and development using parents’ responses on the Ages and Stages Questionnaire, Third Edition (ASQ), which is used to assess communication, motor skills, and other measures; and the Strengths and Difficulties Questionnaire, which is used to score children’s emotional difficulties, hyperactivity, and other difficulties.

A blinded psychologist also assessed children’s scores on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), which is used to assess IQ and similar measures, and the Movement Assessment Battery for Children (Movement ABC), which is used to assess manual dexterity and similar measures.

The researchers found no significant differences between the delayed and early clamping groups with regard to results on the WPPSI-III or the Movement ABC.

However, delayed clamping was associated with a significant improvement over early clamping in ASQ personal-social scores (adjusted mean difference [AMD]=2.8, P=0.006), fine-motor scores (AMD=2.1, P=0.03), and the Strengths and Difficulties Questionnaire prosocial subscale (AMD=0.5, P=0.05).

When the researchers assessed the children according to sex, they found that significant improvements associated with delayed clamping were only present in males.

Males in the delayed clamping group had significantly higher mean scores in tasks involving fine-motor function, including the WPPSI-III processing-speed quotient (AMD=4.2, P=0.02), the Movement ABC bicycle-trail task (AMD=0.8, P=0.03), and fine-motor scores on the ASQ (AMD=4.7, P=0.01). These boys also had significantly higher personal-social scores on the ASQ (AMD=4.9, P=0.004).

The researchers concluded that, although delayed cord clamping and early clamping resulted in similar overall neurodevelopment and behavior among 4-year-old children, there were differences in this study. And this suggests there are some positive, and no harmful, long-term effects of delayed cord clamping.